Intracranial Metastases: Current Management Strategies

Intracranial Metastases CURRENT MANAGEMENT STRATEGIES Edited by Raymond Sawaya, M.D. Professor and Chair Mary Beth Pawe...

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Intracranial Metastases CURRENT MANAGEMENT STRATEGIES Edited by

Raymond Sawaya, M.D. Professor and Chair Mary Beth Pawelek Chair in Neurosurgery Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center Houston, Texas

Intracranial Metastases CURRENT MANAGEMENT STRATEGIES

In loving memory of Barbara Falik and in appreciation of Harold Falik, who both have personiﬁed the human dimension of the consequences of brain metastasis. Raymond Sawaya

Intracranial Metastases CURRENT MANAGEMENT STRATEGIES Edited by

Raymond Sawaya, M.D. Professor and Chair Mary Beth Pawelek Chair in Neurosurgery Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center Houston, Texas

© 2004 by Futura, an imprint of Blackwell Publishing Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia All rights reserved. No part of this publication may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher, except by a reviewer who may quote brief passages in a review. 04 05 06 07 5 4 3 2 1 ISBN: 1-4051-1646-3 Library of Congress Cataloging-in-Publication Data Intracranial metastases : current management strategies / edited by Raymond Sawaya. p. ; cm. Includes bibliographical references and index. ISBN 1-4051-1646-3 1. Brain—Tumors. 2. Metastasis. [DNLM: 1. Brain Neoplasms—secondary. WL 358 I623 2004] I. Sawaya, Raymond. RC280.B7I585 2004 616.99′481—dc22 2003024557 A catalogue record for this title is available from the British Library Acquisitions: Steven Korn Production: Sue Hadden Typesetter: Graphicraft Limited, Hong Kong, in 9.5/12pt Palatino Printed and bound by MPG Books Ltd, Bodmin, Cornwall, UK For further information on Blackwell Publishing, visit our website: www.blackwellfutura.com The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. Notice: The indications and dosages of all drugs in this book have been recommended in the medical literature and conform to the practices of the general community. The medications described do not necessarily have speciﬁc approval by the Food and Drug Administration for use in the diseases and dosages for which they are recommended. The package insert for each drug should be consulted for use and dosage as approved by the FDA. Because standards for usage change, it is advisable to keep abreast of revised recommendations, particularly those concerning new drugs.

Contents

Contributors, viii Preface, xii Acknowledgments, xiv Part I General 1 Management of intracranial metastases: history, 3

Deric Minwoo Park, Jerome B. Posner 2 The epidemiology of brain metastasis, 20

Dima Suki 3 The biology of brain metastasis, 35

Isaiah J. Fidler 4 Brain metastases: histopathological evaluation and diagnostic pitfalls, 55

Teresa Ribalta, Gregory N. Fuller 5 Imaging of metastatic tumors of the brain, 71

Norman E. Leeds, Edward F. Jackson, Ashok J. Kumar Part II Principles of Therapy 6 Intracranial metastases: medical management and prognostic

factors, 97 Susanne M. Arnold, Roy A. Patchell 7 Surgical management and techniques, 106

Frederick F. Lang 8 Whole-brain radiation therapy, 126

Ritsuko Komaki, Eric Chang 9 Radiosurgery for single and multiple brain metastases, 139

Minesh P. Mehta, Ivo Tremont-Lukats 10 Stereotactic radiation of intracranial metastases, 165

Grifﬁth R. Harsh IV

v

vi

Contents

11 Chemotherapy for brain metastases, 183

Sigmund H. Hsu, W. K. Alfred Yung Part III Speciﬁc Tumor Sites 12 Metastatic lung cancer, 199

James L. Frazier, Ira M. Garonzik, Laurence D. Rhines 13 Current management strategies in intracranial breast cancer

metastasis, 221 Stacy Moulder, David H. Johnson, Steven A. Toms 14 Management of brain metastasis in malignant melanoma patients, 245

Andrew A. Kanner, Gene H. Barnett 15 Brain metastases from renal cell carcinoma, 266

Fadi Hanbali, Jeffrey S. Weinberg 16 Metastatic colorectal carcinoma, 279

Vijayabalan Balasingam, Ian E. McCutcheon 17 Brain metastasis from cancer of an unknown primary site, 292

Robert J. Bohinski, Ronald E. Warnick 18 Leptomeningeal carcinomatosis: diagnosis and management, 309

Morris D. Groves, Jr 19 Brain metastases from gynecologic cancers, 331

Maciej S. Lesniak, Alessandro Olivi 20 Brain metastases from genitourinary cancer: germ cell, testicular,

prostate and bladder cancer, 352 Philip V. Theodosopoulos, James L. Rubenstein, Michael W. McDermott 21 Brain metastasis from upper gastrointestinal tract cancers:

esophageal, gastric, hepatic, gallbladder, and pancreatic, 362 Jeffrey S. Weinberg, Renato Lenzi, Ziya L. Gokaslan 22 Brain metastases from thyroid carcinoma and other endocrine

malignancies, 381 Rena Vassilopoulou-Sellin 23 Brain metastasis from sarcomas, 391

Andrew E. Sloan, Michael Kraut

Contents vii

Part IV Special Considerations 24 Metastatic tumors of the skull base, 415

Fadi Hanbali, Franco DeMonte 25 Neuropsychological impact of brain metastasis and its treatment, 430

Anne E. Kayl, Christina A. Meyers 26 Adjuvant approaches for preventing brain metastases, 445

David G. Menter, Anita L. Sabichi, Scott M. Lippman 27 Intracranial metastases: management guidelines and

decision-making, 461 Syed Enam, Jack P. Rock Index, 477 Color plate section facing p. 82

Contributors

Susanne M. Arnold, MD Assistant Professor of Medicine Division of Hematology and Oncology, University of Kentucky Chandler Medical Center Associate Director, Multidisciplinary Lung Cancer Program Markey Cancer Center Lexington, KY Vijayabalan Balasingam, MD, PhD, FRCS (C) Fellow Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center Houston, TX Gene H. Barnett, MD The Brain Tumor and Neuro-Oncology Center of the Taussig Cancer Center & Department of Neurosurgery The Cleveland Clinic Foundation Cleveland, OH Robert J. Bohinski, MD, PhD Department of Neurosurgery The Neuroscience Institute University of Cincinnati College of Medicine Cincinnati, OH Eric Chang, MD Assistant Professor Department of Radiation Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX

Franco DeMonte, MD, FRCSC, FACS Associate Professor Deputy Chairman, Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center, Houston TX

Isaiah J. Fidler, DVM, PhD Professor and Chairman Department of Cancer Biology The University of Texas M. D. Anderson Cancer Center Houston, TX James L. Frazier, ScB Department of Neurosurgery The Johns Hopkins University School of Medicine Baltimore, MD Gregory N. Fuller, MD, PhD Associate Professor of Pathology Chief, Sections of Neuropathology and Immunocytochemistry Department of Pathology The University of Texas M. D. Anderson Cancer Center Houston, TX Ira M. Garonzik, MD Resident in Neurosurgery The Johns Hopkins Hospital Baltimore, MD Ziya L. Gokaslan, MD, FACS Professor of Neurosurgery, Oncology and Orthopaedic Surgery The Johns Hopkins University School of Medicine Director, Neurosurgical Spine Program Vice-Chairman, Department of Neurosurgery The Johns Hopkins Hospital Baltimore, MD Morris D. Groves, Jr, MD, JD Assistant Professor Department of Neuro-Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX Fadi Hanbali, MD

Syed Enam, MD Hermelin Brain Tumor Center Henry Ford Hospital Detroit, MI

viii

Assistant Professor Division of Neurosurgery The University of Texas Medical Branch Galveston, TX

Contributors

Grifﬁth R. Harsh IV, MD Professor of Neurosurgery Department of Neurosurgery Stanford Medical Center Stanford, CA Sigmund H. Hsu, MD Assistant Professor of Neuro-Oncology Department of Neuro-Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX

Edward F. Jackson, PhD, MS, BS Associate Professor of Radiology Department of Diagnostic Radiology The University of Texas M. D. Anderson Cancer Center Houston, TX David H. Johnson, MD Professor and Director Division of Medical Oncology Vanderbilt University Medical Center Nashville, TN

Andrew A. Kanner, MD The Brain Tumor and Neuro-Oncology Center of the Taussig Cancer Center & Department of Neurosurgery The Cleveland Clinic Foundation Cleveland, OH Department of Neurosurgery Tel Aviv Sourasky Medical Center Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel Anne E. Kayl, PhD Assistant Professor Department of Neuro-Oncology The University of Texas, M. D. Anderson Cancer Center Houston, TX

Ritsuko Komaki, MD, FACR Professor Gloria Lupton Tennison Professorship in Lung Cancer Research Department of Radiation Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX Michael Kraut, MD Wayne State University and Karmanos Cancer Institute Detroit, MI

ix

Ashok J. Kumar, MD Professor of Radiology Department of Diagnostic Radiology The University of Texas M. D. Anderson Cancer Center Houston, TX Frederick F. Lang, MD, FACS Associate Professor Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center Houston, TX Norman E. Leeds, MD Professor of Radiology Chief, Section of Neuroradiology and Head & Neck Kenedy Memorial Foundation Chair Department of Diagnostic Radiology The University of Texas M. D. Anderson Cancer Center Houston, TX

Renato Lenzi, MD Associate Professor of Medicine Department of Gastrointestinal Medical Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX

Maciej S. Lesniak, MD Department of Neurological Surgery The Johns Hopkins University School of Medicine Baltimore, MD Scott M. Lippman, MD Professor and Chair Department of Clinical Cancer Prevention The University of Texas M. D. Anderson Cancer Center Houston, TX

Ian E. McCutcheon, MD, FRCS (C) Associate Professor Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center Houston, TX Michael W. McDermott, MD Associate Professor and Vice Chair Department of Neurosurgery University of California, San Francisco San Francisco, CA

Minesh P. Mehta, MD Professor and Chairman Department of Human Oncology University of Wisconsin Medical School Madison, WI

x

Contributors

David G. Menter, PhD Assistant Professor Department of Clinical Cancer Prevention The University of Texas M. D. Anderson Cancer Center Houston, TX

Teresa Ribalta, MD, PhD

Christina A. Meyers, PhD, ABPP

Jack P. Rock, MD Co-Director Surgical Neuro-Oncology Clinic Hermelin Brain Tumor Center Henry Ford Hospital Detroit, MI

Professor of Neuro-Oncology Department of Neuro-Oncology The University of Texas, M. D. Anderson Cancer Center Houston, TX

Stacy Moulder, MD Fellow Division of Medical Oncology Vanderbilt University Medical Center Nashville, TN

Professor Titular d’Anatomia Patològica Universitat de Barcelona Consultor, Department of Pathology Hospital Clinic of Barcelona Barcelona, Spain

James L. Rubenstein, MD Department of Hematology–Oncology University of California, San Francisco San Francisco, CA Anita L. Sabichi, MD

Alessandro Olivi, MD Director Department of Neurosurgery Johns Hopkins Bayview Medical Center Director of Neurosurgical Oncology and Professor of Neurosurgery Department of Neurological Surgery The Johns Hopkins University School of Medicine Baltimore, MD

Deric Minwoo Park, MD Department of Neurology Memorial Sloan-Kettering Cancer Center New York, NY

Roy A. Patchell, MD Associate Professor of Neurosurgery and Neurology and Chief of Neuro-Oncology University of Kentucky Chandler Medical Center Lexington, KY

Assistant Professor Department of Clinical Cancer Prevention The University of Texas M. D. Anderson Cancer Center Houston, TX

Andrew E. Sloan, MD Assistant Professor of Neurologic Surgery Section Leader of Neuro-Oncology Wayne State University and Karmanos Cancer Institute Detroit, MI

Dima Suki, PhD Assistant Professor Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center Houston, Texas

Philip V. Theodosopoulos, MD Jerome B. Posner, MD Professor of Neurology and Neuroscience Weill Graduate School of Medical Sciences Cornell University Department of Molecular Pharmacology & Chemistry Memorial Sloan Kettering Cancer Center New York, NY

Laurence D. Rhines, MD Assistant Professor of Neurosurgery Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center Houston, TX

Department of Neurosurgery University of California, San Francisco San Francisco, CA

Steven A. Toms, MD, MPH Director Section of Metastatic Disease, Department of Neurological Surgery The Cleveland Clinic Foundation Cleveland, OH Ivo Tremont-Lukats, MD Department of Neurology University of Wisconsin Medical School Madison, WI

Contributors

Rena Vassilopoulou-Sellin, MD Professor Department of Endocrine Neoplasia and Hormonal Disorders The University of Texas M. D. Anderson Cancer Center Houston, TX

Jeffrey S. Weinberg, MD Assistant Professor of Neurosurgery Department of Neurosurgery The University of Texas M. D. Anderson Cancer Center Houston, TX

W. K. Alfred Yung, MD Ronald E. Warnick, MD Department of Neurosurgery, The Neuroscience Institute University of Cincinnati College of Medicine; Mayﬁeld Clinic Cincinnati, OH

Professor and Chair Department of Neuro-Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX

xi

Preface

The current incidence of tumors metastasizing to the brain is high, and brain metastases are now the most common type of intracranial tumor. Current estimates indicate that, in the USA alone, more than 200,000 patients per year are developing brain metastases. Treatment of patients who have these intracranial metastases involves many different medical specialties. Therefore, there is a need for a better integration of these specialties in the orchestration of patient care. This volume represents the ﬁrst up-to-date comprehensive textbook devoted to the subject of human brain metastases in more than 20 years (since 1980). There are four main areas of emphasis in the present work: 1 It provides an overview of the topic of brain metastases: their biology, diagnosis, and treatment throughout history. 2 Instead of considering brain metastases that arise from tumors in different tissues collectively in a single chapter, each tumor type that metastasizes to the brain is presented in a separate chapter written by an expert on the subject. 3 Special categories not previously covered have been included, such as the epidemiology of brain metastases and the quality of life in patients who have them, tumor metastasis to the skull base, and strategies that may help prevent metastasis of cancer to the brain. 4 The latest state-of-the-art technology for treatment of brain metastases is reviewed, including surgery, stereotactic radiosurgery, and whole-brain radiation therapy. With such advances in neurosurgical techniques since the mid-1990s, even patients who had traditionally been excluded as surgical candidates, such as some of those with multiple or recurrent brain metastases, have been shown to survive longer after surgical treatment. Nevertheless, in the future, more work on the treatment of brain metastases needs to take place. More prospective randomized studies are required on issues such as: 1 The relative roles of surgery and stereotactic radiosurgery in the treatment of brain metastases. One should note that data on radiosurgery for treatment of brain metastases were not available in 1980 when the last text focusing on brain metastasis was published. 2 Determination of the best balance between treatment of intracranial metastases with whole-brain radiation therapy and the cognitive outcome and quality of life of the patient. A completely understudied area that may hold promise is the role of molecularly targeted therapy for metastatic brain tumors. Scientists in the neurosurxii

Preface

xiii

gical oncology molecular biology laboratories are working hard to translate their discoveries into therapeutic agents for such clinical use. My hope is for this book to provide valuable insight into the nature and current treatment of brain metastases to all those in the many medical specialties and subspecialties who are likely to encounter these tumors. It should be a real time saver to be able to look to this single volume for information on brain metastases from tumors of diverse histological origins. Brain metastasis is a serious neurological complication of cancer, and I believe this is a timely book that addresses this subject in a practical and convenient format.

Acknowledgments

I would like to extend my gratitude to the many authors who contributed such excellent chapters to this text. I also thank Steven Korn at the Futura Division of Blackwell Publishing for his enthusiasm in adopting this project. He is to be commended for checking monthly on its progress, and for his staff who worked hard to put the book into print. In addition, I acknowledge the invaluable assistance of my editor, David M. Wildrick, in helping me review all the manuscripts for scientiﬁc accuracy and clarity. I also thank Linda Duggan and Carol Durham for their administrative assistance.

xiv

PA RT I

General

CHAPTER 1

Management of intracranial metastases: history Deric Minwoo Park, Jerome B Posner

Introduction It has been known for centuries that systemic tumors could metastasize to the brain. Historically, brain metastases were believed to be uncommon or rare, and in any event, little could be done to treat them. In 1888, Gowers1 divided intracranial growths into six categories in descending order of frequency (Table 1.1). Carcinoma was third, but Gowers included in that category some primary tumors, suggesting that carcinoma of the brain “may be primary, or secondary to cancer in any other part”. Also in 1888, Bramwell2 recognized that brain metastases could arise from tumors in any part of the body and suggested that they were especially common from lung cancer. His explanation that pulmonary tissue could ﬁlter out cancer cells circulating from other organs, whereas those circulating from the lung went immediately into the systemic circulation is still germane. In addition, he commented on the fact that “in no other situation in the body is such a variety of tumors met with”. He suggested that “the delicate and soft brain tissue . . . is as ﬁne a forcing and feeding ground for new growths as Koch’s nutrient jelly is for micrococci and allied organisms”, anticipating Paget’s seed and soil theory of metastases in 18893. Most of Bramwell’s book is devoted to clinical descriptions and diagnosis, with only the ﬁnal chapter, consisting of 10 pages in a 264 page book, devoted to the surgical treatment.

Table 1.1 Gowers’ classiﬁcation of “intracranial growth” (in order of the frequency)*. Diathetic—Tubercular and syphilitic Sarcomatous—Glioma, sarcoma, myxoma Carcinoma Osteo-ﬁbroid—Fibroma, osteoma, osteo-ﬁbroma Miscellaneous—Cholesteatoma, lipoma, vascular or erectile tumors, psammoma, neuroma Parasitic—Echinococcus and cysticercus *From Gowers WR: A Manual of Diseases of the Nervous System. Philadelphia, P. Blakiston, Son and Co, 18881 .

3

4

Chapter 1

As indicated above, brain metastases were originally considered rare, and it was often unclear in early reports whether tumors described as carcinomas were indeed metastatic. Even as late as 1927, brain metastases were sufﬁciently exotic to allow Globus and Selinsky4 to publish, in a leading journal, a 32-page report describing the clinical and pathological ﬁndings of 12 patients. However, by 1933, investigators recognized that brain metastases were a clinical entity separate from other intracranial tumors. The basic clinical symptoms were described and the various anatomical-clinical forms were classiﬁed5. Since that time, major advances have been made in our understanding of the pathophysiology of brain metastases6, their diagnosis, and treatment. This chapter brieﬂy traces the history of the diagnosis and treatment of brain metastases up to the present time. Four previous reviews by the same author, the ﬁrst from the early 1970s7, the second from 19808, the third from the early 1990s6, and one published in 20029, illustrate the progress made in the diagnosis and treatment of brain metastases. Nevertheless, as this monograph illustrates, much remains to be done.

Diagnosis In the 19th century, the diagnosis of brain metastases (or indeed, any brain tumor) rested solely on clinical symptomatology as imaging techniques did not exist. Gowers1 discussed in detail the problem of diagnosing cerebral tumors. He ﬁrst attempted to discover if there is “organic disease” of the brain, indicating that focal symptoms were more important than diffuse symptoms. However, he also noted that optic neuritis (presumably papilledema) was the most signiﬁcant sign indicating organic disease; the next most important was “causeless vomiting”. At the present time, these would both be considered diffuse rather than focal symptoms 6. Having established that the disease is organic, the next question was do the symptoms indicate the presence of a tumor? He believed that the most important ﬁnding was “more or less gradual development of symptoms”, thus excluding stroke and cerebral hemorrhage. The third and obviously most important question was where is the tumor? Here, in the absence of imaging, clinical ﬁndings were paramount. In 1884, Rickman Godlee, a surgeon, and Alexander Hughes Bennett, a physician, used the concepts of cerebral localization developed by John Hughlings Jackson to successfully remove a glioma10. Although this was not the ﬁrst craniotomy for a brain tumor, it was the ﬁrst successful tumor operation based on neurological signs alone, i.e., the cranium had not been eroded by the tumor. In 1886, Mills and Lloyd suggested “it may become possible hereafter in some cases to localize . . . brain tumors with sufﬁcient accuracy for purposes of operation”11. In their textbooks, both Gowers and Bramwell elaborated on the concept that surgery may be possible to treat brain tumors. X-rays were discovered in 1895, and by 1901, Hermann Oppenheim demonstrated the presence of a pituitary tumor by destruction of the sella turcica. By

Management of intracranial metastases: history 5 Table 1.2 Laboratory diagnosis of cerebral metastases (162 patients)*.

Test

Number performed

Number abnormal

Percent abnormal

Skull x-ray Intracranial pressure Pineal shift Skull metastasis

160

26 4 6 18

16 2.5 3.7 11

EEG**

140

128

91

Brain scan

156

138

88

Contrast studies Arteriograms Air studies

125*** 123 99

115 106 35

92 85 90

Lumbar puncture

90

83

92

*From Posner JB: Diagnosis and treatment of metastases to the brain. Clin Bull 1974; 4: 47–577. **EEG, electroencephalogram. ***Many patients suffered both arteriogram and air studies.

1912, Arthur Schuller (of Hand-Schuller-Christian disease) had published a textbook on the radiographic anatomy of the cranium12. Walter Dandy introduced pneumoencephalography in 191913, and Antonio Egas Moniz introduced arteriography in 193114. That the brain produces electrical waves that could be recorded as the electroencephalogram (EEG) was discovered in 1875. The EEG was ﬁrst applied to the location of brain tumors in 193615. Until the introduction of computerized tomography (CT), the diagnosis of brain tumors in addition to clinical symptomatology included skull x-rays, electroencephalography (EEG), radionuclide brain scanning, arteriography, pneumoencephalography, or ventriculography and lumbar puncture (Table 1.2)7. In some centers, many patients were treated for clinical symptoms alone and sometimes had no tumor at autopsy. Of 136 patients who had been treated by radiation therapy16 for “brain metastases”, 48 were found to have no tumor at autopsy7. If the absence of tumor in the brain at autopsy is assumed to represent treatment effect rather than mistaken diagnosis, one can understand the enthusiasm of some radiation oncologists for their treatment modality (see below). Once the full panoply of diagnostic techniques listed in Table 1.2 was introduced, only one of 46 patients treated at the same center was discovered not to have a tumor at autopsy. The introduction of CT scanning revolutionized the diagnosis of brain metastases. First-generation CT scans were fairly crude by current standards but were positive in over 90% of patients with symptomatic brain metastases. With each new generation of CT scanning, the diagnostic accuracy improved.

6

Chapter 1

A further revolution in diagnosis occurred with the introduction of magnetic resonance imaging (MRI). A normal high-resolution MRI scan with contrast enhancement excludes a symptomatic brain metastasis in virtually 100% of patients (but see17). Minute asymptomatic brain metastases can sometimes be identiﬁed by double- or triple-dose contrast injection18. Thus, the diagnosis of a brain tumor has changed from a complicated and expensive series of invasive studies to a single study, namely a contrast-enhanced MRI scan. Even with the most sophisticated technology currently available, it is not always possible, short of biopsy, to distinguish between a primary brain tumor and a brain metastasis. A multiplicity of lesions, as well as lesions with a spherical shape, suggest brain metastases, whereas single, irregularly shaped lesions suggest primary tumors. The recent addition of whole-body positron emission tomography (PET) scanning19 to look for hypermetabolic areas outside the brain in order to locate a suspected primary tumor will help differentiate a primary from a metastatic tumor. The introduction of CT and MRI scanning was inhibited by the alleged prohibitive cost of modern medical technology. In the diagnosis of brain metastases, this was never a viable issue. Before CT scanning, patients with symptoms suggesting brain metastases were admitted to the hospital and examined ﬁrst by EEG, then by a radionuclide brain scan, and ﬁnally, for most patients treated at Memorial Sloan-Kettering Cancer Center, by cerebral angiography. The patient was usually hospitalized for three or four days before any treatment was instituted. The current “state-of-the-art” method of diagnosis is an out-patient MRI scan followed by a whole-body PET scan if there is a question as to whether the tumor is primary or secondary. The two together are substantially cheaper in current dollars than the work-up that operated prior to 1980.

Treatment Adrenal corticosteroids (steroids) Adrenal corticosteroids revolutionized the treatment of brain metastasis by substantially improving the patient’s quality of life, although not necessarily extending its duration. Although corticosteroids are also extremely useful in the treatment of primary brain tumors, metastases, which are often small, wellcircumscribed (displacing rather than invading normal surrounding brain tissue), and surrounded by extensive edema, respond even more dramatically than primary brain tumors. Prados, Strowger, and Feindel demonstrated the salutary effect of steroids on brain edema in 194520. These investigators observed that when the brain was exposed to air, the blood-brain barrier was disrupted and brain edema developed. When the brain was sprayed with an adrenal extract, the blood-brain barrier remained intact and the brain did not swell. In 1952, Ingraham et al.21 reported that cortisone and ACTH relieved postoperative symptoms after craniopharyngioma surgery. The beneﬁcial effects of cortisone appeared to be independent of the adrenal insufﬁciency

Management of intracranial metastases: history 7

that resulted from pituitary damage engendered by the surgery. In 1962, Rasmussen and Gulati22 demonstrated that the transient hemiparesis that often followed temporal lobectomy for focal seizures was diminished or prevented by cortisone administration. The ﬁrst demonstration of the effectiveness of corticosteroids in the treatment of brain metastases occurred in 1957, four years before the seminal report of Galicich and French23. Kofman and colleagues24 administered prednisone to 20 patients with brain metastases. Steroid treatment was undertaken after the investigators noticed a striking relief of neurological symptoms in a patient who had been given the drug to suppress adrenal function for treatment of a primary breast cancer. Kofman and colleagues noted amelioration of the neurological symptoms in other patients with breast cancer but concluded that this was an effect of steroids on inﬂammation and edema. However, steroids have a direct oncolytic effect on breast cancer (corticosteroids have been used in the chemotherapy of breast cancer), and thus the clinical implications for other cancers were not immediately recognized. In 1961, Galicich and French23 described the dramatic response to steroid hormones in patients suffering from both primary and metastatic brain tumors and attributed the improvement of neurological symptoms to regression of brain edema. After that report, steroids became a part of the routine treatment of both primary and metastatic brain tumors. Steroid therapy resolves clinical symptoms in 60–80% of patients with brain metastases. In their 1957 report, Kofman and colleagues24 noted a deﬁnite improvement in nine out of 15 patients; Ruderman and Hall25 noted improvement in 11 of 17 patients. Posner7 noted symptomatic improvement in 21 of 30 patients and speciﬁcally addressed the type of symptoms that improved. He divided symptoms into those that suggested diffuse brain dysfunction, e.g., headache, nausea, vomiting, confusion, and those that suggested focal brain dysfunction, e.g., hemiparesis. Fifteen of 19 patients with generalized symptoms (85% with headache) improved whereas only 19 of 26 patients with focal symptoms (73% with hemiparesis) improved. Other symptoms of focal dysfunction, especially visual ﬁeld, sensory abnormalities and hemiparesis, were less responsive than symptoms of diffuse brain dysfunction. French26 described the responses of 249 patients with brain tumors, of whom 46 were metastatic. Dexamethasone was used with 81% of patients who improved, including 91% of those with diffuse brain symptoms, 73% with “hemiplegia”, and 86% with “aphasia”. Visual ﬁeld defects, however, improved in only 41%, and sensory loss in 55%. Corticosteroids are now administered to virtually every patient in whom a brain metastasis has been identiﬁed either by clinical symptomatology or a screening scan. Most physicians reﬂexively begin corticosteroid treatment (usually 16 mg dexamethasone), whenever an MRI scan of the brain shows what appears to be a metastasis. Steroids are often given whether or not the patient is symptomatic and whether or not the tumor is surrounded by edema. This might seem a reasonable approach to take, both because the short-term

8

Chapter 1

use of corticosteroids carries few side-effects and their use may also prevent the development of symptoms, even in asymptomatic patients. However, the use of corticosteroids in all patients with a possible brain metastasis is unwise. Included in the differential diagnosis of brain metastasis is primary lymphoma of the central nervous system (CNS). At times the distinction between these two brain disorders can only be made by biopsy. A signiﬁcant number of patients with primary CNS lymphoma (PCNSL) respond to corticosteroids with necrosis of the tumor, yielding only inﬂammatory and necrotic cells upon biopsy. Thus, the opportunity to make a deﬁnitive diagnosis is lost. Accordingly, we recommend use of corticosteroids only for those patients with a putative brain metastasis who are symptomatic and in whom the nature of the process is clear. In addition, once administration of corticosteroids has started, patients frequently remain on them for prolonged periods of time, even after symptom improvement no longer calls for the drug. This leads to the longterm complications of corticosteroids, which can substantially diminish a patient’s quality of life. Despite their effectiveness and their long history of use in patients with brain metastases, the optimal dose for corticosteroids has not been established. Physicians usually start patients with a dexamethasone dose of 16 mg a day. If there is no response in 48 hours, the dose can be increased, either until an optimal response is achieved or until it is clear that there is not going to be a response. If the patient becomes asymptomatic on a given dexamethasone dose, it should then gradually be tapered to the lowest dose commensurate with control of symptoms. Despite their long history of use, the exact mechanism by which corticosteroids ameliorate the symptoms of a brain metastasis is not known. Among the mechanisms that may play a role are: 1 A direct oncolytic effect of steroids on the tumor, e.g., as in the cases of breast cancer and lymphoma. 2 A direct effect of corticosteroids on neurological function through alteration of brain excitability. 3 A decrease in cerebral edema by reducing either edema production or increasing its reabsorption. 4 A lowering of intracranial pressure independent of the effects on edema. Despite their usefulness in ameliorating symptoms, it is not clear that corticosteroids prolong survival. Early studies by Hazra and colleagues27 indicated that, although patients improved with steroids alone, the median survival was less than three months. Other studies indicated that corticosteroids increase survival time in patients with brain metastasis but only by a very short interval28.

Radiation therapy Roentgen rays were discovered at the turn of the last century and almost immediately were utilized for the treatment of various diseases. Because only low voltage machines were available in the early days, most initial treatments were directed toward tumors close to the surface. Exactly when radiation

Management of intracranial metastases: history 9

therapy was ﬁrst applied to brain metastases is unclear, but it probably began in the late 1920s or early 1930s. In 1931, Lentz and Fried29 evaluated the effects of radiation therapy in ﬁve preterminal patients with brain metastases from carcinoma of the breast. They concluded that “in a few cases, temporary regression of signs of increased intracranial pressure and localized brain involvement occurred following moderate dosage of radiotherapy”. In a 1942 book by Dyke and Davidoff, entitled “Roentgen Treatment of Diseases of the Nervous System”30, brain metastases were covered in less than three of the 198 pages. The authors described their experience with three patients. The ﬁrst had a brain metastasis from an unknown primary source that was irradiated after surgery to a total dose of 4,650 rads. The authors concluded that “the radiation seemed to produce no favorable effect whatever, and six months after the operation, after a steady downhill course, the patient died”. The second patient had a metastasis from breast cancer. She received four courses of radiation over ten months to a total dose of 12,600 rads. She improved after the ﬁrst course for eight months and did well except for seizures. At autopsy, a tumor was found in the right parietal region. The third patient received one course of radiation therapy directed to the right frontal region to a total dose of 2,400 rads. She improved for a few months but then died. The authors conclude “it is clear therefore that carcinomatous metastases to the brain may be beneﬁtted temporarily by radiation therapy”. Chao, Phillips, and Nickson published the ﬁrst systematic report of wholebrain radiation therapy to treat brain metastases in 195431. They described a consecutive series of 38 patients with brain metastases who were identiﬁed by radionuclide scan and treated between January 1949 and June 1953. They reported palliation of neurological symptoms and signs in 24 patients. They recommended radiation therapy as a primary treatment of brain metastases. In 1961, Chu and Hilaris reported32 on 218 patients with clinically identiﬁed intracranial metastases from various primaries who were treated between 1954 and 1958. They described a 78% improvement rate and a mean duration of improvement of ﬁve months. They reported that doses of more than 2,700 rads delivered over three weeks gave better palliation than lesser doses. They recommended that the dose of 3,000 to 3,500 rads be delivered in a period of three to four weeks. A third report from that group by Nisce, Hilaris, and Chu16 from 1971 included 560 patients. In 1968, Order et al.33 reported improvement in quality of survival after whole-brain irradiation in about two-thirds of patients. In the years between 1961 and 1967, radiotherapy techniques changed from low voltage to megavoltage machines. Low initial radiation doses of 50– 100 cGy were originally given. When corticosteroids were introduced prior to radiation therapy, the daily dose could be safely increased to 200–300 cGy. Whole-brain irradiation was selected for two reasons. The ﬁrst was that imaging techniques were not adequate to localize the brain metastasis accurately. The second was that whole-brain irradiation might eliminate

10

Chapter 1

micrometastases that were not detected by the most sensitive imaging techniques. This second rationale has certainly proved true for “prophylactic” radiation therapy given to eliminate micrometastases from small cell lung cancer and acute leukemia34. Whether whole-brain irradiation is necessary in all patients who receive radiation therapy for brain metastases has not yet been determined (see Radiosurgery below). After these initial reports, the Radiation Therapy Oncology Group (RTOG) undertook a series of controlled trials to determine the best dose and dosage schedule of radiation therapy for the treatment of brain metastasis. Doses varied from 4,000 cGy given in 200 cGy fractions to 1,000 cGy given in one fraction35. All of these techniques offered some palliation, but none appeared to be superior. Rapid courses of radiation using doses above 300 cGy/day, particularly in patients with large brain tumors and increased intracranial pressure, sometimes caused neurological deterioration including fatal herniation36. Attempts to enhance the effects of radiation therapy using radiation sensitizers have not been successful. In 1984, Aiken et al.37 conducted a randomized controlled trial of metronidazole as a radiation enhancer. Survival and clinical or radiographic improvement were no better in the treated group than in the control group. In 1991, Komarnicky and colleagues38 conducted a randomized study of misonidazole combined with radiation in the treatment of patients with brain metastases. The agent did not enhance the effects of radiation therapy. Since that time, other agents have been tried, also without success. Radiation therapy for brain metastasis is not curative but palliative. In rare instances when the metastasis is sterilized by radiation therapy, the patient is likely to die of metastases in organs outside the brain. Thus, even with the most effective irradiation of the brain, patients often do not live long. Table 1.3 summarizes the survival data for series on this topic up to 1974. Overall results have improved only slightly since then. The goal of radiation therapy administered to the brain is to deliver maximum palliation in the shortest period of time. To some degree, these are mutually exclusive roles. There are two reasons that fractionated radiation therapy given over a protracted period yields better results than higher doses used over a shorter period: 1 The lower daily doses give normal brain cells the opportunity to repair sublethal damage, thus reversing potential neurotoxicity. 2 Multiple doses administered over a period of time are more likely to affect cancer cells that were originally quiescent but have begun to divide, thus rendering themselves more vulnerable to the toxic effects of radiation. With these considerations in mind, physicians treating brain metastases deliver 300 cGy/day in 10 doses over two weeks to the whole brain. Some radiation oncologists deliver a boost to one or more large metastases in the brain. In patients with a particularly good prognosis for their systemic disease, the dose may be lowered to 200 cGy/day delivered in 20 fractions over four weeks to reduce late neurotoxicity. Doses of 3,000 and 4,000 cGy delivered in

Management of intracranial metastases: history 11 Table 1.3 Radiation therapy of cerebral metastases before 1974*. SURVIVAL

Series

Number 30-day Median Mean One of patients mortality (months) (months) year

Nisce et al. 197116 Young et al. 197436 Hazra** et al. 197227 Montana et al. 197266 Deeley and Edwards 196867

376 162 21 47 61

Hindo et al. 197035 Gottlieb# et al. 197268 Order et al. 196833 Horton et al. 197128 Random Study†

54 41 108 44 44

25% 0

18%

~6 3 3–6 ~4

3 6 3.5 4

Long term

5.6 3.5 6.3

~ 16% 8% ~ 2 years 2.6% 14% ~ 12% 14% 1–3 years 6% 1–6 years 4% 22% < 10% 16%

3.5

9%

*Modiﬁed from Posner JB: Diagnosis and treatment of metastases to the brain. Clin Bull 1974; 4: 47–577. **Lung #Melanoma †Patients were randomized to receive either 15 Gy over 3 days or 30 Gy over 2 weeks. ~Approximately

these fractions are biologically equivalent in respect to the tumor, but the lower daily fractions may reduce toxicity to the normal brain tissue. Corticosteroids, at a dose of 8–16 mg per day (the dose depending on the number and size of the tumors), should be administered throughout the course of the radiation but can be tapered from the initial dose to the lowest dose commensurate with good neurological function. Steroid administration should begin at least 48 hours prior to the ﬁrst radiation treatment.

Radiosurgery Stereotactic radiosurgery is a technique for delivering a focused dose of radiation to a predetermined area of the brain while minimizing radiation exposure to adjacent tissue. The term “stereotaxis” derives from the Greek stereos, meaning “solid” or “three-dimensional”, and Greek taxis, meaning “arrangement”. The term was ﬁrst used by Horsley and Clarke39. Subsequent authors adopted a Greek-Latin hybrid, “stereotactic,” because “to touch” was thought to be more appropriate. The application of the principles of stereotaxis to radiation therapy was conceived by the Swedish neurosurgeon Lars Leksell40. Leksell coined the term “stereotaxic radiosurgery” to describe an apparatus consisting of his stereotactic equipment coupled to an x-ray tube. By rotating the x-ray tube along an arc plane, Leksell was able to deliver a focused beam of ionizing radiation. The

12

Chapter 1

technique was originally developed for functional neurosurgery; thus, the ﬁrst patients suffered from mental disorders, Parkinsonism, and cancer pain. Subsequently, the technique was applied to a craniopharyngioma and to the gasserian ganglia of patients with trigeminal neuralgia41. Either a linear accelerator or the Gamma Knife can deliver the radiation. Leksell and colleagues developed the prototype of the “Gamma Unit” (currently marketed as the “Leksell Gamma Knife”) in 1967 for use in functional neurosurgery42. The instrument, which was initially installed at the Sophiahemmet Hospital, relied on Cobalt 60 as an energy source and created discoid lesions41. A few years later, the Gamma Unit was ﬁrst directed against an intracranial tumor, a vestibular schwannoma43. Encouraging results led to reﬁnements, and the second-generation unit was built in 1974 and installed at the Karolinska Institute. The new machine was able to target larger treatment volumes (of up to 25 mm in maximum diameter) and created a more spherical ﬁeld. In 1984, the third-generation gamma units were developed. In 1988, Winston and Lutz44 wrote of a successful apparatus for performing stereotactic radiosurgery, using a modiﬁed linear accelerator as the energy source. The equipment consisted of a Varian 6-MeV linear accelerator, modiﬁed collimators positioned closer to the isocenter to allow improvement of alignment and decreased size of the penumbra, and a modiﬁed BrownRoberts-Wells stereotactic system. Further reﬁnements of equipment and advances in computer technology led to the development of dedicated commercially-built systems. Most centers performing stereotactic radiosurgery at this time rely on modiﬁed linear accelerators as the source of energy. Prior to developing the Gamma Unit, Leksell investigated this scheme but abandoned the idea for its imprecision and inadequate energy output42. The radiation can be delivered either as a single dose (stereotactic radiosurgery) or in multiple doses (fractionated stereotactic radiotherapy). The terms radiosurgery and Gamma Knife are dramatic but somewhat unfortunate in that many of the lay population believe that the technique is some “magical” form of surgery rather than a modiﬁed technique of brain irradiation. Nevertheless, radiosurgery has become very popular in the ﬁeld of neurosurgery. In 1999, an entire issue of Neurosurgical Clinics of North America was devoted to its uses45, including the treatment of brain metastases either by single or multiple dose stereotactic irradiation. The ﬁrst report of radiosurgery for the treatment of brain metastases described 12 consecutive patients with solitary brain metastases that were radioresistant and deeply seated46. A single dose of 20–30 Gy yielded arrest of tumor growth. In four patients, there was shrinkage of the metastasis as well as a “marked decrease of the edema”. All patients improved clinically. Subsequent reports have supported this enthusiastic early report. When Boyd and Mehta47 performed a comprehensive MEDLINE search of all English language publications between 1987 and 1998, they found that 1,783 patients with over 2,700 lesions had been reported. Response rates varied from 33–92%, local

Management of intracranial metastases: history 13

tumor control rates from 25–97%, and median survival time from 6–15 months47. Although there is strong evidence to indicate that local growth of brain metastases can be controlled or the tumor obliterated, its exact role in the treatment of brain metastases and, in particular, how it compares with surgical removal of single or multiple brain metastases is not yet established.

Surgery In the early days of neurosurgery for brain tumors, most neurosurgeons did not knowingly operate on brain metastases. In 1926, Grant48 concluded that “there are neoplasms in which surgery offers but little and may even be contraindicated. Among these lesions are the metastatic tumors”. He reviewed the experience of the neurosurgical service at Peter Bent Brigham Hospital in the 13 years up to March 1926, which included only 49 cases of metastatic intracranial tumors. Twenty-ﬁve had been operated on, 16 with an “osteoplastic ﬂap and nine with a decompression”. He concluded “that neither radical nor palliative surgery is of any permanent value under these conditions is certain, but surgical intervention for the relief of intracranial pressure is frequently indicated and may go far toward relieving suffering in the last few months of life”. Following this extremely pessimistic approach, in 1931 Meagher and Eisenhardt49 reported ten patients operated on for metastases from breast cancer. The longest survival time after operation was ﬁve months; the average was six weeks. The pessimistic attitude began to change in 1933 after Oldberg50 described three patients with long survivals. One patient was operated on for a metastasis from carcinoma of the breast and survived for two years. No intracranial tumor was found at autopsy. The second patient, with a metastatic carcinoma of the lung, lived for 35 months and died a few days after being operated on for recurrence of the brain metastasis. A third patient, also with carcinoma of the breast, died of recurrence in eight months. A fourth patient, with a clinical diagnosis of metastasis from breast cancer, was operated on and a meningioma was discovered. The authors concluded that “operation on suspected malignant metastases to the brain [is warranted] provided the general condition of the patient warrants it and that the cerebral lesion is apparently single”. In 1951, Stortebecker51 reported a patient series with 125 surgically treated brain metastases. The operative mortality was 24.8%, similar to previous reports. Tumors varied in size. Six percent were smaller than “a hazelnut”, 14% were the size of “a hazelnut”, 31% were the size of “a walnut”, 26% were the size of “a hen’s egg”, 11% were the size of “a goose’s egg”, 6% were the size of “an orange”, and 6% were described as “carpet-like” (probably leptomeningeal seeding). The average survival time of patients after surgery was 10.5 months. One patient with a cerebellar metastatic “hypernephroma” (possibly a hemangioblastoma) was alive more than 17 years after the operation. He compared his patients with untreated patients and concluded that the operated patients lived longer. He recommended “radical neurosurgical treatment”.

14

Chapter 1

Table 1.4 Surgical treatment of cerebral metastases before 1974*. SURVIVAL

Series Lang and Slater 196469 Stortebecker 195451 Haar and Patterson 197270 Vieth and Odom 196571 Richards and McKissock 196372 Raskind et al. 197173 Memorial Sloan-Kettering Cancer Center

No. of patients

Postoperative mortality (1 month)

Median (mos.)

Mean (mos.)

One year

Long-term (# patients, years)

208 125 167 155 108

22% 25% (20 days) 11% 15% (2 weeks) 32%

4.0 3.6 6.0 < 6.0 < 5.0

12.0 10.5

20% 21% 22% 13.5% 17%

27 > 2 years 3 > 4 years 7 > 5 years 12 > 2 years 8 > 2 years

51 40

12% (2 weeks) 20%

< 6.0 5.0

30% 25%

4 > 3 years 1 > 4 years

*Modiﬁed from Posner JB: Diagnosis and treatment of metastases to the brain. Clin Bull 1974; 4: 47–577.

In 1974, when Posner reviewed the results of a surgical series that included more than 50 patients7, he found a postoperative mortality ranging between 11 and 32%, a median survival time of 3 to 6 months, a one-year survival of 13–30%, and isolated long-term survivors (Table 1.4). Advances in neurosurgical techniques and in identifying patients with a single lesion or only a small number of them have reduced operative mortality and morbidity and increased the percentage of long-term survivors. A paper by Patchell et al. in 199052 provided the deﬁnitive endorsement for the surgical treatment of single brain metastasis. In a randomized trial comparing surgery followed by whole-brain radiation therapy with whole-brain radiation therapy alone, they demonstrated that surgery yielded both a longer survival time and an enhanced quality of life. A second randomized trial53 conﬁrmed these results, which are now generally accepted, although one trial found that surgery was not superior to radiotherapy alone54. Increasingly, neurosurgeons are now operating on two or even three brain metastases in appropriate patients with good results and long survival. Whether surgery is superior to radiosurgery still awaits a randomized trial. However, such a trial may never be accomplished. Previous attempts have been abandoned because of refusal of patients to be randomized.

Chemotherapy Chemotherapy is a relatively new modality for the treatment of metastatic brain tumors. There are several reasons for this: 1 Chemotherapeutic agents that effectively treat systemic cancer have only been available since after the Second World War. 2 Using chemotherapy for brain metastases required imaging techniques that would establish an accurate diagnosis and would allow follow up to assess the effects of the chemotherapy.

Management of intracranial metastases: history 15

3 The concept that the blood-brain barrier excluded most chemotherapeutic agents was strongly held by most oncologists, who believed it was futile to apply systemic chemotherapy to the treatment of brain metastases. This concept was held despite the fact that imaging techniques clearly revealed a disrupted blood-brain barrier in brain metastases by the time they became symptomatic. The knowledge that microscopic tumor cells, before they were symptomatic (i.e., before blood-brain barrier disruption), could ﬁnd sanctuary behind the blood-brain barrier was simply, incorrectly extended by oncologists to apply to macroscopic metastatic tumors. There were, however, some early attempts to treat brain metastases using chemotherapeutic agents. In 1952, French and West55 examined the effects of intracarotid administration of nitrogen mustard on normal brain tissue and on brain tumors, some of which were metastatic. The treatment was ineffective and toxic. In 1976, Wilson and colleagues56 examined the effect of single agent chemotherapy on brain tumors, both primary and metastatic. They reported that one metastatic melanoma responded to carmustine (BCNU) chemotherapy and that three of ﬁve metastatic melanomas responded to a combination of carmustine and vincristine. These results were not veriﬁed by imaging techniques and are certainly better than one achieves currently. They examined “other” metastatic tumors as well but did not indicate the source of those metastases. Zero of three patients responded to carmustine, four of seven to lomustine (CCNU), one of one to procarbazine, and one of one to 5-[3,3-bis(2chloroethyl)-1-triazeno]imidazole-4-carboxamide (BIC). In 1980, Shapiro57 used BCNU as a single agent to treat seven patients with brain metastases from lung cancer; only one appeared to improve, and that was for a period of ﬁve months. Seven patients with malignant melanoma were also treated with BCNU; one improved and one stabilized. Six patients with metastatic melanoma were treated with CCNU; one improved for eight months. Five patients with lung cancer were treated with CCNU; one stabilized for three months. Two patients with breast cancer who were treated with CCNU did not improve. Cascino and colleagues58 treated 31 patients with metastatic brain tumors with intra-arterial BCNU. Three with lung cancer, one with breast cancer, and one with melanoma had a partial response of the tumors in the distribution of the injected artery, but the tumors enlarged in two patients with brain metastases not in the distribution of the injected artery. In one of these patients, subsequent infusion of BCNU to the enlarging tumor resulted in a partial response. This experience suggests that the dose of the chemotherapeutic agent delivered to the brain metastasis is important in effecting a response. The reason for using BCNU and CCNU, drugs not very effective against the common metastatic tumors of the lungs, breast, colon, and kidneys, was that they are lipid soluble and cross the blood-brain barrier. The concept that the blood-brain barrier might prevent entry of water-soluble chemotherapeutic agents into the tumor was still a popular one. Only some years later were clinically signiﬁcant amounts of water-soluble chemotherapeutic agents demonstrated to be present in primary and metastatic brain tumors (reviewed by Buckner59). In 1979, Hasegawa and colleagues60 indicated that water-soluble

16

Chapter 1

agents were effective in the treatment of systemic tumors implanted into the brains of experimental animals. Despite these ﬁndings, it was not until 1986 that Rosner and colleagues61 reported the results of chemotherapeutic treatment of 100 consecutive breast cancer patients who had symptomatic brain metastases that were documented by scans. Fifty of the 100 patients demonstrated an objective response similar to the ﬁndings in extracranial metastasis. There were ten complete responders and 40 partial responders. After this report, chemotherapy was used more frequently for the treatment of both symptomatic and asymptomatic brain metastases. Because the response is usually not as fast as radiation therapy, most investigators still prefer radiotherapy to chemotherapy. Despite these positive reports, many physicians have observed that brain metastases often appear to respond less well to systemic chemotherapy than metastatic tumors from the same primary elsewhere in the body. There may be several reasons for this: 1 Brain metastases often arise late in the course of treatment for systemic cancer. These late metastasizing tumor cells may be more resistant to chemotherapeutic agents than the original primary. On the other hand, tumor cells that have found sanctuary behind the blood-brain barrier and only become symptomatic later may be responsive to chemotherapeutic agents to which the primary tumor has now become resistant61. 2 The metastasis in the brain may have arisen from a clone of cells from the primary tumor that are resistant to the chemotherapeutic agent applied. Metastases in other parts of the body may have arisen from more sensitive clones. Multiple metastases in the brain may have differing sensitivities to chemotherapeutic agents. 3 Most symptomatic patients require corticosteroids to treat brain edema and to ameliorate neurological symptoms. The steroids partially repair disruption of the blood-brain barrier, thus decreasing the amount of water-soluble chemotherapy agent able to enter the brain metastasis. Despite these caveats, a number of reports have described the efﬁcacy of chemotherapy in a variety of tumors59 including ovarian cancer62, breast cancer63, small cell lung cancer64 and germ cell cancers65. The exact role of chemotherapy in the treatment of brain metastasis is still not delineated.

References 1 Gowers WR: A Manual of Diseases of the Nervous System. Philadelphia, P. Blakiston, Son & Co, 1888. 2 Hare AW: The surgical treatment of intracranial tumors. In Bramwell B (ed): Intracranial Tumors. Edinburgh, Young J. Pentland, 1888, pp. 254–264. 3 Paget S: The distribution of secondary growths in cancer of the breast. Lancet 1889; 1: 571–573. 4 Globus JH, Selinsky H: Metastatic tumors of the brain. A clinical study of twelve cases with necropsy. Arch Neurol Psychiatry 1927; 17: 481–513.

Management of intracranial metastases: history 17 5 Paillas JE, Pellet W: Brain metastases. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Volume 18. New York, Elsevier, 1975, pp. 201–232. 6 Posner JB: Neurologic Complications of Cancer. Philadelphia, F.A. Davis, 1995. 7 Posner JB: Diagnosis and Treatment of Metastases to the Brain. Clin Bull 1974; 4: 47–57. 8 Weiss L, Gilbert HA, Posner JBE: Brain Metastasis. Boston, G.K. Hall & Co, 1980. 9 DeAngelis LM, Gutin PH, Leibel SA, et al.: Intracranial metastases. In DeAngelis LM, Gutin PH, Leibel SA, Posner JB (eds): Intracranial Tumors: Diagnosis and Treatment. London, Martin Dunitz, 2002, pp. 367–394. 10 Bennett AH, Godlee SRJ: Excision of a tumor from the brain. Lancet 1884; 2: 1090 –1091. 11 Mills CK, Lloyd JH: Tumors of the brain and its envelopes. In Pepper W, Starr L (eds): A System of Practical Medicine. Philadelphia, Lea Brothers & Co, 1886, pp. 1028–1089. 12 Schuller A: Rontgendiagnostik der Erkrankungen des Kopfes. Wien, Holder, 1912. 13 Dandy WE: Rontgenography of the brain after injection of air into the spinal canal. Ann Surg 1919; 70: 397. 14 Moniz E: Diagnostic des Tumeurs Cerebrales et Epreuve de Encephalographie Arterielle. Paris, Masson et Cie, 1931. 15 Walter WG: The location of cerebral tumours by electro-encephalography. Lancet 1936; 2: 305. 16 Nisce LZ, Hilaris BS, Chu FCH: A review of experience with irradiation of brain metastasis. AJR Am J Roentgenol 1971; 111: 329–333. 17 Nakamura H, Toyama M, Uezu K, et al.: Diagnostic dilemmas in oncology: case 1. Lung cancer with military brain metastases undetected by imaging studies. J Clin Oncol 2001; 19: 4340–4341. 18 Van Dijk P, Sijens PE, Schmitz PIM, et al.: Gd-enhanced MR imaging of brain metastases: contrast as a function of dose and lesion size. Magn Reson Imaging 1997; 15: 535 –541. 19 Rees JH, Hain SF, Johnson MR, et al.: The role of [(18)F]ﬂuoro-2-deoxyglucose-PET scanning in the diagnosis of paraneoplastic neurological disorders. Brain 2001; 124: 2223 –2231. 20 Prados M, Strowger B, Feindel WH: Studies on cerebral edema. II. reaction of the brain to exposure to air; physiologic changes. Arch Neurol Psychiatry 1945; 54: 290 –300. 21 Ingraham FD, Matson DD, McLaurin RL: Cortisone and ACTH as an adjunct to surgery of craniopharyngiomas. N Engl J Med 1952; 246: 568 –571. 22 Rasmussen T, Gulati DR: Cortisone in the treatment of postoperative cerebral edema. J Neurosurg 1962; 19: 535 –544. 23 Galicich JH, French LA: Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Practit-DigTreat 1961; 12: 169–174. 24 Kofman S, Garvin JS, Nagamani D, et al.: Treatment of cerebral metastases from breast carcinoma with prednisolone. JAMA 1957; 163: 1473 –1476. 25 Ruderman NB, Hall TC: Use of glucocorticoids in the palliative treatment of metastatic brain tumors. Cancer 1965; 18: 298–306. 26 French LA: The use of steroids in the treatment of cerebral edema. Bull N Y Acad Med 1966; 42: 301–311. 27 Hazra T, Mullins GM, Lott S: Management of cerebral metastases from bronchogenic carcinoma. Johns Hopkins Med J 1972; 130: 377–383. 28 Horton J, Baxter DH, Olson KB: The management of metastases to the brain by irradiation and corticosteroids. AJR Am J Roentgenol 1971; 111: 334 –336. 29 Lenz M, Freid JR: Metastases to the skeleton, brain, spinal cord from cancer of the breast and the effect of radiotherapy. Ann Surg 1931; 93: 278–293. 30 Dyke CG, Davidoff LM: Roentgen Treatment of Diseases of the Nervous System. Philadelphia, Lea & Febiger, 1942.

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31 Chao J-H, Phillips R, Nickson JJ: Roentgen-ray therapy of cerebral metastases. Cancer 1954; 7: 682–689. 32 Chu FCH, Hilaris BS: Roentgen-ray therapy of cerebral metastases. Cancer 1954; 7: 682–689. 33 Order SE, Hellman S, Von Essen CF, et al.: Improvement in quality of survival following whole-brain irradiation for brain metastasis. Radiology 1968; 91: 149 –153. 34 Rubenstein JH, Dosoretz DE, Katin MJ, et al.: Low doses of prophylactic cranial irradiation effective in limited stage small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1995; 33: 329–337. 35 Hindo WA, DeTrana FA III, Lee M-S, et al.: Large dose increment irradiation in treatment of cerebral metastases. Cancer 1970; 26: 138 –141. 36 Young DF, Posner JB, Chu F, et al.: Rapid-course radiation therapy of cerebral metastases: results and complications. Cancer 1974; 4: 1069 –1076. 37 Aiken R, Leavengood JM, Kim J-H, et al.: Metronidazole in the treatment of metastatic brain tumors. Results of a controlled clinical trial. J Neurooncol 1984; 2: 105 –111. 38 Komarnicky LT, Phillips TL, Martz K, et al.: A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916). Int J Radiat Oncol Biol Phys 1991; 20: 53 –58. 39 Horsley V, Clarke RH: The structure and functions of the cerebellum examined by a new method. Brain 1908; 31: 45–124. 40 Leksell L: The stereotaxic method and radiosurgery of the brain. Acta Chir Scand 1951; 102: 316–319. 41 Ganz JC: Gamma Knife Surgery: A Guide for Referring Physicians. New York, SpringerVerlag, 1993. 42 Leksell L: Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry 1983; 46: 797– 803. 43 Leksell L: A note on the treatment of acoustic tumours. Acta Chir Scand 1971; 137: 763 –765. 44 Winston KR, Lutz W: Linear accelerator as a neurosurgical tool for stereotactic radiosurgery. Neurosurgery 1988; 22: 454 – 464. 45 Kondziolka D, Lunsford LD, Flickinger JC: The radiobiology of radiosurgery. Neurosurg Clin N Am 1999; 10(2): 157–166. 46 Sturm V, Kober B, Hover KH, et al.: Stereotactic percutaneous single dose irradiation of brain metastases with a linear accelerator. Int J Radiat Oncol Biol Phys 1987; 13: 279 –282. 47 Boyd TS, Mehta MP: Radiosurgery for brain metastases. Neurosurg Clin N Am 1999; 10: 337–350. 48 Grant FC: Concerning intracranial malignant metastases: their frequency and the value of surgery in their treatment. Ann Surg 1926; 84: 635 – 646. 49 Meagher R, Eisenhardt L: Intracranial carcinomatous metastases. Ann Surg 1931; 93: 132–140. 50 Oldberg E: Surgical considerations of carcinomatous metastases to the brain. JAMA 1933; 101: 1458–1461. 51 Stortebecker TP: Metastatic tumors of the brain from a neurosurgical point of view: a follow-up study of 158 cases. J Neurosurg 1954; 11: 84 –111. 52 Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 53 Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al.: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993; 33: 583 –590. 54 Mintz AH, Kestle J, Rathbone MP, et al.: A randomized trial to assess the efﬁcacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996; 78: 1470–1476.

Management of intracranial metastases: history 19 55 French JD, West PM, Von Amerongen FK, et al.: Effects of intracarotid administration of nitrogen mustard on normal brain and brain tumors. J Neurosurg 1952; 9: 378 –389. 56 Wilson CB, Gutin P, Boldrey EB, et al.: Single-agent chemotherapy of brain tumors. A ﬁveyear review. Arch Neurol 1976; 33: 739–744. 57 Shapiro WR: Chemotherapy of metastatic central nervous system carcinoma. In Weiss L, Gilbert HA, Posner JB (eds): Brain Metastasis. Boston, G. K. Hall & Co, 1980, pp. 328–339. 58 Cascino TL, Byrne TN, Deck MDF, et al.: Intra-arterial BCNU in the treatment of metastatic brain tumors. J Neurooncol 1983; 1: 211–218. 59 Buckner JC: The role of chemotherapy in the treatment of patients with brain metastases from solid tumors. Cancer Metastasis Rev 1991; 10: 335 –341. 60 Hasegawa H, Shapiro WR, Posner JB: Chemotherapy of experimental metastatic brain tumors in female Wistar rats. Cancer Res 1979; 39: 2691–2697. 61 Rosner D, Nemoto T, Lane WW: Chemotherapy induces regression of brain metastases in breast carcinoma. Cancer 1986; 58: 832–839. 62 Cormio G, Gabriele A, Maneo A, et al.: Complete remission of brain metastases from ovarian carcinoma with carboplatin. Eur J Obstet Gynecol Reprod Biol 1998; 78: 91–93. 63 Franciosi V, Cocconi G, Michiara M, et al.: Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 1999; 85: 1599–1605. 64 Malacarne P, Santini A, Maestri A: Response of brain metastases from lung cancer to systemic chemotherapy with carboplatin and etoposide. Oncology 1996; 53: 210 –213. 65 Yoshida S, Morii K: Brain metastasis from germinal tumors of the testis. Case report. J Neurosurg 1998; 88: 761–763. 66 Montana GS, Meacham WF, Caldwell WL: Brain irradiation for metastatic disease of lung origin. Cancer 1972; 29: 1477–1480. 67 Deeley TJ, Edwards JM: Radiotherapy in the management of cerebral secondaries from bronchial carcinoma. Lancet 1968; 1: 1209 –1213. 68 Gottlieb JA, Frei E 3rd, Luce JK: An evaluation of the management of patients with cerebral metastases from malignant melanoma. Cancer 1972; 29: 701–705. 69 Lang EF, Slater J: Metastatic brain tumors: results of surgical and nonsurgical treatment. Surg Clin North Am 1964; 44: 865 – 872. 70 Haar F, Patterson RHJ: Surgery for metastatic intracranial neoplasm. Cancer 1972; 30: 1241–1245. 71 Vieth RG, Odom GL: Intracranial metastases and their neurosurgical treatment. J Neurosurg 1965; 23: 375 –383. 72 Richards P, McKissock W: Intracranial metastases. Br Med J 1963; 1: 15 –18. 73 Raskind R, Weiss SR, Manning JJ et al.: Survival after surgical excision of single metastatic brain tumors. AJR Am J Roentgenol 1971; 111: 323 –328.

CHAPTER 2

The epidemiology of brain metastasis Dima Suki

Brain metastases are neoplasms that originate in tissues outside the central nervous system and spread secondarily to the brain. They are a common and signiﬁcant cause of morbidity and mortality in patients with systemic cancer. Published data on the frequency of brain metastases vary greatly, and in some studies, the incidence and prevalence of brain metastases appear to be underreported. In recent years, the reported frequency of brain metastases has taken an upward trend, although it is unclear whether the trend is due to an actual increase in the incidence of brain metastases or to more accurate reporting. The main factor affecting the incidence of brain metastases is the histology of the primary tumor. Age also determines the types and frequency of primary cancers that metastasize to the brain, whereas gender lacks a signiﬁcant independent effect. A better understanding of the epidemiological factors associated with brain metastasis would lead to a ﬁrmer grip on the various research and clinical needs in this area at the prevention, diagnosis, and treatment levels.

A review of published data on the overall frequency of metastatic brain tumors Published estimates of the frequency of brain metastases can be found in population-based epidemiologic studies, neurosurgical and clinical series, and autopsy series.

Population-based epidemiologic studies A limited number of population-based epidemiologic studies address the incidence of brain metastases. Studies from Europe (Iceland and Central Finland) report incidences of brain metastases in 2.8 to 3.4 per 100,000 people, with corresponding primary brain tumor incidences in 7.8 and 12.3 per 100,000, respectively1, 2. Estimates from the United States are higher3, 4, ranging from 8.3 to 11.1 cases of brain metastasis per 100,000 individuals, with the primary brain tumor incidence ranging from 8.2 to 12.5 per 100,000. In addition to limitations that are inherent to most surveys, such as sampling variability and sample size, inadequate reporting of metastatic brain cancer is a limiting factor in all these studies. The fact that a large proportion of brain metastases are asymptomatic often hinders the attainment of an antemortem 20

The epidemiology of brain metastasis 21

diagnosis. Indeed, one-fourth to one-third of all metastatic brain tumors are only discovered post mortem5. Moreover, cancer registries tend to focus on the incidence of primary tumors rather than that of the metastases. For example, a patient presenting with brain metastasis from a primary breast cancer is usually classiﬁed as having recurrent breast cancer. Inadequate ascertainment of the presence of brain metastases is another limitation of the above studies. In a national survey of intracranial neoplasms reported by Walker et al.3, only 20% of the metastatic cases diagnosed during 1973 and 1974 were veriﬁed by tissue examination. The impact of this factor on the estimates of the overall incidence of brain metastases is of lesser magnitude than the other factors presented. For the reasons stated above, it appears that existing population-based studies underestimate the true incidence of metastatic brain tumors and the true ratio of primary to metastatic tumors. No recent population-based studies of metastatic brain tumors have been conducted.

Neurosurgical series The bulk of the data on the frequency of brain metastases originates from neurosurgical series. From the 1930s through the 1950s, most of these series estimated that 3% to 7% of neurosurgical cancer patients had brain metastases6 –13. Neurosurgeons at that time were reluctant to perform surgery on patients with known systemic cancer. This, added to the fraction of brain metastases that are radiosensitive and thus treated with radiation alone and to the frequent diagnosis of brain metastases at a late disseminated stage, led to a large underestimation of the actual frequency of brain metastases in neurosurgical series. Series from the 1960s and 1970s reported that 10% to 13% of patients undergoing neurosurgery had brain metastases14 –17. The much higher proportion (48%) reported in a recent series reﬂects a strong and sustained increase in the use of palliative surgery for metastatic brain tumors18. Overall, data derived from neurosurgical series remain an uncertain source of data on the frequency of brain metastases because they depend on the referral patterns and the management strategies of various tertiary care facilities.

Clinical series Clinical series of patients treated for brain tumors are another source of data on the frequency of brain metastases. The factors leading to the underestimation of the number of brain metastases in these series are the same as those in population-based epidemiologic series. Often, these studies rely on discharge diagnoses, which may lack speciﬁcity. Walker et al.3 reported that 10% of hospital discharge summaries used imprecise discharge diagnoses such as “rule out brain tumor”, “suspected brain tumor”, “possible brain tumor”, “probable brain tumor”, and “brain tumor”. Moreover, variation in the referral patterns of various healthcare facilities also reﬂects on the ﬁndings from various studies. Data from recent clinical series point toward a higher frequency of metastatic brain tumors than primary brain tumors, supporting evidence from other types of studies19, 20. In a retrospective study of patients with brain

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tumors treated at a hospital in Scotland19, 57% had brain metastases, and 43% had primary brain tumors. In a retrospective clinical series of elderly patients with cancer in Japan treated between 1973 and 1987, 75% of 322 consecutive malignant tumors were metastatic brain tumors, and 25% were primary brain tumors20.

Autopsy series Earlier autopsy series show a very low prevalence of brain tumors (< 6%)21, 22. Later estimates, however, have been consistently higher. Indeed, with the exception of Pickren23, who found brain metastases in 8.7% of 10,916 patients with central nervous system lesions, authors of smaller series generally agree that one-sixth to one-fourth of patients with cancer will have brain metastases at autopsy5, 24 –26. As can be noted, estimates of the frequency of brain metastasis from autopsy studies are generally higher than estimates from other types of studies. This is due, in part, to the large proportion of tumors only found post mortem. Indeed, autopsies do allow for a better ascertainment of the presence of a metastatic brain tumor. Still, autopsy data are generally obtained from referral centers, and only a select group of patients are autopsied. Moreover, the clinical signiﬁcance of asymptomatic brain tumors found only at autopsy is unclear. The above review supports the following conclusions: 1 The frequency of brain metastases is difﬁcult to determine with precision and is probably underestimated. 2 The existence and extent of an increase in the frequency of brain metastases remain unknown. Increased incidences of lung cancer and melanoma (two main contributors to brain metastasis cases), longer survival times for patients with cancer as a result of early diagnosis and more effective treatment regimens, and an aging patient population could lead to a true increase. However, a case of more accurate and complete reporting of brain metastases owing to more adequate representation of brain metastases in more recent neurosurgical series, advances in neuroimaging techniques, and routine staging that assesses the central nervous system can also inﬂate the ﬁgures. 3 Metastatic brain tumors are the most common type of brain neoplasm. 4 Around 25% of patients with cancer develop brain metastases during the course of their illness. Based on estimates by the American Cancer Society of 1,268,000 new cases of cancer in the year 200127, 317,000 patients would have had diagnosis of brain metastasis (ante mortem or post mortem) in that year. 5 Because one-fourth to one-third of brain metastases are only diagnosed at autopsy, 209,220 to 237,750 cases of brain metastasis were expected to develop in the United States in the year 2001 among live patients with cancer, with an incidence of 7.4 to 8.4 per 100,000, based on the latest national United States Census (April 2000). 6 Between one-sixth and one-fourth of patients with cancer have brain metastases at autopsy. This translates into 91,864 to 138,350 cancer patients who

The epidemiology of brain metastasis 23

were expected to die with brain metastases in 2001, based on the American Cancer Society estimates of 553,400 cancer deaths in that year27. It should be noted that these ﬁgures exclude dural and leptomeningeal metastases.

Histology of the primary cancer The histology of the primary tumor appears to be the major dictator of the frequency and pattern of intracranial extension. Therefore, a discussion of the incidence of brain metastases should include a study of the frequencies and patterns seen among speciﬁc primary cancers. Virtually any type of cancer has the ability to produce brain metastases. However, (in decreasing relative frequency) lung cancer, breast cancer, melanoma, renal cancer, and colon cancer account for most brain metastases. Half of the patients with brain metastases in autopsy series have lung or breast cancer as the primary tumor.

Lung cancer Primary lung tumors account for 30% to 60% of all cases of brain metastasis26, . Lung cancer ranks second among all cancers in its tendency to invade the brain. Of patients with lung cancer, 18% to 65% will develop brain metastases26, 39 – 42, and the speciﬁc histology of a primary lung tumor is very important in determining metastatic frequency. Indeed, more than 40% of patients with small cell lung cancer and lung adenocarcinoma have brain metastases in clinical series or at autopsy, more than twice the rate of metastasis found with the other types of lung cancer such as squamous cell carcinoma26, 42– 44. In a clinical series of patients with brain metastases from lung cancer in Turkey42, adenocarcinoma, epidermoid carcinoma, and small cell carcinoma gave rise to 84% of these metastatic lesions and were responsible in 80% of the patients who presented initially with brain tumors. In a clinical series of patients presenting with brain metastases as the ﬁrst sign of their malignancy at the Gustave-Roussy Institute, France45, 44% had adenocarcinoma and 30% had undifferentiated or small cell lung carcinoma, compared with only 12% who had squamous cell lung carcinoma. Ten per cent of patients with squamous cell lung carcinoma have cerebral metastases at initial presentation, but this increases to 80% after two years41. The median interval between the diagnosis of lung cancer and the detection of brain metastasis falls between two and nine months and is shorter than is seen for other cancers11, 15, 36, 37, 42. 28 –38

Breast cancer Breast cancer ranks second to lung cancer as the most frequently occurring primary tumor in patients with brain metastases. Among women, breast cancer is the most common cause of brain metastasis, resulting in 5% to 30% of all brain metastases26, 28, 29, 31, 32, 34, 36, 38, 46, 47. Breast cancer ranks third among primary cancers in its tendency to metastasize to the brain. Approximately 20% to 30%

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of patients with breast cancer will develop a brain metastasis24, 25, 39, 46, 48, 49. Brain metastases from breast cancer typically occur late in the course of the disease, between 2 and 3.3 years after diagnosis11, 15, 36, 37.

Melanoma Melanoma ranks third among primary brain tumors in giving rise to brain metastases. Of patients with brain metastases, approximately 5% to 21% will have melanoma as their primary tumor24, 31, 32, 34 –36, 38, 50, 51. Interestingly, malignant melanoma, which represents only 4% of all cancers27, has the highest propensity of all systemic malignant tumors to metastasize to the brain23, 24, 52. The incidence of brain metastases among patients with malignant melanoma is 6% to 43% in clinical series52–55, 12% to 90% in autopsy series23, 24, 52, 56 –59, and 11% in neurosurgical series51. The median interval between the diagnosis of melanoma and the detection of brain metastasis is 1.2 to 3.5 years37, 51. Among patients with brain metastasis, the prognosis is worst for patients with melanoma.

Renal cancer Renal cancer frequently metastasizes to the brain. In an autopsy series, the frequency of brain metastases in renal adenocarcinoma patients was 11%60. In a clinical series by Harada et al.61, 5.5% of 325 patients who had renal cell carcinoma that was treated at Osaka University Hospital from 1957 to 1993, developed brain metastases. Although the median interval between diagnosis of renal cancer and brain metastasis caused by it ranges from 1 year to 2.3 years37, 61, 62, such metastases may not present for decades63.

Gastrointestinal cancer Metastatic brain tumors from colorectal cancers are relatively rare, with a reported frequency of 1.8% to 4.8% of all metastatic brain tumors38, 64. Between 0.74% and 10% of patients with colorectal cancer develop brain metastases65 –70, with an incidence of 10% seen among patients with stage IV disease71, 72. The median interval from diagnosis of colorectal cancer to detection of brain metastasis ranges from 22 to 33 months36, 65, 66, 68, 73. Brain metastases from gastric cancer are extremely rare. Kim74 found 13 patients (0.2%) with brain metastases in a cohort of 8,080 patients with advanced gastric carcinoma, and York et al.75 reported an incidence of 0.7% in a review of 3,320 patients with gastric cancer at The University of Texas M. D. Anderson Cancer Center (M. D. Anderson). Patients with gastric cancer account for less than 1% of all cases of brain metastases in autopsy and clinical series36, 38. In the study by York et al.75, brain metastases occurred at a median of four months (range, 1 to 23 months) after the diagnosis of gastric cancer75. Gastric cancer is generally diagnosed in its advanced stages, and the diagnosis of brain metastases is a late event in the course of the disease. This is demonstrated by a low median survival (median, 9 weeks) after the diagnosis of brain metastasis75.

The epidemiology of brain metastasis 25

Brain metastases from esophageal cancer are also rare. In a series of 334 patients undergoing esophagectomies for squamous carcinomas, adenocarcinomas, and undifferentiated carcinomas between January 1984 and March 1993, 3.6% had brain metastases. The metastases tended to occur in patients with large primary neoplasms, especially adenocarcinomas involving the esophagogastric junction, and in conjunction with ﬁndings of local invasion and lymph node metastases by computed tomography (CT) and/or microscopy76. In clinical and autopsy series of brain metastases, esophageal cancer contributed less than 1% of the cases36, 38.

Genitourinary cancer Intracranial metastases from prostate cancer are rare (range, 0.6% to 4.4% of cases), with most cases detected at autopsy77– 80. Catane et al.77 reviewed the incidence of brain metastases in 11 published series and determined that prostate cancer was the primary cancer in 0.8% of 1,202 patients with brain metastases from a variety of primary sites. In a combined autopsy series of 856 cases of prostate carcinoma, Lynes et al.81 reported 11 cases (1.3%) with brain metastases. In a combined clinical and autopsy series of 9,964 patients with prostate cancer, 40 cases of brain metastasis were identiﬁed, 15 of which were identiﬁed antemortem. Similarly, Demierre and Berney79 found brain metastases in 0.1% of 17,812 autopsy brain specimens of patients with prostate cancer treated at the University Hospital of Geneva, Switzerland. A review by Sutton et al.82 of all parenchymal brain metastases secondary to prostate cancer found a frequency of 0.9% in 6,107 patients with prostate cancer (0.6% diagnosed antemortem). In a clinical review of 7,994 patients treated for prostate cancer over an 18-year period at M. D. Anderson, McCutcheon et al.83 found 38 patients (0.5%) with antemortem intracerebral metastasis. In that study, the mean time from diagnosis of prostate carcinoma to discovery of brain metastasis was 28 months, similar to the median of 22 months reported by Nussbaum et al.37. Small cell carcinomas and primary transitional-cell carcinomas of the prostate were much more likely to produce brain metastases than were adenocarcinomas. Interestingly, in this prostate carcinoma cohort, the authors noted a separate group of 16 patients with brain metastases that had developed from a lung cancer or melanoma primary tumor. The incidence of brain metastases in patients with testicular cancer ranges from 2% to 25% in clinical series and was 20.7% in an autopsy series23. However, brain metastases are extremely rare in surgical series of patients with testicular cancer (2%)84.

Gynecologic cancer In the autopsy series by Graf38, gynecologic tumors accounted for 2.6% of the brain metastasis cases. Intracranial metastases are extremely rare in endometrial carcinoma (0.3% in one clinical series of patients with endometrial carcinoma treated at the Norwegian Radium Hospital in Norway85) and usually occur in disseminated disease, although invasive high-grade endometrial

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Chapter 2

carcinoma with vascular invasion may metastasize very early in the course of the disease, even before clinical symptoms related to the primary tumor become apparent86. At autopsy, 5% of patients with endometrial cancer have brain metastases, although this percentage decreases to 3% if skull metastases are excluded87. Autopsy studies have shown a wide variation in the incidence of brain metastases from cervical carcinoma. Behney88 and Brunschwig and Pierce89 separately evaluated a total of 181 patients with cervical cancer and found no cerebral metastases. Holzaepfel and Ezell90 documented a 1.5% to 2.3% incidence, and Posner and Chernik5 found a 5% incidence. The time from initial diagnosis of cervical cancer to presentation of the brain lesions is also quite variable, ranging from the time of primary diagnosis to 8 years, with a mean interval of 30 months. Ikeda et al.91 reported on eight patients who developed brain metastases after diagnosis of cervical cancer. The mean interval between diagnosis of the primary cancer and diagnosis of the brain metastasis was 28.4 months (range, 6.1 to 61.8 months). In a study by Saphner et al.92, 0.5% of 1,219 women with stage I or greater cervical cancer and 0 of 1,042 women with stage 0 cervical cancer developed brain metastasis. With the exception of one small series, in which the incidence of cerebral metastases secondary to epithelial ovarian cancer was 11.6%93, there is agreement in the literature that brain metastases from ovarian cancer are rare. A review of the histories of 413 ovarian cancer patients treated from 1981 to 1989 with platinum-based combination chemotherapy showed that only 2.2% developed clinical evidence of cerebral metastases94. A review by Mayer et al.95 of several autopsy series shows brain metastasis in only 0.9% of 567 patients with ovarian cancer. Ovarian cancers account for only a small fraction of brain metastasis cases (2%)37. Cerebral metastases in ovarian cancer occur at a median interval of 19 months (range, 3 to 36 months) from diagnosis94. Choriocarcinoma metastasizes to the brain at a frequency of 9% to 21%96, 97, but because it is rare, only 0.9% of the patients with brain metastases have a primary choriocarcinoma38.

Patients with unknown primary tumors Patients with no known history of cancer sometimes present with symptoms caused by a brain metastasis from an undiagnosed primary malignancy. The frequency of such presentation varies98. As detection improves, a reduction in the number of patients presenting with brain metastases from an unknown primary site is expected; this is coupled with an increase in brain metastases from other tumors. Indeed, the primary site was unknown in 38% and 28% of 86 patients with brain metastases examined antemortem and antemortem and postmortem combined, respectively, at the Gustave-Roussy Institute in France between 1959 and 197945. The primary tumor was unknown in 11.5% of 276 consecutive patients with brain metastases seen over a period of eight years prior to 1997 at the University of Mississippi Medical Center98, and only 5% of

The epidemiology of brain metastasis 27

patients in a clinical series of 729 cases of brain metastasis treated at the University of Minnesota Hospital and Clinic from 1973 to 1993 had unknown primary tumors37.

Thyroid cancer Patients with thyroid cancer have a brain metastasis frequency of about 0.1% to 5% in reported series99, 100. Time from diagnosis to metastasis varies in reported series from 1 year to 12 years99. The mean interval between the diagnosis of thyroid cancer and the detection of brain metastasis is 2.8 years for papillary cancers and 1.2 years for anaplastic cancers101.

Patient age The incidence and primary source of brain metastases vary with patient age25, . Brain metastases occur more frequently in adults than in children5, 49, 50, 104 –107 . Among adults, the highest incidence (over 60%) is observed in patients 50 to 80 years old26, 38, 104. In a national survey of intracranial neoplasms conducted by Walker et al.3, the incidence of brain metastases in people less than 35 years old was less than 1 per 100,000 but rose rapidly to more than 30 per 100,000 at age 60 before decreasing drastically after age 70. The most common sources of brain metastases in adults are cancers of the lung, breast, and skin, in descending order. Younger patients with a given type of cancer have exhibited a higher likelihood of developing brain metastases than older ones25, 26, 102, 103. This observation was independent of duration of survival and may represent a biological difference in the aggressiveness of cancer cells in younger patients. Brain metastases occur in 4% to 13% of children with solid tumors49, 104, 106, 107 . The frequency of brain metastases in neurosurgical series of children is < 1%108. The duration of time from diagnosis of the primary disease to development of intracranial metastases varies widely (0 days to 755 days; mean, 327 days)107. The most common cause of brain metastases in children is leukemia, followed by lymphoma26; osteogenic sarcoma, rhabdomyosarcoma, and Ewing’s sarcoma are the most frequent causes of solid brain metastases in children younger than 15 years old104. Rhabdomyosarcoma metastasizes to the brain signiﬁcantly earlier than Ewing’s sarcoma. In a study by Parasumaran et al.109, a median of 12 months (range, 0 to 55 months) elapsed between the diagnosis of the primary tumor and the diagnosis of brain metastasis in patients with rhabdomyosarcoma compared with 22 months (range, 8 to 54 months) in patients with Ewing’s sarcoma (P = 0.034). Germ cell tumors most frequently produce brain metastases in patients 15 to 21 years of age104. Interestingly, among 44 children with malignant melanoma treated at Saint Jude Children’s Hospital in Memphis, Tennessee over a 33-year period prior to 1997, a signiﬁcant proportion of patients (18%) developed brain metastases110. Brain metastases developed at a median of 20 months (range, 0 to 50 months) after diagnosis of the primary melanoma. 26, 102, 103

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Sex Walker et al.3 reported a higher incidence of brain metastases in men than in women (9.7 versus 7.1 per 100,000, respectively). However, judging from other published series, neither the overall incidence of brain metastases, nor the incidence of brain metastasis from a given primary appears to be affected by the patient’s sex. Overall, differences in the incidence of primary cancers between the two genders result in differences in the relative proportions of brain metastases from the various primary tumors between the two sexes. Lung cancer is the most common source of brain metastasis in men3, 26. In the national survey of intracranial neoplasms3, 62.7% of the estimated 9,750 new brain metastases were from a pulmonary cancer. The incidence of brain metastases in men with lung cancer was 6.1 per 100,000, three times higher than the 2.2 per 100,000 reported among women with lung cancer. Among women, however, the breast was the primary origin of brain metastases3. The larger number of lung cancer cases in men relative to women explains the large difference in the incidence of brain metastasis. Interestingly, a substantial increase in the proportion of brain metastases of lung cancer origin in women is being observed. More recent reports show that 46.3%, 59.6% and 58.7% of brain metastases from a primary lung cancer occurred in women38, 111, 112 compared with 21.1% and 15.8% in earlier series11, 28. This increase is accompanied by a decrease in brain metastases from breast carcinoma, 22.6% and 39.0%13, 113 in earlier reports versus 10.0%, 9.9%, 4.8% and 7.4% in later ones38, 45, 114, 115. These ﬁndings are probably related to the earlier diagnosis and more successful treatment of breast carcinoma. Lung cancer could soon become the most common primary tumor for women with brain metastasis as well. Genitourinary and gastrointestinal malignancies had an equal tendency to metastasize to the brain in the two sexes, but malignant melanoma was apparently more likely to spread to the brain in men26, 54, 116. The fact that, in males, melanoma develops in locations that are more likely to spread to the brain (namely, the head, neck, or trunk) could explain this observation52, 117. Interestingly, in some reports, testicular cancers have been noted to result in a higher frequency of brain metastases than ovarian cancer (20.7% versus 1.9%), and the same is true of penial cancer compared with female genital organ cancer (12.5% versus 3.5%)23.

Conclusions 1 In the absence of complete and speciﬁc reporting at both the community and the clinic/hospital level, as well as accurate ascertainment of all potential cases of brain metastasis, estimates of the frequency of brain metastases and frequency trends will continue to be speculative. 2 It is apparent that metastatic brain tumors outnumber primary brain tumors and contribute signiﬁcantly to the morbidity and mortality of patients with cancer. A look at the overall number of brain metastases that occur in the

The epidemiology of brain metastasis 29

general population is important in order to direct attention and activity towards issues common to all such patients, such as management issues (patient referral patterns, etc.), functional and cognitive abilities, and quality of life, to name only a few. 3 However, given the wide variation among different primary tumors in the propensity (frequency, timing, and other issues that are beyond the scope of this chapter) to metastasize to the brain and a wide variation in the prognosis of patients with brain metastases based on the type of primary cancer (discussed in other chapters in this book), efforts in the areas of prevention, diagnosis, and treatment should focus on the peculiarities of brain metastases from speciﬁc primary cancers.

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18 Sawaya R, Hammoud M, Schoppa D, et al.: Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery 1998; 42: 1044 – 1055. 19 Grant R, Whittle IR, Collie DA, et al.: Referral pattern and management of patients with malignant brain tumours in South East Scotland. Health Bull (Edinb) 1996; 54: 212–222. 20 Kawahata N, Ohtomo E: Metastatic brain tumor in the elderly. Rinsho Shinkeigaku 1989; 29: 1106–1109. 21 Krasting K: Beitrag zur Statistik und Kasuistik metastatischer Tumoren, besonders der Carcinommetastasen im Zentralnervensystem: Auf Grund von 12,730 Sektionen der pathologisch-anatomischen Anstalt. In Schumacher L (ed). Berlin, 1906, pp. 315–379. 22 Neustaedter M: Incidence of metastases to the nervous system. Arch Neurol Psychiatr 1944; 51: 423–425. 23 Pickren JW, Lopez G, Tsukada Y, et al.: Brain metastases: an autopsy study. Cancer Treat Symposia 1983; 2: 295 –313. 24 Chason JL, Walker FB, Landers JW: Metastatic carcinoma in the central nervous system and dorsal root ganglia: a prospective autopsy study. Cancer 1963; 16: 781–787. 25 Aronson SM, Garcia JH, Aronson BE: Metastatic neoplasms of the brain: their frequency in relation to age. Cancer 1964; 17: 558 –563. 26 Takakura K, Sano K, Hojo S, et al.: Metastatic Tumors of the Central Nervous System. Tokyo, Igaku-Shoin, 1982, pp. 5–35. 27 Greenlee RT, Hill-Harmon MB, Murray T, et al.: Cancer statistics, 2001. CA Cancer J Clin 2001; 51: 15–36. 28 Baker AB: Metastatic tumors of the nervous system. Arch Pathol Lab Med 1942; 34: 495 – 537. 29 Baker GS, Kernohan JW, Kiefer EJ: Metastatic tumors of the brain. Surg Clin North Am 1951; 31: 1143–1145. 30 Chang DB, Yang PC, Luh KT, et al.: Late survival of non-small cell lung cancer patients with brain metastases. Inﬂuence of treatment. Chest 1992; 101: 1293 –1297. 31 Lang EF, Slater J: Metastatic brain tumors. Results of surgical and nonsurgical treatment. Surg Clin North Am 1964; 44: 865 – 872. 32 Le Chevalier T, Smith FP, Caille P, et al.: Sites of primary malignancies in patients presenting with cerebral metastases. A review of 120 cases. Cancer 1985; 56: 880 – 882. 33 MacGee EE: Surgical treatment of cerebral metastases from lung cancer. The effect on quality and duration of survival. J Neurosurg 1971; 35: 416 – 420. 34 Markesbery WR, Brooks WH, Gupta GD, et al.: Treatment for patients with cerebral metastases. Arch Neurol 1978; 35: 754–756. 35 Sundaresan N, Galicich JH: Surgical treatment of brain metastases: clinical and computerized tomography evaluation of the results of treatment. Cancer 1985; 55: 1382–1388. 36 Zimm S, Wampler GL, Stablein D, et al.: Intracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer 1981; 48: 384 –394. 37 Nussbaum ES, Djalilian HR, Cho KH, et al.: Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 1996; 78: 1781–1788. 38 Graf A, Buchberger W, Langmayr H, et al.: Site preference of metastatic tumours of the brain. Virchows Arch A Pathol Anat Histopathol 1988; 412: 493 – 498. 39 Abrams HL, Spiro R, Goldstein N: Metastases in carcinoma: analysis of 1000 autopsied cases. Cancer 1950; 3: 74 – 85. 40 Burt M, Wronski M, Arbit E, et al.: Resection of brain metastases from non-small-cell lung carcinoma. Results of therapy. Memorial Sloan-Kettering Cancer Center Thoracic Surgical Staff. J Thorac Cardiovasc Surg 1992; 103: 399– 410.

The epidemiology of brain metastasis 31 41 Nugent JL, Bunn PA, Jr, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 1979; 44: 1885–1893. 42 Sen M, Demiral AS, Cetingoz R, et al.: Prognostic factors in lung cancer with brain metastasis. Radiother Oncol 1998; 46: 33 –38. 43 Cox JD, Yesner RA: Adenocarcinoma of the lung: recent results from the Veterans Administration Lung Group. Am Rev Respir Dis 1979; 120: 1025–1029. 44 Cox JD, Barber-Derus S, Hartz AJ, et al.: Is adenocarcinoma/large cell carcinoma the most radiocurable type of cancer of the lung? Int J Radiat Oncol Biol Phys 1986; 12: 1801–1805. 45 Le Chevalier B, Derouesne C, Chapon F: Confrontation de la Salpetriere. 6 juillet 1983. Paralysies de nerfs craniens et instabilite cerebelleuse progressives. Rev Neurol (Paris) 1984; 140: 523–529. 46 Tsukada Y, Fouad A, Pickren JW, et al.: Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 1983; 52: 2349 –2354. 47 Vieth RG, Odom GL: Intracranial metastases and their neurosurgical treatment. J Neurosurg 1965; 23: 375 –383. 48 Cifuentes N, Pickren JS: Metastases from carcinoma of mammary gland: an autopsy study. J Surg Oncol 1979; 11: 193 –205. 49 Posner JB: Neurologic Complications of Cancer. Philadelphia, F. A. Davis, 1995, pp. 3– 14; 77–110. 50 Posner JB: A clinician’s view. In Weiss L, Gilbert HA, Posner JB (eds): Brain Metastasis. Boston, G. K. Hall, 1980, pp. 2–29. 51 Wronski M, Arbit E: Surgical treatment of brain metastases from melanoma: a retrospective study of 91 patients. J Neurosurg 2000; 93: 9 –18. 52 Amer MH, Al-Sarraf M, Baker LH, et al.: Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer 1978; 42: 660 – 668. 53 Atkinson L: Melanoma of the central nervous system. Aust N Z J Surg 1978; 48: 14 –16. 54 Sampson J, Carter JJ, Friedman A, et al.: Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998; 88: 11–20. 55 Moser RP: Primary tumors and neurological complications of cancer. In Twijnstra A, Keyser A, Ongerboer de Visser BW (eds): Neuro-Oncology. Amsterdam, Elsevier, 1993, 208pp. 56 Madajewicz S, Karakousis C, West CR, et al.: Malignant melanoma brain metastases: review of Roswell Park Memorial Institute experience. Cancer 1984; 53: 2550 –2552. 57 Patel KJ, Didolkar MS, Pickren JW, et al.: Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. Am J Surg 1978; 135: 807– 810. 58 de la Monte SM, Moore GW, Hutchins GM: Patterned distribution of metastases from malignant melanoma in humans. Cancer Res 1983; 43: 3427–3433. 59 Moon D, Maafs E, Peterson-Schaefer K, et al.: A review of 567 cases of brain metastases from malignant melanoma. Melanoma Res 1993; 3: 40. 60 Saitoh H: Distant metastasis of renal adenocarcinoma. Cancer 1981; 48: 1487–1491. 61 Harada Y, Nonomura N, Kondo M, et al.: Clinical study of brain metastasis of renal cell carcinoma. Eur Urol 1999; 36: 230 –235. 62 Badalament RA, Gluck RW, Wong GY, et al.: Surgical treatment of brain metastases from renal cell carcinoma. Urology 1990; 36: 112–117. 63 Radley MG, McDonald JV, Pilcher WH, et al.: Late solitary cerebral metastases from renal cell carcinoma: report of two cases. Surg Neurol 1993; 39: 230 –234. 64 Ishikura A, Hunaki N, Watanabe K: Brain metastases of colorectal canceraa case report. Gan No Rinsho-Japanese Journal of Cancer Clinics 1987; 33: 188 –192.

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65 Wronski M, Arbit E: Resection of brain metastases from colorectal carcinoma in 73 patients. Cancer 1999; 85: 1677–1685. 66 Salvati M, Cervoni L, Paolini S, et al.: Solitary cerebral metastases from intestinal carcinoma. Acta Neurochir 1995; 133: 181–183. 67 Cascino TL, Leavengood JM, Kemeny N, et al.: Brain metastases from colon cancer. J Neurooncol 1983; 1: 203 –209. 68 Ko FC, Liu JM, Chen WS, et al.: Risk and patterns of brain metastases in colorectal cancer: 27-year experience. Dis Colon Rectum 1999; 42: 1467–1471. 69 Chyun Y, Hayward E, Lokich J: Metastasis to the central nervous system from colorectal cancer. Med Pediatr Oncol 1980; 8: 305 –308. 70 Temple DF, Ledesma EJ, Mittelman A: Cerebral metastases. From adenocarcinoma of the colon and rectum. N Y State J Med 1982; 82: 1812–1814. 71 Welch JP, Donaldson GA: The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg 1979; 189: 496 –502. 72 Patanaphan V, Salazar OM: Colorectal cancer: metastatic patterns and prognosis. South Med J 1993; 86: 38–41. 73 Hammoud MA, McCutcheon IE, Elsouki R, et al.: Colorectal carcinoma and brain metastasis: distribution, treatment, and survival. Ann Surg Oncol 1996; 3: 453– 463. 74 Kim M: Intracranial involvement by metastatic advanced gastric carcinoma. J Neurooncol 1999; 43: 59–62. 75 York JE, Stringer J, Ajani JA, et al.: Gastric cancer and metastasis to the brain. Ann Surg Oncol 1999; 6: 771–776. 76 Gabrielsen TO, Eldevik OP, Orringer MB, et al.: Esophageal carcinoma metastatic to the brain: clinical value and cost-effectiveness of routine enhanced head CT before esophagectomy. AJNR Am J Neuroradiol 1995; 16: 1915 –1921. 77 Catane R, Kaufman J, West C, et al.: Brain metastasis from prostatic carcinoma. Cancer 1976; 38: 2583–2587. 78 Cheng CL, Greenberg J, Hoover LA: Prostatic adenocarcinoma metastatic to chronic subdural hematoma membranes. Case report. J Neurosurg 1988; 68: 642– 644. 79 Demierre B, Berney J: Intracranial metastases of cancer of the prostate. Neurochirurgie 1983; 29: 143–149. 80 Castaldo JE, Bernat JL, Meier FA, et al.: Intracranial metastases due to prostatic carcinoma. Cancer 1983; 52: 1739–1747. 81 Lynes WL, Bostwick DG, Freiha FS, et al.: Parenchymal brain metastases from adenocarcinoma of prostate. Urology 1986; 28: 280 –287. 82 Sutton MA, Watkins HL, Green LK, et al.: Intracranial metastases as the ﬁrst manifestation of prostate cancer. Urology 1996; 48: 789 –793. 83 McCutcheon IE, Eng DY, Logothetis CJ: Brain metastasis from prostate carcinoma: antemortem recognition and outcome after treatment. Cancer 1999; 86: 2301–2311. 84 Guenot M, Wager M, Bataille B, et al.: Metastases cerebrales des cancers testiculaires. A propos de deux cas et revue de la litterature. Neurochirurgie 1994; 40: 135 –137. 85 Aalders JG, vd Syde R, Poppema S, et al.: Prognostic factors and changing trends in the treatment of Stage 1 endometrial cancer: a clinical and histopathological study of 182 patients. Int J Radiat Oncol Biol Phys 1984; 10: 2083 –2088. 86 Martinez-Manas RM, Brell M, Rumia J, et al.: Brain metastases in endometrial carcinoma. Gynecol Oncol 1998; 70: 282–284. 87 Henriksen E: The lymphatic dissemination in endometrial carcinoma. A study of 188 necropsies. Am J Obstet Gynecol 1975; 123: 570 –576.

The epidemiology of brain metastasis 33 88 Behney CA: Advanced carcinoma of the cervix with a report of 166 necropsies. Am J Obstet Gynecol 1933; 26: 608 – 614. 89 Brunschwig A, Pierce V: Necropsy ﬁndings in patients with carcinoma of the cervix. Am J Obstet Gynecol 1948; 56: 1134 –1137. 90 Holzaepfel JH, Ezell HE: Sites of metastasis of uterine carcinoma. Am J Obstet Gynecol 1955; 69: 1027–1038. 91 Ikeda S, Yamada T, Katsumata N, et al.: Cerebral metastasis in patients with uterine cervical cancer. Jpn J Clin Oncol 1998; 28: 27–29. 92 Saphner T, Gallion HH, Van Nagell JR, et al.: Neurologic complications of cervical cancer: a review of 2261 cases. Cancer 1989; 64: 1147–1151. 93 Hardy JR, Harvey VJ: Cerebral metastases in patients with ovarian cancer treated with chemotherapy. Gynecol Oncol 1989; 33: 296 –300. 94 Bruzzone M, Campora E, Chiara S, et al.: Cerebral metastases secondary to ovarian cancer: still an unusual event. Gynecol Oncol 1993; 49: 37– 40. 95 Mayer RJ, Berkowitz RS, Grifﬁths CT: Central nervous system involvement by ovarian carcinoma: a complication of prolonged survival with metastatic disease. Cancer 1978; 41: 776–783. 96 Athanassiou A, Begent RHJ, Newlands ES, et al.: Central nervous system metastases of choriocarcinoma: 23 years experience at Charing Cross Hospital. Cancer 1983; 52: 1728 – 1735. 97 Ishizuka T, Tomoda Y, Kaseki S, et al.: Intracranial metastasis of choriocarcinoma. A clinicopathologic study. Cancer 1983; 52: 1896 –1903. 98 Khansur T, Routh A, Hickman B: Brain metastases from unknown primary site. J Miss State Med Assoc 1997; 38: 238 –242. 99 Altimari-Romero RA, Montenegro FL, Michaluart PJ, et al.: Brain metastases from papillary thyroid carcinoma: a case report and review of the literature. Rev Hosp Clin Fac Med Sao Paulo 1997; 52: 263 –266. 100 Jyothirmayi R, Edison J, Nayar PP, et al.: Case report: brain metastases from papillary carcinoma thyroid. Br J Radiol 1995; 68: 767–769. 101 Salvati M, Cervoni L, Celli P: Solitary brain metastases from thyroid carcinoma: study of 6 cases. Tumori 1995; 81: 142–143. 102 de la Monte SM, Hutchins GM, Moore GW: Inﬂuence of age on the metastatic behavior of breast carcinoma. Hum Pathol 1988; 19: 529 –534. 103 Sorensen JB, Hansen HH, Hansen M, et al.: Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988; 6: 1474 –1480. 104 Graus F, Walker RW, Allen JC: Brain metastases in children. J Pediatr 1983; 103: 558 –561. 105 Posner JB: Management of brain metastases. Rev Neurol (Paris) 1992; 148: 477– 487. 106 Vannucci RC, Baten M: Cerebral metastatic disease in childhood. Neurology 1974; 24: 981–985. 107 Tasdemiroglu E, Patchell RA: Cerebral metastases in childhood malignancies. Acta Neurochirurgica 1997; 139: 182–187. 108 Tomita T, Larsen MB: Calciﬁed metastases to the brain in a child: case report. Neurosurgery 1983; 13: 435 – 437. 109 Parasuraman S, Langston J, Rao BN, et al.: Brain metastases in pediatric Ewing sarcoma and rhabdomyosarcoma: the St. Jude Children’s Research Hospital experience. J Pediatr Hematol Oncol 1999; 21: 370 –377. 110 Rodriguez-Galindo C, Pappo AS, Kaste SC, et al.: Brain metastases in children with melanoma. Cancer 1997; 79: 2440 –2445.

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111 Young DF, Posner JB, Chu FHC, et al.: Rapid-course radiation therapy of cerebral metastases: results and complications. Cancer 1974; 34: 1069 –1076. 112 Schreiber D, Janisch W, Zimmermann K: Die Frequenz von Metastasen im Zentralnervensystem (ZNS) in Abhangigkeit von Tumorarten und Lebensalter Ein Untersuchung am Obduktionsgut. Neuropathol Pol 1978; 16: 269–279. 113 Chu FHC, Hilaris BS: Value of radiation therapy in the management of intracranial metastasis. Cancer 1961; 14: 577–581. 114 Winston KR, Walsh JW, Fisher EG: Results of operative treatment of intracranial metastatic tumors. Cancer 1980; 45: 2639–2645. 115 Schreiber D, Bernstein K, Warzok R: Metastases of the central nervous system. A prospective study. Zentralbl Allg Pathol Patholog Anat 1982; 126: 41–52. 116 Fell DA, Leavens ME, McBride CM: Surgical versus nonsurgical management of metastatic melanoma of the brain. Neurosurgery 1980; 7: 238 –242. 117 Robinson JB, Morris M: Cervical carcinoma metastatic to the brain. Gynecol Oncol 1997; 66: 324–326.

CHAPTER 3

The biology of brain metastasis Isaiah J Fidler

Introduction Of tumors found in the brain, more than 25% are metastatic lesions produced by cancers such as lung and breast malignancies and melanoma1, 2. The progressive growth of metastases in the brain is often associated with the terminal stage of the disease. The treatment of choice for a solitary metastasis is surgical excision plus radiation1–3, whereas for multiple metastases in the brain and meningeal carcinomatosis, radiation and/or chemotherapy are employed. Although brain metastases can be surgically extirpated without producing severe neurological complications, the prognosis is poor. After surgery alone, the median survival time ranges from 4 to 6 months; with surgery and radiation, the median survival time may exceed 6 months3. A major reason for these poor results is the recurrent growth of tumors at the site of resected lesions, as well as the development of multiple metastases in and outside of the brain4. A better understanding of the biology of brain metastasis is clearly needed.

The pathogenesis of a metastasis The process of tumor metastasis is highly selective and consists of a series of sequential, interrelated steps. To produce clinically relevant lesions, metastatic cells must complete all steps of this process. After the initial transformation and growth of cells, vascularization must occur if a tumor mass is to exceed 1 mm3 in diameter. The synthesis and secretion of several proangiogenic factors by tumor and host cells and the absence of antiangiogenic factors play a key role in establishing a capillary network from the surrounding host tissues. Next, local invasion of the host stroma occurs as a consequence of the enhanced expression of a series of enzymes (i.e., collagenase). Once the invading cells penetrate the lymphatic or vascular channels, they may grow there, or a single cell or clumps of cells may detach and be transported within the circulatory system. The tumor emboli must survive immune and nonimmune defenses and the turbulence of the circulation and then arrest in the capillary bed of receptive organs, extravasate into the organ parenchyma, proliferate, and establish a micrometastasis. Growth of these microscopic lesions requires development of a vascular supply and evasion of host defense cells. When the

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metastases grow, they can shed tumor cells into the circulation, producing metastasis of metastases5, 6. The outcome of the metastatic process depends on multiple and complex interactions of metastatic cells with host homeostatic mechanisms5 –7. Clinical observations of cancer patients and studies with experimental rodent tumors have concluded that certain tumors produce metastasis to speciﬁc organs that is independent of vascular anatomy, rate of blood ﬂow, and the number of tumor cells delivered to each organ. Indeed, the distribution and fate of hematogenously disseminated, radiolabeled melanoma cells in experimental animals conclusively demonstrated that tumor cells can reach the microvasculature of many organs, but growth in the organ parenchyma only occurred in speciﬁc organs8 –11. More than a century ago, Stephen Paget questioned whether the organ distribution of metastases produced by different human neoplasms was due to chance and analyzed more than 1,000 autopsy records of women with breast cancer. His research documented a nonrandom pattern of metastasis, suggesting that the process was not due to chance but rather, that certain tumor cells (the “seed”) had a speciﬁc afﬁnity for the milieu of certain organs (the “soil”). Metastases resulted only when the seed and soil were compatible12. Some 40 years later, J. Ewing challenged Paget’s “seed and soil” theory and hypothesized that metastatic dissemination occurs by purely mechanical factors that are a result of the anatomical structure of the vascular system13. These explanations have been evoked separately or together to explain the metastatic site preference of certain types of neoplasms, i.e., common regional metastatic involvements could be attributed to anatomical or mechanical considerations, such as efferent venous circulation or lymphatic drainage to regional lymph nodes, whereas metastases in distant organs (from numerous types of cancers) are indeed site-speciﬁc10. Early experimental data supporting the “seed and soil” hypothesis of Paget were derived from studies on the preferential invasion and growth of mouse melanoma metastases in speciﬁc organs14. In addition, the introduction of peritoneovenous shunts for palliation of malignant ascites provided an opportunity to study some of the factors affecting metastatic propagation in patients with malignant ascites draining into the venous circulation, with the resulting entry of viable tumor cells into the jugular veins15. Good palliation with minimal complications was reported for 29 patients with ovarian cancer. The autopsy ﬁndings in 15 patients substantiated the clinical observations that the shunts do not signiﬁcantly increase the risk of metastasis. In fact, despite continuous entry of millions of tumor cells into the circulation, metastases in the lung (the ﬁrst capillary bed encountered) were rare15. A current deﬁnition of the “seed and soil” hypothesis consists of three principles. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties5, 7, 16, 17. Second, the process of metastasis is selective for cells that succeed

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in invasion, embolization, survival in the circulation, arrest in a distant capillary bed, and extravasation into and multiplication within the organ parenchyma9, 18–20. Although some of the steps in this process contain stochastic elements, as a whole, metastasis favors the survival and growth of a few subpopulations of cells that preexist within the parent neoplasm19, 21. Thus, metastases can have a clonal origin, and different metastases can originate from the proliferation of different single cells9, 21, 22. Third, the outcome of metastasis depends on multiple interactions (“cross-talk”) of metastatic cells with homeostatic mechanisms, which the tumor cells can usurp7, 8.

In vivo models for studying the biology of brain metastasis To better understand the biology of cancer metastasis to the brain, we developed a murine model in which tumor lesions in the brain were produced by the injection of metastatic cells into the internal carotid artery of anesthetized mice. In this model, the high incidence of brain lesions and the low incidence of visceral lesions allowed for the study of the pathogenesis of brain tumors and especially, brain metastases. To develop a model of brain metastasis, we injected tumor cells such as murine melanoma cells, which have a high metastatic potential23, into the carotid arteries of syngeneic mice. In parallel experiments, we introduced the tumor cells into the cerebrum by direct implantation to verify that these cells, once in the brain, could proliferate into grossly visible lesions. Unlike that of rats24, the common carotid artery of mice is too short to allow proper injection of cells without leakage into surrounding tissues, and so we resorted to a specialized injection technique by introducing cells into the external or internal carotid artery25, 26. Mice were anesthetized by intraperitoneal (i.p.) injection of sodium pentobarbitol, restrained on a cork board on their backs, and placed under a dissecting microscope. The carotid artery was prepared for an injection distal to the point of its division into the internal and external carotid arteries. A ligature of 5–0 silk suture was placed in the distal part of the common carotid artery. A second ligature was placed and tied loosely proximal to the injection site. A sterile cotton tip applicator was inserted under the artery just distal to the injection site to elevate the carotid artery. The procedure controlled bleeding from the carotid artery by regurgitation from distal vessels. The artery was nicked with a pair of microscissors, and a < 30-gauge glass cannula was inserted into the lumen. To assure proper delivery, the cells were injected slowly, and the cannula was removed. The second ligature was tightened, and the skin was closed by sutures. Because the injection of cells into the carotid artery of nude mice simulates the hematogenous spread of tumor emboli to the brain, we used the technique to examine the last steps of the metastatic process: release of tumor cells into the circulation, arrest in capillaries, penetration and extravasation into the brain through the blood-brain barrier, and continuous growth of cells in the brain tissue27.

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The internal carotid artery supplies the brain parenchyma whereas the external carotid artery supplies the musculature and glands in the head and neck region as well as the meninges. For this reason, we ﬁrst examined whether the injection into the internal or external carotid would inﬂuence the growth of tumor cells in the brain. For the highly metastatic K-1735 melanoma cells, both routes of injection resulted in the development of highly melanotic lesions in the brain parenchyma. Distant metastases developed in the lungs and heart, but the mice died from the brain lesions28. In some syngeneic C3H/HeN mice, tumor cells injected into the external carotid artery produced tumors in the neck and cheek. The injection of nonmetastatic K-1735 cells23 into the internal, but not the external, carotid artery produced melanotic lesions in the brain parenchyma28. The nonmetastatic K-1735 cells die rapidly in the circulation29–31, which may partly explain the absence of extracranial lesions.

Metastasis of murine melanomas to the brain parenchyma or meninges Malignant melanoma will produce metastases in the brains of most patients32. Of these brain metastases, 49% will be intraparenchymal, 22% will be leptomeningeal, and 32% will be dural in location32–34. To determine whether this distribution pattern is random or speciﬁc, we used cells from the K-1735 melanoma (syngeneic to C3H/HeN mice)23 and the B16 melanoma (syngeneic to C57BL/6 mice)35. Regardless of whether we injected the melanoma cells into the external or internal carotid arteries, the K-1735 cells produced melanotic lesions only in the brain parenchyma of 151 of 167 mice receiving injections, and the B16 cells produced lesions only in the meninges and ventricles of 49 of 49 mice receiving injections via either the internal or external carotid artery. The unique patterns of experimental brain metastases were therefore not due to the circulatory system of the brain36, 37. Studies on the distribution and fate of hematogenously disseminated radiolabeled tumor cells have concluded that, although tumor cells can reach the microvasculature of many organs, the growth of the arrested cells into clinically relevant metastases occurs in only some31. Subsequent to the injection of radiolabeled murine melanoma cells into the internal carotid artery, we found that most cells were trapped in the vasculature of the brain. For both types of melanomas, only a few cells reached the meninges. The K-1735 cells failed to proliferate at this site, but the B16 cells grew rapidly28. These data conﬁrm that initial tumor cell arrest in the microvasculature did not correlate with the development of progressively growing metastases28, 31, 38.

Regulation of site-speciﬁc brain metastasis To determine the mechanisms that regulate the site-speciﬁc brain metastasis of murine melanomas, we transfected the K-1735 and B16 melanoma cells

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with DNA from plasmids pSV2neo or pSV2hygro, which confer resistance to the drugs neomycin and hygromycin, respectively. Somatic cell hybrids between the B16 and K-1735 cells were obtained by fusion. Cells of the K1735/K-1735 hybrids produced lesions only in the brain parenchyma of mice, whereas B16/K-1735 hybrids produced lesions only in the meninges and the ventricles. Subsequent to intracarotid injection, tumor cells must ﬁrst reach the microvasculature of the brain, arrest, extravasate into the organ parenchyma, and then proliferate into lesions of measurable size. Theoretically, the differences in site-speciﬁc brain metastasis observed between the different melanomas could be due to different behaviors at different steps of the metastatic process. Using the two melanoma cell lines and several somatic cell hybrids, we searched for differences in cell arrest, extravasation, and growth that could account for the presence or absence of brain parenchymal metastases26. The arrest of tumor cells in the capillary bed is regulated by multiple factors that include adhesion molecules and the size of circulating emboli39, 40. The expression of cell-surface CD44 antigen has been shown to play a role in organ-speciﬁc homing of lymphocytes41. This molecule binds to components of the extracellular matrix such as ﬁbronectin, hyaluronate, and collagen (types I and IV)41– 43. Although the expression of CD44 antigen on mouse or human melanomas has been shown to correlate with metastatic potential42, 43, neither the expression of cell-surface CD44 antigen nor the formation of homotypic aggregates correlated with initial cell arrest as measured by using [125I] iododeoxyuridine-labeled tumor cells. Hence, initial cell arrest in brain parenchyma or meninges did not predict the development of metastases26, 30. Once tumor cells arrest in a capillary bed, they can extravasate into the organ parenchyma. Increased cell motility44 and production of degradative enzymes facilitate this process45 – 47. Although we did not ﬁnd signiﬁcant differences in the motility of the melanoma cells, we found signiﬁcant differences in collagenase IV activity among the different cell types. The B16 cells did not produce measurable gelatinase A activity, whereas the K-1735 cells did. However, even though both B16/K-1735 hybrid cells (meninges) and K-1735/K-1735 hybrid cells (brain parenchyma) produced similar high levels of gelatinase A activity, this did not explain why the B16 melanoma (or hybrid) cells failed to grow in the brain parenchyma26. Because the growth of cells at a metastatic site is essential to the development of measurable lesions, we studied the tumorigenic properties of the melanomas subsequent to direct intracerebral injection. Both B16 and B16/K1735 hybrid cells grew in the brain parenchyma. The B16 cells produced welldeﬁned lesions, whereas the B16/K-1735 hybrid cells were invasive, probably because they produced gelatinases. Subsequent to inoculation of the cells into the cisterna magna, all cell types grew rapidly on the leptomeninges. B16 cells did not inﬁltrate the brain parenchyma, whereas all other cell types did. Because the B16 and B16/K-1735 hybrid cells did not proliferate in the brain parenchyma (except after direct intracerebral injection), it suggested the

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absence of stimulatory growth factors or the presence of inhibitory growth factors in the microenvironment48. The various melanomas were next cultured in the presence of several growth factors49. However, the presence of epidermal growth factor (EGF), basic ﬁbroblast growth factor (FGF), or platelet-derived growth factor (PDGF) did not inﬂuence growth of any of the cell lines tested. Signiﬁcant differences were found when the cells were cultured with transforming growth factor beta (TGF-β). In addition to its effects on cell proliferation50 and differentiation51, TGF-β also regulates many biological processes such as glycolysis52, angiogenesis53, extracellular matrix metabolism54, and protein phosphorylation55. TGFβ is also functionally interactive with hormones56 and growth factors such as EGF57, PDGF58, and bFGF59, suggesting a signal-transducing role for TGF-β. Both TGF-β1 and TGF-β2 stimulated the growth of K-1735 and K-1735/ K-1735 hybrid cells but inhibited the growth of both B16 and B16/K-1735 hybrid cells. Previous reports have shown that the level of TGF-β binding to its receptors on tumor cells correlates with growth inhibition60, 61. Indeed, TGF-β bound to B16 and B16/K-1735 cells at a higher level than to K-1735 cells alone. Because the concentration of TGF-β2 is high in the brain62– 65, our ﬁndings suggest that the failure of B16 or B16/K-1735 hybrid cells to produce intraparenchymal brain metastases could be due to their sensitivity to growth inhibition by TGF-β.

Production of brain metastases by human melanoma cells injected into nude mice To determine whether human melanoma cells also produced metastases at speciﬁc sites in the brain, we examined the ability of human melanoma cells from eight different lines to cross the blood-brain barrier and proliferate in the brains of nude mice30, 66. The human cell lines were established from melanoma metastases at subcutaneous, lymph node, or brain parenchymal sites. All but one human melanoma cell line produced experimental brain metastases after its intracarotid injection into nude mice. The melanoma metastases were found in the meninges, ventricles, and parenchyma, and each melanoma cell line showed a slightly different pattern of growth. One striking feature, however, was that two cell lines derived from two different brain parenchyma metastases from different patients showed a preference for growth in the brain parenchyma. The cell lines derived from lymph node lesions or subcutaneous metastases of patients grew more frequently in the meninges or ventricles than in the brain parenchyma of the nude mouse. The biological behavior of different human melanoma cell lines and cells isolated from fresh surgical specimens of cutaneous melanoma, lymph node metastases, and brain metastases was determined subsequent to intracisternal implantation in nude mice66. Mice anesthetized by i.p. injection of pentobarbital were restrained on a cork board in a prone position, their limbs were

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immobilized with adhesive tape, and they were placed under a dissecting microscope. The skin was prepared for surgery with alcohol-iodine, a transverse skin incision was made just behind the lambdoid suture, and the fascia was incised. Occipital muscles (musculus proprius cervicalis) were dissected away from the occipital bone to expose the atlantooccipital membrane. A tumor cell suspension of 1 × 104 to 1.5 × 106 cells in a 50–100 μl volume was injected into the cisterna magna using a 30-gauge needle. The fascia and skin were closed with a 5–0 nylon suture66. Melanoma cells isolated from cutaneous lesions or lymph node metastases produced leptomeningeal disease but did not invade the brain parenchyma, whereas cells isolated from brain metastases produced leptomeningeal disease and inﬁltrative intraparenchymal lesions66. Like other neoplasms, human melanomas consist of heterogeneous populations of cells with differences in properties such as growth rate, growth factor receptors, enzyme production, angiogenesis induction, immunogenicity, and response to anticancer agents5. In this study, direct intracisternal injection of tumor cells determined the tumorigenicity of the cells in the leptomeninges, and all the types of melanoma cells, regardless of origin, produced leptomeningeal disease. In contrast, all cells isolated from brain metastases produced parenchymal lesions, as did cells that originated from a cutaneous metastasis. This pattern of metastasis follows previously established patterns, showing that the organ site of a metastasis is independent of vascular anatomy and the number of cells delivered5, 31. The “seed and soil” hypothesis of Paget suggested that metastases result from the interaction of speciﬁc tumor cells with the environment of certain organs12. The ﬁnding that melanoma cells that give rise to multiple lung metastases do not also give rise to brain parenchyma metastases supports Paget’s hypothesis and suggests that metastases to different organs may be produced by different metastatic cells. Melanoma lesions in the brain were associated with cells that invaded via the Virchow-Robin space surrounding blood vessels and directly connected to the subarachnoid space. Tumor cell invasion is enhanced by increased motility67, 68 and production of degradative enzymes69 –72; however, under the in vitro conditions used in these studies, signiﬁcant differences in motility or production of gelatinase activity among the cell lines were not found. Whether the brain parenchyma per se can upregulate the expression of these phenotypes in some, but not all, melanoma cells73 remains unclear. Because the concentration of TGF-β2 is high in the brain62–65, we tested the response of the different human melanoma cell types to this regulatory cytokine and found that the ability of human melanoma cells to grow in the brain parenchyma is inversely correlated with their sensitivity to the antiproliferative effects of TGF-β2. One interpretation of this result is that the brain-metastases-derived cell lines were already selected (in the patient) for the ability to proliferate in the presence of TGF-β2. These data are in close agreement with those derived from the use of murine melanoma cells in similar experiments26.

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The origin of brain metastases Clinical observations have suggested that brain metastases produced by many solid tumors occur late in the disease74 and have raised the question of whether brain metastases are produced by cells populating lymph node or visceral metastases, i.e., metastasis of metastases. Indeed, it has been proposed that metastasis by solid tumors occurs by the initial spreading of cells to a generalizing site, such as regional lymph nodes, where malignant cells proliferate and then spread to additional organs. This process has been termed the “metastatic cascade”11, 75. One consequence of this process is that metastasis can occur after a primary lesion has been surgically removed because the generalizing site remains intact76. For the pathogenesis of brain metastasis, this is not an academic issue. If brain metastasis occurs by the metastasis of metastases, then aggressive, prophylactic resection of lymph node or visceral metastases may reduce the risk of development of fatal brain lesions. On the other hand, if brain metastasis occurs by the direct propagation of specialized metastatic cells from the primary lesion77, 78, then prophylactic dissection of extracranial metastases may not prevent brain metastasis from occurring. Thus, it is important for neurooncologists to determine whether or not brain metastasis represents shedding from generalizing site metastases or the primary tumor. One surrogate for that determination is the metastatic potential of the cells. We studied the correlation between the formation of brain metastasis and the malignant growth potential of seven human melanoma cell lines, isolated from lymph node metastases or from brain metastases, and the potential of three variants of the mouse K-1735 melanoma79. Growth rates in different concentrations of fetal bovine serum and colony-forming efﬁciency in semisolid agarose were measured, and the tumorigenicity and metastatic ability were determined in nude mice (for the human melanoma cell lines) or in syngeneic mice (for the K-1735 variants). The ability to form brain metastasis was tested by injection of cells into the carotid artery. A high colony-forming efﬁciency for these cell lines in agarose, especially at concentrations of agarose greater than 0.6%80, corresponded with high tumor take rates, rapid tumor growth rates, and metastatic colonization of the lungs of the recipient mice79. For the human melanomas, the lymph node metastasis-derived cells were more tumorigenic and metastatic than the brain metastasis-derived cells. In the K-1735 mouse melanoma, the tumorigenic and metastatic behavior of the cells after intravenous (i.v.) and subcutaneous (s.c.) injection corresponded with growth in agarose cultures79, 80. However, for growth in the brain after intracarotid injection, the different melanoma cell lines showed similar frequencies of tumor take, regardless of tumorigenicity at other sites of the recipient mice, although mice given injections of brain metastasis-derived cells survived longer than mice given injections of lymph node metastasis (human melanoma)-derived or lung metastasis (K-1735)-derived cell lines. The results from the human and mouse melanoma cell lines show that the brain metastasis-derived cell lines were not more malignant than the lymph node metastasis- or lung metastasis-

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derived cells. Thus, the data imply that the production of brain metastasis is not always the ﬁnal stage of a metastatic cascade79.

Unique patterns of brain metastasis produced by different human carcinomas Human tumor cell lines from 8 different carcinomas of the colon, breast, kidney, and lung (two from each tissue type) were separately injected into athymic mice, either by a direct intracerebral route or via the internal carotid artery. All carcinoma cell types invaded the brain through the blood-brain barrier and produced progressively growing lesions in the brain parenchyma. Unique patterns of growth were discernible among the carcinomas. Subsequent to direct intracerebral injection, all the human carcinoma cell lines grew in the brains of nude mice, thus demonstrating that if carcinoma cells can reach the brain parenchyma, they can proliferate there. Most mice with human carcinoma cells injected into the internal carotid artery developed lesions in the brain. There was more tumor growth in the parenchyma than in other regions of the brain, with lesions distributed throughout the right hemisphere (the side of injection) and, in some instances, in the left hemisphere and in the cerebellum. The seeding of tumor cells in the brain parenchyma reveals that some cells from all of the carcinoma cell lines were able to cross the blood-brain barrier36, 81. Discrete colony formation by the colon carcinomas was seen in both of the cell lines that were injected. Notable was the growth by extension via the corpus callosum to the left hemisphere subsequent to injection of tumor cells into the right hemisphere. This result demonstrates a possible mechanism of secondary metastasis within the brain, leading to undetected satellite micrometastases at the time of diagnosis and surgery that could give rise to early recurrences of tumors close to the surgical cavity82. Clinical data show that the length of the latent period between the diagnosis of a primary tumor and its cerebral metastasis varies greatly83. Short intervals are common for cerebral metastases of lung carcinomas, whereas longer latent periods of several years have been reported for breast carcinoma brain metastases83, 84. In our study, the breast carcinoma cell lines lacking estrogen receptors produced brain tumors within two months after injection by either route. The longest time for the development of brain lesions was seen in mice injected intraarterially with the estrogen-responsive MCF-7 breast carcinoma cell line. The recipient mice that were not given estrogen supplements survived for up to 6 months before succumbing to the cerebral tumors. In mice given estrogen supplements and killed within 60 days after injection, MCF-7 lesions grew rapidly at extracerebral sites following intraarterial (i.a.) injection, but no tumors were detected in the brain. In mice that did not receive estrogen and survived 200 days, metastases grew more slowly and were found only in the brain. Brain tissue can concentrate more estrogen than subcutaneous tissues85. This observation, together with the more recent ﬁndings that breast carcinoma

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cells produce autocrine growth factors whose production is modulated by estrogen86, 87, may explain how the MCF-7 cells were able to remain viable and gradually proliferate in the brain while cells arrested in other sites did not proliferate in the absence of additional estrogen. Brain metastases develop in approximately 6% of patients with renal cell carcinoma, and the lesions are usually highly vascularized88. In our study, the brain metastases of a human renal cell carcinoma in nude mice were highly vascularized. The function of the blood-brain barrier in metastases of different human tumors and the relationship to the degree of vascularization are important issues, especially with regard to drug treatment of brain tumors89. We demonstrated that the function of the blood-brain barrier in mouse melanoma and ﬁbrosarcoma brain metastases resulting from i.a. injection was unimpaired90. Thus, the nude mouse can be very useful for studies on the bloodbrain barrier of human tumor metastases.

Angiogenesis and brain metastasis The growth and spreading of neoplasms depends on the establishment of adequate blood supply, i.e., angiogenesis91–94. The onset of angiogenesis is determined by the balance between proangiogenic and antiangiogenic molecules at the local tissue level91–94. Angiogenesis can occur by either sprouting or nonsprouting processes95. Sprouting angiogenesis occurs by the branching (true sprouting) of new capillaries from preexisting vessels. Nonsprouting angiogenesis results from the enlargement, splitting, and fusion of preexisting vessels produced by the proliferation of endothelial cells within the wall of a vessel. Transcapillary pillars (or transluminal bridges) are sometimes observed in enlarged vessels produced by nonsprouting angiogenesis95. This type of angiogenesis can occur concurrently with sprouting angiogenesis in the vascularization of organs or tissues such as the lung, heart, and yolk sac during development95. The mechanism of nonsprouting angiogenesis in metastasis is not yet known, but vascular endothelial growth factor (VEGF), also called vascular permeability factor (VPF), which plays a pivotal role in developmental, physiological, and pathological neovascularization96 –99, is a candidate effector. VEGF stimulates the proliferation and migration of endothelial cells and induces the expression of metalloproteinases and plasminogen activator activity in these cells100 –103. Moreover, overexpression of VEGF in tumor cells enhances tumor growth and metastasis in several animal models by stimulating vascularization (increased microvessel density)104 –106. We investigated the molecular mechanisms of angiogenesis in experimental brain metastasis. Six different human cancer cell lines (proven to produce visceral metastasis) were tested separately by injection into the internal carotid artery of nude mice. Colon carcinoma cells (KM12SM) and lung adenocarcinoma cells (PC14PE6, PC14Br) produced large, fast-growing parenchymal brain metastases, whereas cell lines from lung squamous cell carcinoma (H226), renal cell carcinoma (SN12PM6), and melanoma (TXM13) produced

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only a few slow-growing brain metastases107. Rapidly progressing brain metastases contained many enlarged blood vessels. The expression of VEGF mRNA and protein by these six tumor cell lines directly correlated with the observed extent of angiogenesis and the growth rate of brain metastases they produced. Causal evidence for the essential role of VEGF in this process was provided by transfecting human lung cancer cells and colon cancer cells with the antisense form of the VEGF165 gene, which signiﬁcantly decreased the incidence of brain metastasis. In contrast, transfection of human lung squamous cell carcinoma cells with the sense form of the VEGF121 gene or the VEGF165 gene neither enhanced nor inhibited formation of brain metastases. Collectively, the results indicate that VEGF expression is necessary but not sufﬁcient for the production of brain metastasis and that the inhibition of VEGF represents an important therapeutic target107.

The blood-brain barrier in brain metastasis The microvasculature of the brain parenchyma is lined with a continuous, nonfenestrated endothelium that has tight junctions and little pinocytotic vesicle activity81, 108 –110. This structure, designated as the blood-brain barrier, limits the entrance of circulating macromolecules into the brain parenchyma. The blood-brain barrier and the lack of a lymphatic system are responsible for maintaining the brain as an immunologically privileged site36, 111–112 and protecting the brain against the entry of most drugs and invasion by microorganisms113. The blood-brain barrier does not prevent the invasion of the brain parenchyma by circulating metastatic cells. In fact, the integrity of the blood-brain barrier is altered in some brain tumors and in metastases114 –122. Indeed, some, but not all, neoplastic cells can affect the integrity of this structure115, 116, 123, 124. In general, primary brain neoplasms and brain metastases are resistant to treatment by most chemotherapeutic drugs2, 112, 113, and this resistance has been attributed to the inability of drugs to cross the blood-brain barrier125–127. However, because this structure is morphologically, biochemically, and functionally heterogeneous in different regions of the brain81, 110, 128 –130, its relationship to the failure of anticancer drugs to eradicate brain metastases is still unclear. We investigated the functional viability of the blood-brain barrier in experimental brain metastases using the experimental animal model to study the establishment, progression, and therapy of brain metastases25, 26, 90. Eight different human tumor cell lines were tested separately by inoculation into the internal carotid artery of nude mice. These cell lines produced lesions in different regions of the brain; these varied in appearance from diffuse to discrete with well-deﬁned margins. Of several molecular tracers that have been used to study the permeability of the blood-brain barrier, we chose sodium ﬂuorescein. Despite its low molecular weight (MW 376), this hydrosoluble molecule is excluded from the brain by an intact blood-brain barrier131, 132. Sodium ﬂuorescein is not sensitive to minor or transient changes in blood-brain barrier

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permeability, and unlike horseradish peroxidase, it is not transported into brain tissue by nonspeciﬁc endocytosis133. This molecule is therefore most suitable for studies of blood-brain barrier functions in brain metastases. Before studying the function of the blood-brain barrier in such brain lesions, we ruled out the possibilities that the procedure of intracarotid injection (which is followed by ligation of the artery) or the entry of a bolus of tumor cells into the brain, damages the endothelial cells of the cerebromicrovessels and thus, changes the permeability of the blood-brain barrier134. Leakage through the blood-brain barrier may be due to endothelial alterations brought about by tumor cells in the perivascular space135. Several ultrastructural studies concluded that brain tumors disrupt adjacent endothelium115, 136. In our study with eight different human tumor cell lines, the lesions in the brain parenchyma were either well demarcated with welldeﬁned margins, or they were diffuse lesions throughout a region of the parenchyma. We found that the solitary well-deﬁned lesions had a lower density of blood vessels than is seen in normal brain tissue. The blood-brain barrier is known to become permeable in ischemic regions of the brain where increased endothelial pinocytosis, opening of the interendothelial tight junctions, and damage to endothelial cells have all been observed136, 137. We found that degeneration and central necrosis often occurred in large (> 0.5 mm in maximum diameter, 0.2 mm2 in cross-sectional area) brain metastases. In these lesions, therefore, damage to endothelial cells may compromise the integrity of the blood-brain barrier. The diffusion coefﬁcient of oxygen within tissues is on the order of 150– 200 μm138, 139. Immunostaining of sections with anti-bromodeoxyuridine (BrdU) antibodies allowed us to detect the presence of viable tumor cells (undergoing DNA synthesis) and determine their proximity to blood vessels; tumor cell viability and proximity to blood vessels directly correlated with each other. We base this conclusion on two lines of evidence. First, all viable cells undergoing DNA synthesis (showing positive BrdU staining) were located within 100 μm from a blood vessel. Second, tumor cells located at distances greater than 100 μm from a blood vessel were positive by the terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay, i.e., undergoing apoptosis. We have previously reported that the blood-brain barrier was intact in established mouse ﬁbrosarcoma brain metastases90. Two human melanoma cell lines produced the same phenomenon. The characteristic common to these mouse and human brain metastases was their diffuse pattern of growth. The permeability of the blood-brain barrier in these lesions was not increased relative to that of normal brain tissue unless the tumor cell clusters coalesced to form large tumor masses. Studies using the transplantation of quail avascularized embryonic mesodermal tissue into the brains of chick embryos11 and an in vitro study of endothelial cell-astrocyte interactions140 demonstrated that signals arising within the brain, rather than a programmed commitment of the endothelial cells, are responsible for the function of the blood-brain barrier. The integrity of the barrier around small lesions (metastases) shows that the

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barrier can repair itself after passage of metastatic cells into the brain parenchyma. Moreover, the interactions of astrocytes with endothelial cells and with elongated cytoplasmic processes of oligodendrocytes are likely to be important in maintaining a functional blood-brain barrier81. A growing tumor mass may disturb this interaction, especially if it depends on contact between astrocytes and endothelial cells. Indeed, the normal brain tissue interspersed among the small tumor clusters or surrounding small tumor lesions might be responsible for the normal function of the blood-brain barrier. In any event, because the blood-brain barrier is not intact in experimental brain metastases that exceed 0.2 mm2 in cross-sectional area, the resistance to chemotherapy may be due to other mechanisms.

Summary The development of a relevant mouse model for studying the establishment and growth of brain metastasis has been extremely useful for studies of the biology and therapy of this fatal aspect of cancer. Injection of murine or human tumor cells into the internal carotid artery of syngeneic or nude mice produces tumor growth in speciﬁc regions of the brain. This site-speciﬁc metastasis is not due to patterns of initial cell arrest, motility, or invasiveness, but rather to the ability of metastatic tumor cells to proliferate in the brain parenchyma, ventricles, or the meninges. Analysis of the malignant behavior of several human melanoma cell lines isolated from brain or visceral metastases revealed that cells from brain metastases have a slower growth rate and exhibit lower metastatic potential than tumor cells isolated from visceral metastases. These data suggest that brain metastases do not necessarily represent the end stage in the metastatic cascade, i.e., brain metastases do not necessarily develop as a consequence of “metastasis of a metastasis”. Rather, brain metastases are likely to originate from a unique subpopulation of cells within the primary neoplasm. The blood-brain barrier is intact in and around brain metastases that are smaller than 0.25 mm in diameter. Although the blood-brain barrier is leaky in larger metastases, the lesions are resistant to many chemotherapeutic drugs. How the brain microenvironment modiﬁes the phenotype of metastatic cells, including resistance to chemotherapy, is the subject of intense investigation.

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87 Goustin AS, Leof EB, Shipley GD, et al.: Growth factors and cancer. Cancer Res 1986; 46: 1015–1029. 88 Gay PC, Litchy WJ, Carcino TL: Brain metastasis in hypernephroma. J Neurooncol 1987; 5: 51–56. 89 Groothuis DR, Fischer JM, Lapin G, et al.: Permeability of different experimental brain tumor models to horseradish peroxidase. J Neuropathol Exp Neurol 1982; 41: 164 –185. 90 Schackert G, Simmons RD, Buzbee TM, et al.: Macrophage inﬁltration into experimental brain metastases: occurrence through an intact blood-brain barrier. J Nat Cancer Inst 1988; 80: 1027–1034. 91 Folkman J: Clinical applications of research on angiogenesis. N Engl J Med 1995; 333: 1757–1763. 92 Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991; 64: 327–332. 93 Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353 –364. 94 Harris AL: Anti-angiogenesis therapy and strategies for integrating it with adjuvant therapy. Cancer Res 1998; 152: 342–352. 95 Risau W: Mechanisms of angiogenesis. Nature 1997; 386: 671– 674. 96 Ferrara N: The role of vascular endothelial growth factor in the regulation of blood vessel growth. In Bicknell R, Lewis CE, Ferrara N (eds): Tumor Angiogenesis. New York, NY, Oxford, 1997, pp. 185–199. 97 Carmeliet P, Ferreira V, Breier G, et al.: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380: 435– 439. 98 Ferrara N, Carver-Moore K, Chen H, et al.: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380: 439 – 442. 99 Senger DR, Galli SJ, Dvorak AM, et al.: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites ﬂuid. Science 1983; 219: 983 –985. 100 Ferrara N, Henzel WJ: Pituitary follicular cells secrete a novel heparin-binding growth factor speciﬁc for vascular endothelial cells. Biochem Biophys Res Commun 1989; 161: 851–859. 101 Pepper MS, Ferrara N, Orci L, et al.: Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor type 1 in microvascular endothelial cells. Biochem Biophys Res Commun 1991; 181: 902–908. 102 Unemori E, Ferrara N, Bauer EA, et al.: Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 1992; 153: 557–562. 103 Kumar R, Yoneda J, Bucana CD, et al.: Regulation of distinct steps of angiogenesis by different angiogenic molecules. Int J Oncol 1998; 12: 749 –757. 104 Cheng SY, Nagane M, Huang HS, et al.: Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF121 and VEGF165 but not VEGF189. Proc Natl Acad Sci USA 1997; 94: 12081–12087. 105 Oku T, Tjuvajev JG, Miyagawa T, et al.: Tumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: effects on angiogenesis, vascular permeability, blood volume, blood ﬂow, ﬂuorodeoxyglucose uptake, and proliferation of human melanoma intracerebral xenografts. Cancer Res 1998; 58: 4185 – 4192. 106 Claffey KP, Brown LF, del Aguila LF, et al.: Expression of vascular permeability factor/ vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res 1996; 56: 172–181. 107 Yano S, Shinohara H, Herbst RS, et al.: Expression of vascular endothelial growth factor is necessary but not sufﬁcient for production and growth of brain metastasis. Cancer Res 2000; 60: 4959–4967.

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108 Johansson BB: The physiology of the blood-brain barrier. Adv Exp Med Biol 1990; 274: 25–39. 109 Gregoire N: The blood-brain barrier. J Neuroradiol 1989; 16: 238 –250. 110 Pardridge WM, Oldendorf WH, Cancilla P, et al.: Blood-brain barrier: interface between internal medicine and the brain. Ann Intern Med 1986; 105: 82–95. 111 Medawar PB: Immunity to homologous grafted skin: III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 1948; 29: 58 – 69. 112 Scheinberg LC, Edelman FL, Levy WA: Is the brain “an immunologically privileged site”? Arch Neurol 1964; 11: 248 –264. 113 Shapiro WR, Shapiro JR: Principles of brain tumor chemotherapy. Semin Oncol 1986; 13: 56–69. 114 Debbage PL, Gabius HJ, Bise K, et al.: Cellular glyco-conjugates and their potential endogenous receptors in the cerebral microvasculature of man: a glycohistochemical study. Eur J Cell Biol 1988; 46: 425 – 434. 115 Steward PA, Hayakawa K, Farrell CL, et al.: Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood-brain barrier defect. J Neurosurg 1987; 67: 697–705. 116 Zagzag D, Goldenberg M, Brem S: Angiogenesis and blood-brain barrier breakdown modulate CT contrast enhancement: an experimental study in a rabbit brain-tumor model. AJR Am J Roentgenol 1989; 153: 141–146. 117 Iannotti F, Fleschi C, Alfano B, et al.: Simpliﬁed, noninvasive PET measurement of blood brain barrier permeability. J Comput Assist Tomogr 1987; 11: 390 –397. 118 Front D, Israel O, Kohn S, et al.: The blood-tissue barrier of human brain tumors: correlation of scintigraphic and ultrastructural ﬁndings: concise communication. J Nucl Med 1984; 25: 461–465. 119 Kohn S, Front D, Nir I: Blood-brain barrier permeability of human gliomas as determined by quantitation of cytoplasmic vesicles of the capillary endothelium and scintigraphic ﬁndings. Cancer Invest 1989; 7: 313 –321. 120 Nir I, Levanon D, Iosilevsky G: Permeability of blood vessels in experimental gliomas: uptake of 99Tc-glucoheptonate and alteration in blood-brain barrier as determined by cytochemistry and electron microscopy. Neurosurgery 1989; 25: 523 –532. 121 Coomber BL, Stewart PA, Hayakawa K, et al.: Quantitative morphology of human glioblastoma multiforme microvessels: structural basis of blood-brain barrier defect. J Neurooncol 1987; 5: 299 –307. 122 Vriesendorp FJ, Peagram C, Bigner DD, et al.: Concurrent measurements of blood ﬂow and transcapillary transport in xenotransplanted human gliomas in immunosuppressed rats. J Natl Cancer Inst 1987; 79: 123 –130. 123 Nicolson GL: Organ speciﬁcity of cancer metastasis is determined, in part, by tumor cell properties and cytokines expressed at particular organ sites. Cancer Res 1990; 31: 506–507. 124 Schlingemann RO, Rivetveld FJ, De Wall RM, et al.: Expression of the high molecular weight melanoma-associated antigen by pericytes during angiogenesis in tumors and in healing wounds. Am J Pathol 1990; 136: 1393 –1405. 125 Greig NH: Optimizing drug delivery to brain tumors. Cancer Treat Rev 1987; 13: 1–28. 126 Genka S, Deutsch J, Stahle PL, et al.: Brain and plasma pharmacokinetics and anticancer activities of cyclophosphamide and phosphoramide mustard in the rat. Cancer Chemother Pharmacol 1990; 27: 1–7. 127 Greig NH, Soncrant TT, Shetty HU, et al.: Brain uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and binding to plasma constituents in rat. Cancer Chemother Pharmacol 1990; 26: 263 –268.

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128 Owman C, Hardebo JE: Functional heterogeneity of the cerebrovascular endothelium. Brain Behav Evol 1988; 32: 65 –75. 129 Fenstermacher J, Gross P, Sposito N, et al.: Structural and functional variations in capillary systems within the brain. Ann NY Acad Sci 1988; 529: 21–30. 130 Bauer HC, Tontsch U, Amberger A, et al.: Gamma-glutamyl-transpeptidase (GGTP) and NA+K(+)-ATPase activities in different subpopulations of cloned cerebral endothelial cells: responses to glial stimulation. Biochem Biophys Res Commun 1990; 168: 358 –363. 131 Nakagawa Y, Fujimoto N, Matsumoto K, et al.: Morphological changes in acute cerebral ischemia after occlusion and reperfusion in the rat. Adv Neurol 1990; 52: 21–27. 132 Kawamura S, Schurer L, Goetz A, et al.: An improved closed cranial window technique for investigation of blood-brain barrier function and cerebral vasomotor control in the rat. Int J Microcirc Clin Exp 1990; 9: 369 –383. 133 Malmgren LT, Olsson Y: Differences between the peripheral and the central nervous system in permeability to sodium ﬂuorescein. J Comp Neurol 1980; 191: 103 –117. 134 Zhang R, Price JE, Fujimaki T, et al.: Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol 1992; 141: 1115 –1124. 135 Ballinger WE Jr, Schimpff RD: An experimental model for cerebral metastasis: preliminary light and ultrastructural studies. J Neuropathol Exp Neurol 1979; 38: 19–34. 136 Hirano A, Zimmerman HM: Fenestrated blood vessels in metastatic renal carcinoma in the brain. Lab Invest 1972; 26: 465 – 468. 137 Dietrich WD, Busto R, Hailey M, et al.: The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 1990; 49: 486–497. 138 Brown JM, Giaccia AJ: The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998; 58: 1408 –1416. 139 Tannock IF: The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 1968; 22: 258 –273. 140 Goldstein GW: Endothelial cell-astrocyte interactions: a cellular model of the bloodbrain barrier. Ann NY Acad Sci 1988; 529: 31–39.

CHAPTER 4

Brain metastases: histopathological evaluation and diagnostic pitfalls Teresa Ribalta, Gregory N Fuller

Introduction The central nervous system (CNS) is a common site for metastatic lesions. Although partially protected by the blood-brain barrier and lacking a lymphatic system, it is nevertheless a preferred site for the dissemination for several malignancies. Metastases to the brain are frequent in the elderly, paralleling the increase in solid tumors with increasing age, but are also relatively frequent in childhood secondary to the high incidence of hematologic malignancies in the pediatric age group. The frequency of brain metastases varies widely among published series due to institutional, diagnostic, and geographical biases that inﬂuence statistical evaluation1. There is general agreement, however, that the overall incidence is increasing as a result of two major factors: 1 cancer patients are living longer secondary to signiﬁcant improvements in therapy, and 2 there is a continued increase in the incidence of lung cancer and melanoma, both of which exhibit high rates of dissemination to the CNS2. Metastatic intracranial tumors may initially involve any one of the three principal CNS anatomic compartments: dura, leptomeninges (subarachnoid space), and intra-axial parenchyma. Extension to compartments adjacent to that of the primary focus is common. Isolated intraparenchymal metastasis is more frequent than either purely dural or purely leptomeningeal metastasis, but the combination of meningeal and parenchymal metastasis is common. Hematogenous dissemination is the primary route of propagation to the CNS for most systemic malignancies. However, direct extension (by either primary or secondary tumors) in adjacent bone or epidural space also represents a signiﬁcant source of CNS involvement by extraneural malignancies. Primary CNS tumors can also produce distant, noncontiguous “metastases” via dissemination through the cerebrospinal ﬂuid (CSF) pathways. It should also be noted that several types of primary CNS tumors can occasionally be the source of extraneural metastases, most commonly following an invasive procedure.

55

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Table 4.1 Common sources of central nervous system metastases according to anatomic location of metastasis. Location of metastasis

Tumor origin

References

Cranial bones and epidural space

Lung, breast, prostate, kidney, peripheral neuroblastoma, lymphoma

Meyer and Reah29 1953 Posner and Chernik20 1978

Cranial dura

Breast, lymphoma, prostate, peripheral neuroblastoma

Posner and Chernik20 1978 Tsukada et al.5 1983

Leptomeninges

Adenocarcinoma (lung, breast, stomach), hematologic malignancies, melanoma, medulloblastoma, glioma

Bigner and Schold34 1984

Supratentorial Intra-axial

Lung, breast, skin (melanoma), kidney, colon, choriocarcinoma, sarcoma, unknown primary

Delattre et al.4 1988

Posterior fossa

Colorectal, pelvic organs, kidney

Delattre et al. 1988

Intraparenchymal metastasis of extraneural nonhematologic neoplasms Virtually any systemic malignant tumor may metastasize to the brain. However, by far the most common sources are cancers of the lung, breast, skin (melanoma), the genitourinary tract (renal cell carcinoma), and the digestive tract (colorectal carcinoma)3, 4. These ﬁve types of tumors collectively account for approximately 85% of all metastases to the brain. Melanoma is most prone to develop brain metastases (40%), followed by lung carcinoma (35%), and breast carcinoma (10–30%)5 –7. Among the various types of lung malignancies, small cell carcinoma, large cell carcinoma, and adenocarcinoma metastasize to the brain far more frequently than does squamous cell carcinoma1. No known difference exists between the metastatic frequencies of the ductal and lobular subtypes of breast carcinoma8. Choriocarcinoma, although a relatively rare tumor, exhibits a notable proclivity for CNS metastasis9, 10. Many other systemic malignant neoplasms may produce CNS metastases. A summary of the most frequent sources according to anatomic site of origin and destination within the CNS is provided in Table 4.1. Brain metastasis can occur at any time during the evolution of a systemic neoplasm. Not infrequently, CNS metastasis is responsible for the patient’s initial clinical presentation, and a speciﬁc diagnosis of a systemic malignancy is made based on biopsy or resection of the brain metastasis11–13. Various clinical series have shown that this well-recognized clinical scenario occurs in 16% to 48% of all patients with cerebral metastases3, 12–15. The CNS may represent the sole site of metastasis. In one recent study, the brain constituted the only metastatic site in 50 of 927 patients (5.4%)16. In some cases of isolated CNS metastasis, the primary tumor may be too small to be clinically detected, and the brain lesion represents a very early site of dissemina-

Brain metastases: histopathological evaluation and diagnostic pitfalls

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tion; this is most commonly observed with small cell carcinoma of the lung. At the other end of the temporal spectrum, brain metastases sometimes present more than a decade after resection and apparent “cure” of the primary malignancy. This pattern of late brain metastasis is a rare but well-recognized feature seen with certain tumors, especially renal cell carcinoma17 and melanoma. A proportion of late metastases may appear clinically solitary but are ultimately found to be associated with extensive systemic carcinomatosis18. In terms of sheer numbers, most brain metastases are supratentorial and predominantly involve the gray matter-white matter junction. Tumors of the kidney, colon, and pelvic organs show a relatively high incidence of infratentorial metastasis compared with those from extra-pelvic primary sites4, 19. Brain metastases have an approximately equal tendency to occur in single or multiple form4, 20. Melanoma and carcinomas of lung, breast, kidney, colon, and pelvic organs commonly give rise to multiple metastases but are also the principal sources of solitary metastases5, 20 –22. In one study of a series of 288 patients with brain metastases identiﬁed by computerized tomography (CT) scanning, single metastases of pelvic (prostate or uterus) and gastrointestinal origin were located in the posterior fossa in 50% of cases4. Differences in metastatic pattern can be seen for the same histological type of cancer originating from different organs. For example, brain metastases from choriocarcinoma of the testis are commonly multiple10, whereas gestational choriocarcinoma is most frequently associated with solitary brain lesions23, 24. Although sarcomas metastasize to the brain signiﬁcantly less frequently than carcinomas, most types do have the potential for CNS metastasis. Among sarcomas, alveolar soft-part sarcoma, in particular, is prone to CNS metastasis. There are some data to suggest that CNS metastasis from some types of sarcomas, such as rhabdomyosarcoma and malignant ﬁbrous histiocytoma, may be increasing in incidence secondary to prolonged survival from improved chemotherapeutic regimens25 –27. Similarly, the incidence of metastatic neuroblastoma may also be increasing. In one recent report, the CNS constituted the sole site of disease recurrence in 64% of patients28.

Metastasis to cranial bones and meninges The most frequent tumors that metastasize to the cranium are carcinomas from the lung, breast, prostate, or kidney in adults, and peripheral neuroblastoma in children20, 29. In contrast to vertebral and spinal epidural metastases, which only very rarely transgress the dura1, 30, 31, cranial bone metastases quite frequently invade the dura. This discrepant behavior of cranial versus spinal osseous metastases may be based in part on the close apposition of the dura to the inner table of the cranium32. The breast is the most frequent site of origin of isolated cranial dural metastases in most autopsy series, ranging in incidence from 22% to 26%5, 20. Other tumors that produce cranial dural metastases are lymphomas (16%), prostatic carcinoma (12%), and peripheral extra-adrenal neuroblastoma (11%)20.

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One unique and exceptional form of metastatic dural disease is pachymeningitis interna hemorrhagica, which was ﬁrst described by Meyer and Reah in 195329. This form is characterized by extensive, often bilateral, diffuse dural involvement with subdural hematoma. In the majority of cases presenting with this clinicopathological picture, the metastatic tumor is an adenocarcinoma, most frequently of breast origin33. Leptomeningeal metastasis (meningeal carcinomatosis) may occur in isolation but is far more frequently found in conjunction with parenchymal metastasis. Direct extension from a focus of dural or bone metastatic disease into the leptomeninges and subarachnoid space is relatively rare because the desmosome-rich arachnoid membrane tends to constitute an anatomic barrier. The most common sources of meningeal carcinomatosis are carcinoma of the lung, followed by breast carcinoma and melanoma34. In the presence of leptomeningeal dissemination, tumor cells may be identiﬁed in CSF samples. A common complication of leptomeningeal dissemination is inﬁltration of the segments of cranial nerves that traverse the subarachnoid space, with the speciﬁc clinical deﬁcits depending on the particular nerves inﬁltrated. In the vast majority of cases of leptomeningeal dissemination, the primary site is well established prior to the time of presentation. Leptomeningeal dissemination can also occur in association with primary brain tumors, such as is commonly seen with primitive neuroectodermal tumors and, occasionally, with gliomas (leptomeningeal gliomatosis).

Secondary CNS involvement by lymphoid and hematopoietic neoplasms Most lymphomas and leukemias invade the CNS through seeding of the subarachnoid space. The acute leukemias largely predominate in this respect over the chronic forms. Because of the high rate of subarachnoid space involvement, CSF cytological evaluation is a critical step in the initial evaluation of patients with leukemia, particularly acute lymphocytic leukemia35. Secondary involvement of the CNS by non-Hodgkin’s lymphoma (NHL) is less common than with leukemia. However, as the treatment of lymphoma patients has improved, the incidence of CNS involvement has also increased. The incidence is around 10% in most series36, 37 and is most often seen in the setting of widespread and progressive systemic disease. A majority of NHLs that inﬁltrate the CNS show a diffuse histological pattern36. Burkitt’s lymphoma involves the CNS in almost 50% of cases38, and the endemic form has an even greater incidence39. The CNS or peripheral nerves are involved in up to 30% of cases of lymphomatoid granulomatosis40, 41. Angiotropic (intravascular) lymphoma is a rare form of systemic NHL with predominant skin and neurological manifestations. In many cases, involvement appears to be restricted to the CNS42. Dementia occurs in approximately half of this patient population43. Mycosis fungoides (cutaneous T-cell lymphoma) spreads to the CNS and peripheral nerves in approximately 14% of cases44.

Brain metastases: histopathological evaluation and diagnostic pitfalls

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Metastasis from Hodgkin’s disease (HD) was previously very uncommon (0.5% in a series of 2185 patients published in 1983)45 but is increasingly reported in recent years46. In most instances, the presence of an intracranial tumor is associated with widespread extra-CNS systemic disease. Dural metastases account for a majority of cases. Langerhans’ cell histiocytosis (histiocytosis X) often involves the CNS. Hand-Schüller-Christian disease is the most frequent form,47 and the hypothalamic region is primarily affected. Multiple myeloma usually invades the epidural space directly from adjacent bony lesions48. Subdural or subarachnoid involvement is very unusual. Subarachnoid inﬁltration probably occurs through hematogenous seeding of the meninges.

Macroscopic appearance As mentioned previously, brain metastases are most often supratentorial and located at the gray matter-white matter junction of the cerebral hemispheres, where tumor microemboli are trapped in the distal parts of the superﬁcial arterioles1, 49. Large growths usually reach the surface of the brain and often subsequently invade the overlying leptomeninges. The vascular distribution of the middle cerebral arteries, particularly the arterial border zone (“watershed” area), is the preferred location. Other common sites are the cerebellum and the deep cerebral gray nuclei and white matter. Although these are the most frequent sites, metastatic disease can involve any anatomic locus within the CNS, including the neurohypophysis, choroid plexus1, and pineal gland50. Preexisting intracranial lesions, such as tumors, infarcts, or vascular malformations are rare recipient sites for secondary tumors51–53. Slow growing neoplasms such as meningiomas and pituitary adenomas account for a majority of recipient tumors that harbor metastatic disease. A single case of melanoma metastatic to central neurocytoma, which ﬁts the general pattern of an aggressive systemic neoplasm metastasizing to an indolent CNS tumor, has also been reported54. Conversely, brain metastasis may result in cerebral infarction secondary to the obstruction of cerebral arteries by tumor emboli55, or exceptionally, metastases may present with subdural, subarachnoid, or intraventricular hemorrhage33. Brain metastases, whatever their origin, are characteristically grossly circumscribed, tend to be rounded, and are usually associated with marked peritumoral edema. After cross-sectioning the cut surface of the tumor is typically gray-white and granular. Central, or often more extensive, yellow discoloration due to necrosis is commonly observed. Frank hemorrhage is characteristic of metastatic choriocarcinoma, melanoma, renal cell carcinoma, and lung carcinoma7, 17, 23. Mucinous carcinomas may display an overtly mucoid or gelatinous consistency. Melanotic melanoma metastases can show a variety of gross morphologies depending on the presence and degree of hemorrhage and of melanin, ranging from tan to dark-red to brown to black. Amelanotic metastatic

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melanomas, which give rise to at least one-third or more of CNS metastases, are grossly indistinguishable from other amelanotic metastatic tumors. Leptomeningeal carcinomatosis produces a vague diffuse opaciﬁcation of the leptomeninges, similar in appearance to bacterial meningitis. Subarachnoid space tumor material masks blood vessels, especially at the base of the brain. The cranial nerves may be involved. Concomitant nodules of different sizes are sometimes observed on the leptomeningeal surface and in the brain parenchyma. A diffuse opaciﬁcation of the leptomeninges is also the most common macroscopic alteration in cases of brain involvement by leukemia and lymphoma. Multiple parenchymal hemorrhagic foci may also be observed in leukemic patients who have high numbers of circulating blasts. Inﬁltration of the subarachnoid space by NHL may be relatively circumscribed or diffuse. Diffuse invasion may involve the cranial nerves as they course through the area. Isolated brain parenchymal involvement by secondary NHL is uncommon33. Angiotropic (intravascular) lymphoma usually manifests as multiple ischemic foci in brain parenchyma resulting from occlusion of small- and medium-sized vessels by neoplastic cells. Lymphomatoid granulomatosis can present as single or multiple solid masses, necrotic cavities, meningeal or parenchymal inﬁltrates, infarction, hemorrhage, or aneurysm formation56. Mycosis fungoides invades the meninges more frequently than the parenchyma57. Intracranial deposits of Hodgkin’s disease typically occur in the dura. Multiple myeloma can invade the cranial epidural space and the dura from adjacent bone foci.

Histopathological appearances and most frequent diagnostic pitfalls The circumscription of brain metastatic nodules is only relative. On microscopic examination, small nests and trabeculae of tumor cells at the borders can be seen invading the adjacent nervous tissue for short distances. Direct extension to the leptomeninges is often observed in superﬁcial metastasis to the cerebral convexities and cerebellum. In metastatic tumors adjacent to the ventricles, neoplastic cells may perforate the ependymal lining and disseminate through the CSF. The effects of metastasis on the brain are a combination of tissue destruction produced by tumor cells and host reactive processes occurring around the metastases. Reactive astrocytic and microglial gliosis is commonly found at the periphery of parenchymal metastatic foci. Tumor cells and activated indigenous cellular constituents produce numerous biologically active compounds that can inﬂuence the structure and function of peritumoral brain tissue58. Microvascular proliferation similar to that seen with malignant gliomas is also characteristically observed in and around metastatic deposits, although usually not to the degree or extent seen with glioblastoma. This abnormal vasculature is the cause of the intensive edema present in the parenchymal tissue surrounding metastases. The microscopic appearance of metastases variably recapitulates the morphology of the primary tumor, sometimes so similarly and distinctively as to

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immediately suggest the primary site, as is seen in some cases of metastatic clear cell renal cell carcinoma, heavily pigmented melanoma, or folicular thyroid carcinoma, and at other times, it is quite dissimilar to the primary site. For example, an amelanotic metastasis may arise from a heavily pigmented primary melanoma. The degree of differentiation of the metastatic lesion is also unpredictable and variable, ranging from well-differentiated to so poorly differentiated as to lack even the barest histological feature suggesting the site of origin. Amelanotic melanoma metastases, in particular, may simulate the morphological features of a carcinoma, lymphoma, sarcoma, or primary neuroepithelial tumor. In well-differentiated neoplasms, the origin of the metastasis can often be readily identiﬁed through routine techniques. However, with limited biopsies, extensively necrotic tumors, and poorly differentiated neoplasms, diagnostic difﬁculties often arise. Distinguishing malignant from reactive lesions, primary versus metastatic tumors, and determining the speciﬁc tumor type and organ of origin when the metastatic nature of the tumor is clearly evident are the three principal diagnostic challenges that face the pathologist evaluating a circumscribed lesion in the brain. The two principal ancillary techniques used to identify the site of origin for metastatic tumors are immunohistochemistry and electron microscopy. Immunohistochemical differentiation markers, such as prostate-speciﬁc antigen (PSA), prostatic acid phosphatase (PAP), HMB-45, cytokeratins (CK) 7 and 20, thyroid transcription factor-1 (TTF-1), epithelial membrane antigen (EMA), glial ﬁbrillary acidic protein (GFAP), and various leukocyte markers, among others, are very helpful and routinely used for neuropathological diagnosis of metastases59–61. Electron microscopy may be of assistance via the identiﬁcation of ultrastructural markers of differentiation62. Occasionally, molecular studies may be required for some speciﬁc differential diagnoses63 –70. In most cases, adequate clinical information combined with a thorough morphological examination and judicious application of pertinent ancillary techniques allows the pathologist to make a conﬁdent diagnosis. Nevertheless, there always exists a small but deﬁnite percentage of unknown primary cases in which the site of metastasis origin cannot be determined despite full use of the diagnostic armamentarium, even at autopsy. Two of the tumors most frequently metastatic to the brain and meninges are poorly-differentiated adenocarcinoma of the lungs and high-grade ductal carcinoma of the breast. It is frequently difﬁcult to histologically distinguish between these two types of tumors based on hematoxylin and eosin staining alone71. In such cases, the observation of immunoreactivity for anti-TTF-1 antibody strongly suggests a pulmonary origin60. Coordinate expression of CK7 and CK20 has also proved useful in deﬁning the site of the primary malignancy72–75. CK7/CK20 immunohistochemistry can also be used to differentiate between metastatic carcinoma and primary CNS tumors with epithelial differentiation, such as choroid plexus tumors59 and secretory meningioma76. Pigment-bearing cells in the meninges and brain parenchyma cannot simply be assumed to be melanoma as there are a number of pigmented cell types that can be seen in the CNS, including normal leptomeningeal melanocytes,

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hemosiderin-laden macrophages, neuromelanin-bearing catecholaminergic neurons, and rare primary CNS pigmented tumors. A careful evaluation of the characteristics of nuclei, cytoplasm, and size and distribution pattern of the pigment granules may permit distinction between these different cell types. Immunohistochemistry and electron microscopy may be of help in difﬁcult cases. The subarachnoid space is ﬁlled with neoplastic cells in meningeal carcinomatosis. The predominant histological types in cases of lung metastasis are small cell carcinoma and adenocarcinoma31. Differentiation among morphologically similar metastatic tumors is usually possible when clinical information is available, and speciﬁc markers may allow localization of the primary site. In patients with acute leukemias who have a high proportion of circulating blasts (> 100,000/mm3)35, diffuse meningeal invasion by leukemic cells may be accompanied by multiple intraparenchymal perivascular inﬁltrates. These intraparenchymal foci are composed of both blastic elements and red blood cells. The leukemic blasts of acute lymphocytic leukemia are larger than normal or reactive lymphocytes, with higher nuclear/cytoplasmic ratios, round or convoluted nuclei, a smooth, evenly distributed chromatin pattern, and visible nucleoli. Myelogenous blasts of nonlymphocytic leukemias may show cytoplasmic granules in the maturing elements. Monocytic blasts are morphologically similar to macrophages, and they may also simulate lobular carcinoma of the breast, especially on Papanicolaou-stained CSF specimens35. A panel of epithelial and leukocytic markers may be useful in such cases. CNS involvement by chronic lymphocytic leukemia is exceedingly rare. As with primary CNS lymphomas, the majority of NHLs that secondarily involve the CNS are B-cell large-cell lymphomas, although T-cell phenotypes may also be observed37, 77. In contrast to primary CNS lymphoma, which is mainly intraparenchymal, secondary lymphomas are predominantly meningeal. In some cases, foci of perivascular lymphoma with inﬁltration into the adjacent nervous parenchyma may be seen. The neoplastic cells of small cell lymphoma variants are of a size similar to that of mature or reactive lymphocytes but have convoluted nuclei, clumped chromatin, and visible nucleoli. Atypical lymphocytes with cribriform nuclei and strong immunoreactivity for T-cell markers are characteristic of mycosis fungoides. In large cell lymphomas, at least a proportion of the tumor cells are patently atypical. The diagnostic problem in such cases may be distinguishing lymphoma from morphologically similar tumors such as undifferentiated carcinoma and melanoma. Again, adequate clinical information and the use of an appropriate panel of immunohistochemical markers usually allows correct identiﬁcation of the nature of the process (Table 4.2). Angiotropic (intravascular) lymphomas are characterized by the proliferation of atypical lymphocytes, mostly of the B-cell type, within the lumen of capillaries, small veins, and arteries, with no or minimal involvement of the adjacent brain parenchyma. Occlusive intravascular aggregations of neoplastic lymphocytes cause perfusion deﬁcits and areas of ischemic necrosis. In

Brain metastases: histopathological evaluation and diagnostic pitfalls

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Table 4.2 Most common differential diagnoses in the microscopic evaluation of metastatic CNS* disease.

Differential diagnosis

Helpful markers and/or techniques

Undifferentiated large cell tumor with single cell invasion

Carcinoma, melanoma, lymphoma, glioblastoma

Cytokeratin, vimentin, HMB-45, leukocytic markers, GFAP

Papillary neoplasm

Metastatic papillary carcinoma, papillary meningioma, papillary ependymoma, pituitary adenoma, choroid plexus carcinoma

Cytokeratin, vimentin, GFAP, EMA, thyroglobulin, synaptophysin Electron microscopy

Small blue-cell tumor

Small cell carcinoma, lymphoma, small cell glioblastoma, medulloblastoma, cPNET, pPNET, small cell sarcoma, small cell melanoma

Cytokeratin, leukocytic markers, synaptophysin, GFAP, HMB-45, MART-1, vimentin, CD99 Electron microscopy Molecular biology techniques

Large pink-cell tumor

Metastatic carcinoma, metastatic alveolar soft-part sarcoma, amelanotic melanoma, epithelioid glioblastoma

Cytokeratins, HMB-45, MART1, GFAP

Clear cell tumor

Metastatic renal cell carcinoma, adrenal carcinoma, and other clear cell carcinomas, hemangioblastoma, oligodendroglioma, clear cell meningioma, clear cell ependymoma

EMA, cytokeratin, vimentin, GFAP PAS stain, Oil Red O stain

Lymphoid inﬁltrate

Lymphoma, leukemia, reactive lymphocytes, small cell carcinoma, melanoma, “small blue-cell tumors,” small cell glioblastoma, lymphoplasmacyte-rich meningioma, histiocytosis X, CNS Castleman’s disease

Leukocytic markers, EBV, keratin, synaptophysin, HMB45, MART-1, synaptophysin, CD99, myosin, actin, CD1a, S-100 protein, GFAP Electron microscopy Molecular biology techniques

Poorly differentiated adenocarcinoma

Lung, breast, gastrointestinal, genitourinary system, thyroid, and other adenocarcinomas

TTF-1, CK 7, CK 20, PSA, PAP, estrogen and progesterone receptors, thyroglobulin

Histopathological appearance of metastasis

*CNS, central nervous system; HMB-45, antibody to premelanosome glycoprotein; GFAP, glial ﬁbrillary acidic protein; EMA, epithelial membrane antigen; cPNET, central primitive neuroectodermal tumor; pPNET, peripheral primitive neuroectodermal tumor; MART-1, melanoma antigen recognized by T-cells; CD99, cell differentiation antigen-99; PAS, periodic acid-Schiff; EBV, Epstein-Barr virus; CD1a, cell differentiation antigen-1a; TTF-1, thyroid transcription factor1; CK, cytokeratin; PSA, prostate-speciﬁc antigen; PAP, prostatic acid phosphatase.

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lymphomatoid granulomatosis, the histopathological hallmark is an angiocentric and angiodestructive mixed cellular inﬁltrate that contains a variable number of atypical large and small lymphoid cells. This lesion has also been documented in AIDS patients. Epstein-Barr virus (EBV) can be detected in most cases78, 79. Although still included within the group of T-cell proliferations, it has been recently suggested that some cases may be EBV-driven clonal expansions of B lymphocytes with a prominent inﬂammatory T-cell reaction and vasculitis78 – 80. The diagnostic ﬁnding in cases of meningeal or meningocerebral involvement by HD81 is numerous Reed-Sternberg cells in a polymorphous inﬂammatory background of small lymphocytes, monocytes, plasma cells, and eosinophils. Atypical plasma cells are abundant in tissues involved by multiple myeloma and solitary plasmacytoma. Deﬁnitive diagnosis, however, requires supportive clinical information and clonality studies as immature plasma cells can also be seen in some infectious (cysticercosis) and non-neoplastic immunologic diseases such as multiple sclerosis82. An additional caveat is that abundant plasma cells and lymphocytes are characteristic of the lymphoplasmacyte-rich variant of meningioma83, 84. The extensive plasma cell reaction in this meningioma subtype can mimic solitary plasmacytoma of the meninges. The plasma cells in lymphoplasmacyte-rich meningioma, however, are polyclonal85. The distinction between small round blue-cell tumors of childhood, which include Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (pPNET), neuroblastoma, and rhabdomyosarcoma, is often impossible based on morphological criteria alone86. Clinical information regarding the body site of origin is mandatory for correct interpretation, and panels of antibodies are used to determine diagnosis (Table 4.2). Immunoexpression of the MIC-2 gene product (CD99) and the presence of the chimeric transcript EWS/FLI-1 indicates Ewing’s sarcoma/pPNET; central PNETs such as medulloblastoma and peripheral neuroblastoma do not express the abnormal protein87, 88. Electron microscopy may also be of use in characterizing tumors in this group89. Occasionally a cerebellar medulloblastoma of an adult patient must be differentiated from metastatic small cell carcinoma90.

Intraneural dissemination of primary brain tumors The incidence of intraneural metastasis from primary brain tumors depends on the type of tumor and the criteria used for diagnosis. Early dissemination through the CSF is common in medulloblastoma (MDB) and can also be seen, with lower frequency, in malignant glioma (MG). Extraneural metastasis may occur in both conditions but is extremely rare16. The sites with a predilection for intraneural metastasis in MDB are the ﬂoor of the third ventricle, the orbital surface of the frontal lobe, and the spinal cord. Spinal metastases can be observed in 50% to 90% of patients at postmortem examination91, reﬂecting the fact that generalized CSF propagation of MDB is a very frequent late phenomenon. According to Balhuizen92, an elevated cell

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count may be found in the postoperative samples of CSF in 91% of patients, with tumor cells clearly demonstrated in one-third of them. Supratentorial metastasis occurs in 6%–10% of patients, and a similar incidence is observed for metastasis in the posterior fossa93. Intraneural CSF metastasis by malignant gliomas (MG) is not uncommon. Neoplastic cells may penetrate the ependymal lining or the superﬁcial cortical pia-glial barrier to gain access to the CSF. Malignant glial cells have been reported to be present in CSF cytology samples in as high as 40% of patients with MG94. Controversy remains concerning the primary versus secondary nature (multicentric versus multifocal, respectively) of multiple intraparenchymal glioma foci. Multicentric tumors (excluding cases associated with phakomatoses) are seen in up to 7.5% of glioma patients95. A similar incidence (4%–6%) has been reported in CT scanning studies with postmortem histopathological conﬁrmation of tumor presence96. By deﬁnition, in multicentric glioma there is no identiﬁable physical contiguity between tumor foci, with each tumor presumed to be an independent growth. By convention, if routes of propagation are identiﬁed between one focus and another, the tumor is designated as multifocal rather than multicentric. In a series studied with magnetic resonance imaging (MRI) and CT by Kyritsis et al.97, the most frequent route of dissemination in the latter group was the subarachnoid space, followed by the subependymal-intraventricular route, with secondary brain invasion. Deﬁnitive histopathological differentiation between multicentric and multifocal glioma requires autopsy study with intensive histological investigation98. The same situation is applicable to multifocal CNS lymphoma98. Because of the generally distant separation of the tumor foci in multicentric glioma, with no evidence of interconnection appearing on MRI and CT studies, these patients are often suspected of harboring multiple metastases from an unknown primary site at presentation, and the correct diagnosis is made only at the time of intraoperative rapid frozen-section consultation. As in the situation for multicentric versus multifocal gliomas, the origin of multiple meningiomas has also been debated. Whereas it has often been assumed that these tumors represent multiple independent primary growths, evidence for a monoclonal origin has been recently reported99, raising the possibility of early subarachnoid extension from a primary lesion as a mechanism for the formation of such tumors.

References 1 Henson RA, Urich H: Cancer and the Nervous System. The Neurological Manifestations of Systemic Malignant Diseases. Oxford, Blackwell Scientiﬁc, 1982, 657pp. 2 Galicich JH, Sundaresan N, Arbit E, et al.: Surgical treatment of single brain metastasis: factors associated with survival. Cancer 1980; 45: 381–386. 3 Nussbaum ES, Djalilian HR, Cho KH, et al.: Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 1996; 78: 1781–1788.

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4 Delattre JY, Krol G, Thaler HT, et al.: Distribution of brain metastases. Arch Neurol 1988; 45: 741–744. 5 Tsukada Y, Fouad A, Pickren JW, et al.: Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 1983; 52: 2349 –2354. 6 Cascino TL, Leavengood JM, Kemeny N, et al.: Brain metastases from colon cancer. J Neurooncol 1983; 1: 203–209. 7 Byrne TN, Cascino TL, Posner JB: Brain metastasis from melanoma. J Neurooncol 1983; 1: 313–317. 8 Borst MJ, Ingold JA: Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery 1993; 114: 637– 641. 9 Altintas A, Vardar MA: Central nervous system involvement in gestational trophoblastic neoplasia. Eur J Gynaecol Oncol 2001; 22: 154 –156. 10 Vugrin D, Cvitkovic E, Posner J, et al.: Neurological complications of malignant germ cell tumors of testis: biology of brain metastases (I). Cancer 1979; 44: 2349 –2353. 11 Moser RP, Johnson ML: Surgical management of brain metastases: how aggressive should we be? Oncology (Huntingt) 1989; 3: 123 –127. 12 Merchut MP: Brain metastases from undiagnosed systemic neoplasms. Arch Intern Med 1989; 149: 1076–1080. 13 Eapen L, Vachet M, Catton G, et al.: Brain metastases with an unknown primary: a clinical perspective. J Neurooncol 1988; 6: 31–35. 14 Salvati M, Cervoni L, Raco A: Single brain metastases from unknown primary malignancies in CT-era. J Neurooncol 1995; 23: 75 – 80. 15 Debevec M: Management of patients with brain metastases of unknown origin. Neoplasma 1990; 37: 601–606. 16 Bruner JM, Tien RD: Secondary tumors. In Bigner DD, McLendon RE, Bruner JM, (eds): Russell and Rubinstein’s Pathology of Tumors of the Nervous System. 2 vol. 6th edn. New York, Oxford University Press, Inc, 1998, pp. 419–450. 17 Radley MG, McDonald JV, Pilcher WH: Late solitary cerebral metastases from renal cell carcinoma: report of two cases. Surg Neurol 1993; 39: 230 –234. 18 Gay PC, Litchy WJ, Cascino TL: Brain metastasis in hypernephroma. J Neurooncol 1987; 5: 51–56. 19 Engelhoff JC, Ross JS, Modic MT, et al.: MR imaging of metastatic gastrointestinal adenocarcinomas in the brain. AJNR Am J Neuroradiol 1992; 13: 1221–1224. 20 Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv Neurol 1978; 19: 579–592. 21 Boogerd W, Vos VW, Hart AA, et al.: Brain metastases in breast cancer; natural history, prognostic factors and outcome. J Neurooncol 1993; 15: 165 –174. 22 Brega K, Robinson WA, Winston K, et al.: Surgical treatment of brain metastases in malignant melanoma. Cancer 1990; 66: 2105 –2110. 23 Kobayashi T, Kida Y, Yoshida J, et al.: Brain metastasis of choriocarcinoma. Surg Neurol 1982; 17: 395–403. 24 Ishizuka T, Tomoda Y, Kaseki S, et al.: Intracranial metastasis of choriocarcinoma. A clinicopathologic study. Cancer 1983; 52: 1896 –1903. 25 Lewis AJ: Sarcoma metastatic to the brain. Cancer 1988; 61: 593 – 601. 26 Bindal RK, Sawaya RE, Leavens ME, et al.: Sarcoma metastatic to the brain: results of surgical treatment. Neurosurgery 1994; 35: 185 –190. 27 Trigg ME, Makuch R, Glaubiger D: Actuarial risk of isolated CNS involvement in Ewing’s sarcoma following prophylactic cranial irradiation and intrathecal methotrexate. Int J Radiat Oncol Biol Phys 1985; 11: 699 –702.

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28 Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 2001; 91: 1510 –1519. 29 Meyer PC, Reah T: Secondary neoplasms of the central nervous system and meninges. Br J Cancer 1953; 7: 438 – 448. 30 Stark RJ, Henson RA, Evans SJ: Spinal metastases. A retrospective survey from a general hospital. Brain 1982; 105: 189 –213. 31 Okamoto H, Shinkai T, Matsuno Y, et al.: Intradural parenchymal involvement in the spinal subarachnoid space associated with primary lung cancer. Cancer 1993; 72: 2583 – 2588. 32 Sze G, Soletsky S, Bronen R, et al.: MR imaging of the cranial meninges with emphasis on contrast enhancement and meningeal carcinomatosis. AJR Am J Roentgenol 1989; 153: 1039–1049. 33 Russell DS, Rubinstein L: Pathology of Tumors of the Nervous System. Fifth ed. Baltimore, Williams and Wilkins, 1989, 1012pp. 34 Bigner SH, Schold SC: The diagnosis of metastases to the central nervous system. Pathol Annu 1984; 19: 89 –119. 35 Bigner SH, Johnston WW: Cytopathology of the Central Nervous System. Chicago, ASCP, 1994, 190pp. 36 Levitt LJ, Dawson DM, Rosenthal DS, et al.: CNS involvement in the non-Hodgkin’s lymphomas. Cancer 1980; 45: 545 –552. 37 Mead GM, Kennedy P, Smith JL, et al.: Involvement of the central nervous system by non-Hodgkin’s lymphoma in adults. A review of 36 cases. Q J Med 1986; 60: 699 –714. 38 Ziegler JL, Bluming AZ, Morrow RH, et al.: Central nervous system involvement in Burkitt’s lymphoma. Blood 1970; 36: 718 –728. 39 Janota I: Involvement of the nervous system in malignant lymphoma in Nigeria. Br J Cancer 1966; 20: 47–61. 40 Kokmen E, Billman JK, Jr, Abell MR: Lymphomatoid granulomatosis clinically conﬁned to the CNS. A case report. Arch Neurol 1977; 34: 782–784. 41 Schmidt BJ, Meagher-Villemure K, Del Carpio J: Lymphomatoid granulomatosis with isolated involvement of the brain. Ann Neurol 1984; 15: 478 – 481. 42 Glass J, Hochberg FH, Miller DC: Intravascular lymphomatosis. A systemic disease with neurologic manifestations. Cancer 1993; 71: 3156–3164. 43 Treves TA, Gadoth N, Blumen S, et al.: Intravascular malignant lymphomatosis: a cause of subacute dementia. Dementia 1995; 6: 286 –293. 44 Rappaport H, Thomas LB: Mycosis fungoides: the pathology of extracutaneous involvement. Cancer 1974; 34: 1198 –1229. 45 Sapozink MD, Kaplan HS: Intracranial Hodgkin’s disease. A report of 12 cases and review of the literature. Cancer 1983; 52: 1301–1307. 46 Vera R, Jr, Enriquez R, Papac R: Hodgkin’s disease, intracranial involvement. Report of a case and review of the literature. Am J Clin Oncol 1985; 8: 73 –76. 47 Kim EY, Choi JU, Kim TS, et al.: Huge Langerhans cell histiocytosis granuloma of choroid plexus in a child with Hand-Schuller-Christian disease. Case report. J Neurosurg 1995; 83: 1080–1084. 48 Roddie P, Collie D, Johnson P: Myelomatous involvement of the dura mater: a rare complication of multiple myeloma. J Clin Pathol 2000; 53: 398 –399. 49 Peretti-Viton P, Margain D, Murayama N, et al.: Brain metastases. J Neuroradiol 1991; 18: 161–172. 50 Ortega P MN, Shimkin MB: Metastasis to pineal body. Arch Pathol 1951; 52: 518 –528.

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51 Muller W, Schroder R: Spreading of metastases into cranial tumors: metastasis of a breast carcinoma to a pilocytic astrocytoma. Clin Neuropathol 1999; 18: 109 –112. 52 Nielsen SL, Posner JB: Brain metastasis localized to an area of infarction. J Neurooncol 1983; 1: 191–195. 53 Schmitt HP: Metastases of malignant neoplasms to intracranial tumours: the “tumour-ina-tumour” phenomenon. Virchows Arch A Pathol Anat Histopathol 1984; 405: 155 –160. 54 Brown HM, McCutcheon IE, Leeds NE, et al.: Melanoma metastatic to central neurocytoma: a novel case of tumor-to-tumor metastasis. J Neurooncol 2000; 61: 209–214. 55 O’Neill BP, Dinapoli RP, Okazaki H: Cerebral infarction as a result of tumor emboli. Cancer 1987; 60: 90–95. 56 Kapila A, Gupta KL, Garcia JH: CT and MR of lymphomatoid granulomatosis of the CNS: report of four cases and review of the literature. Am J Neuroradiol 1988; 9: 1139 –1143. 57 Lundberg WB, Cadman EC, Skeel RT: Leptomeningeal mycosis fungoides. Cancer 1976; 38: 2149–2153. 58 Zhang M, Olsson Y: Hematogenous metastases of the human brainacharacteristics of peritumoral brain changes: a review. J Neurooncol 1997; 35: 81– 89. 59 Gyure KA, Morrison AL: Cytokeratin 7 and 20 expression in choroid plexus tumors: utility in differentiating these neoplasms from metastatic carcinomas. Mod Pathol 2000; 13: 638–643. 60 Bohinski RJ, Bejarano PA, Balko G, et al.: Determination of lung as the primary site of cerebral metastatic adenocarcinomas using monoclonal antibody to thyroid transcription factor-1. J Neurooncol 1998; 40: 227–231. 61 Mackay B, Ordonez NG: The role of the pathologist in the evaluation of poorly differentiated tumors. Semin Oncol 1982; 9: 396 – 415. 62 Mackay B, Ordonez N: Electron microscopy in the immunocytochemical era. Adv Pathol 1996; 9: 277–310. 63 Camilleri-Broet S, Devez F, Tissier F, et al.: Quality control and sensitivity of polymerase chain reaction techniques for the assessment of immunoglobulin heavy chain gene rearrangements from ﬁxed- and parafﬁn-embedded samples. Ann Diagn Pathol 2000; 4: 71–76. 64 Collini P, Sampietro G, Bertulli R, et al.: Cytokeratin immunoreactivity in 41 cases of ES/PNET conﬁrmed by molecular diagnostic studies. Am J Surg Pathol 2001; 25: 273 – 274. 65 Athale UH, Shurtleff SA, Jenkins JJ, et al.: Use of reverse transcriptase polymerase chain reaction for diagnosis and staging of alveolar rhabdomyosarcoma, Ewing sarcoma family of tumors, and desmoplastic small round cell tumor. J Pediatr Hematol Oncol 2001; 23: 99–104. 66 Schleiermacher G, Delattre O: Detection of micrometastases and circulating tumour cells using molecular biology technics in solid tumours. Bull Cancer 2001; 88: 561–570. 67 Hibshoosh H, Lattes R: Immunohistochemical and molecular genetic approaches to soft tissue tumor diagnosis: a primer. Semin Oncol 1997; 24: 515 –525. 68 McManus AP, Gusterson BA, Pinkerton CR, et al.: The molecular pathology of small round-cell tumoursarelevance to diagnosis, prognosis, and classiﬁcation. J Pathol 1996; 178: 116–121. 69 d’Amore ES, Ninfo V: Clear cell tumors of the somatic soft tissues. Semin Diagn Pathol 1997; 14: 270–280. 70 Gu M, Antonescu CR, Guiter G, et al.: Cytokeratin immunoreactivity in Ewing’s sarcoma: prevalence in 50 cases conﬁrmed by molecular diagnostic studies. Am J Surg Pathol 2000; 24: 410–416.

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71 Raab SS, Berg LC, Swanson PE, et al.: Adenocarcinoma in the lung in patients with breast cancer. A prospective analysis of the discriminatory value of immunohistology. Am J Clin Pathol 1993; 100: 27–35. 72 Han AC, Duszak R, Jr: Coexpression of cytokeratins 7 and 20 conﬁrms urothelial carcinoma presenting as an intrarenal tumor. Cancer 1999; 86: 2327–2330. 73 Lagendijk JH, Mullink H, Van Diest PJ, et al.: Tracing the origin of adenocarcinomas with unknown primary using immunohistochemistry: differential diagnosis between colonic and ovarian carcinomas as primary sites. Hum Pathol 1998; 29: 491– 497. 74 Perry A, Parisi JE, Kurtin PJ: Metastatic adenocarcinoma to the brain: an immunohistochemical approach. Hum Pathol 1997; 28: 938 –943. 75 Fernandez C, Liprandi A, Bouvier-Labit C, et al.: Value of cytokeratin 7 and 20 for the diagnosis of cerebral metastases of adenocarcinoma: study of 78 cases. Ann Pathol 2001; 21: 129–135. 76 Assi A, Declich P, Iacobellis M, et al.: Secretory meningioma, a rare meningioma subtype with characteristic glandular differentiation: an histological and immunohistochemical study of 9 cases. Adv Clin Path 1999; 3: 47–53. 77 Teshima T, Akashi K, Shibuya T, et al.: Central nervous system involvement in adult T-cell leukemia/lymphoma. Cancer 1990; 65: 327–332. 78 Medeiros LJ, Peiper SC, Elwood L, et al.: Angiocentric immunoproliferative lesions: a molecular analysis of eight cases. Hum Pathol 1991; 22: 1150 –1157. 79 Guinee D, Jr., Jaffe E, Kingma D, et al.: Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994; 18: 753 –764. 80 Myers JL, Kurtin PJ, Katzenstein AL, et al.: Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol 1995; 19: 1300 –1312. 81 Perez-Jaffe LA, Salhany KE, Green RJ, et al.: Cerebral spinal ﬂuid involvement by Hodgkin’s disease diagnosed by CSF cytology and immunocytochemistry. Diagn Cytopathol 1999; 20: 219 –223. 82 Peter A: The plasma cells of the cerebrospinal ﬂuid. J Neurol Sci 1967; 4: 227–239. 83 Horten BC, Urich H, Stefoski D: Meningiomas with conspicuous plasma cell-lymphocytic components: a report of ﬁve cases. Cancer 1979; 43: 258 –264. 84 Kleihues P, Cavenee WK (eds): Pathology and Genetics of Tumors of the Nervous System. 2nd ed. Lyon, IARC Press, 2000, 314pp. 85 Mirra SS, Tindall SC, Check IJ, et al.: Inﬂammatory meningeal masses of unexplained origin. An ultrastructural and immunological study. J Neuropathol Exp Neurol 1983; 42: 453–468. 86 Dehner LP: On trial: a malignant small cell tumor in a child: four wrongs do not make a right. Am J Clin Pathol 1998; 109: 662– 668. 87 Folpe AL, Hill CE, Parham DM, et al.: Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing’s sarcoma/primitive neuroectodermal tumor. Am J Surg Pathol 2000; 24: 1657–1662. 88 Gyure KA, Prayson RA, Estes ML: Extracerebellar primitive neuroectodermal tumors: A clinicopathologic study with bcl-2 and CD99 immunohistochemistry. Ann Diagn Pathol 1999; 3: 276–280. 89 Schmidt D, Harms D, Pilon VA: Small-cell pediatric tumors: histology, immunohistochemistry, and electron microscopy. Clin Lab Med 1987; 7: 63 –89. 90 Ramsay DA, Bonnin J, MacDonald DR, et al.: Medulloblastomas in late middle age and the elderly: report of 2 cases. Clin Neuropathol 1995; 14: 337–342.

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91 Jacobi G, Kornhuber B: Malignant Brain Tumors in Children. Berlin, Springer-Verlag 1987, pp. 396–493. 92 Balhuizen JC, Bots GT, Schaberg A, et al.: Value of cerebrospinal ﬂuid cytology for the diagnosis of malignancies in the central nervous system. J Neurosurg 1978; 48: 747–753. 93 Todd NV, Graham DI: Complications of primary malignant brain tumors. In Thomas DGT, Graham DI, (eds): Malignant Brain Tumors. London, Springer-Verlag 1995, pp. 128– 131. 94 Bigner SH, Johnston WW: The diagnostic challenge of tumors manifested initially by the shedding of cells into cerebrospinal ﬂuid. Acta Cytol 1984; 28: 29 –36. 95 Barnard RO, Geddes JF: The incidence of multifocal cerebral gliomas. A histologic study of large hemisphere sections. Cancer 1987; 60: 1519 –1531. 96 Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 1980; 30: 907–911. 97 Kyritsis AP, Levin VA, Yung WK, et al.: Imaging patterns of multifocal gliomas. Eur J Radiol 1993; 16: 163–170. 98 Nahser HC, Gerhard L, Reinhardt V, et al.: Diffuse and multicentric brain tumors – correlation of histological, clinical and CT appearance. Acta Neuropathol Suppl 1981; 7: 101–104. 99 von Deimling A, Larson J, Wellenreuther R, et al.: Clonal origin of recurrent meningiomas. Brain Pathol 1999; 9: 645 – 650.

CHAPTER 5

Imaging of metastatic tumors of the brain Norman E Leeds, Edward F Jackson, Ashok J Kumar

Introduction Metastatic brain tumors are more common than primary neoplasms of the brain, with over 100,000 new cases occurring each year compared with 17,000 to 18,000 for primary brain neoplasms1, 2. Speciﬁcally, Posner2 reported in 1992 that 18% of patients having systemic cancers at the Memorial Sloan-Kettering Cancer Center were observed to have brain metastases at autopsy. Also, Cappuzzo et al.3 estimated that 20% to 40% of cancer patients develop cerebral metastases, although only two-thirds of them develop symptoms of metastasis. The number of patients having brain metastases continues to rise as a consequence of improvements in therapy and the fact that magnetic resonance (MR) imaging is now more readily available for identifying the presence of lesions. The neoplasms that metastasize to the brain with the greatest frequency include lung cancer, breast cancer, melanoma, renal cell cancer, and colorectal cancer4. Additionally, among patients having metastasis to the brain, a solitary metastasis occurs in 40% of them2, 5. Furthermore, Patchell et al.5 reported that 10% of solitary lesions suspected of being metastases in patients having solid tumors were not really metastases.

Tumor growth and location Metastatic neoplasms depend on angiogenesis (the development of new blood vessels) for growth. It has been observed that micrometastases will barely grow if angiogenesis does not occur6, 7. Also, Folkman7 stated that, in the perivascular phase, a tumor is rarely larger than 2–3 mm3 in maximum diameter and may contain one million or more cells. These tumors will not grow without the development of microvasculature7, however. In another study, Frank et al.8, using VX2 rabbit carcinoma cells injected into the internal carotid artery of rabbits, demonstrated rapid growth of tumor cells within the brain. They observed leakage of contrast enhancing material from the newly formed abnormal vessels in the tumors as a result of angiogenesis. Tumor angiogenesis superﬁcially resembles embryonic angiogenesis but requires an additional

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cascade for development, e.g., cell cycle progression, remodeling of cell adhesions and junctions, and induction of proteolytic activities and neutralizing inhibitors9. In addition, genetic switches that may regulate angiogenesis also occur, but it is unclear whether these are direct effects or are related to deviations in the microenvironment9. Current studies using therapeutic agents that target angiogenesis are being performed10. The complexity of the events that result in angiogenesis makes one wonder whether a single agent or multiple agents will be required for successful treatment9, 10. Cytotoxic therapy may also be required10. Tumor cells may shed from primary neoplasms, and they have various modes of spreading. Tumors that spread to the brain are primarily hematogenous and in the majority of cases are observed at gray matter-white matter junctions and the border zones between the anterior and middle cerebral artery, the anterior and posterior cerebral artery, and the middle and posterior cerebral artery. A slight constriction occurs at the connection sites, with a resultant minimal reduction in blood ﬂow at these intersections, producing tumor or emboli seeding at these sites. In addition, brain metastases may be identiﬁed relative to the cortical surface of the brain, the overlying dura and pachymeninges (dura and arachnoid), or leptomeninges (arachnoid and pia). However, tumors occur at these locations much less frequently11. Metastases also may seed to the calvaria. As it grows, a metastatic neoplasm, depending on its location, may invade adjacent parenchymal structures, shed cells into the subarachnoid space, or reinvade the brain by growing along the perivascular Virchow-Robin spaces. Therefore, tumors may extend to the leptomeninges from the brain or invade the brain from leptomeninges along these routes. The brain reacts to these growing tumors with the development of edema.

Imaging features Metastases have been demonstrated by using computed tomography (CT) imaging after intravenous contrast medium administration to the patient, most commonly as ring lesions visualized prior to and following contrast administration12. Also, Davis et al.13 observed during CT examinations that delaying imaging after the injection of intravenous contrast medium and/or increasing the volume of contrast medium injected improved the ability to detect metastases. They also reported that combining delayed imaging with the use of double-dose intravenous contrast medium administration signiﬁcantly improved the conspicuity of lesions. Yuh et al.14 used this information in an MR imaging study of metastases in administering a triple dose of intravenous contrast medium, not only observing improved lesion recognition but also revealing new lesions in one third of the cases. Schörner et al.15 performed a study to evaluate the optimum time from contrast medium administration to imaging in order to observe the presence of intracranial metastases. This time was observed to be 8.5 to 30.00 minutes and was considered to be related to capillary permeability.

Imaging of metastatic tumors of the brain 73

Figure 5.1 48-year-old woman with lung cancer. (A) Contrast-enhanced axial T1-weighted MR image. (B) Axial T2-weighted MR image. A ring-enhancing metastatic lesion within the left frontal lobe (arrow in A) at the corticomedullary junction with edema (E in A, B) is demonstrated.

Figure 5.2 63-year-old woman with stage IV breast cancer. (A), (B) Contrast-enhanced coronal T1-weighted MR images. Metastatic tumor with a large central cyst (C) with a peripheral rim of enhancement (arrows), a focal mural nodule (T), and edema (E) is shown.

Due to the features described above, metastatic lesions are observed more commonly at a corticomedullary location (border zone) when hematogenous seeding occurs (Figure 5.1). There are multiple lesions in 50% to 60% of the cases. If a single metastasis is observed on a CT scan or the scan appears to be normal, then MR imaging with contrast administration is warranted because of its improved conspicuity of the tumor focus and ability to demonstrate whether additional lesions are present16. Finally, the metastasis can be solid, cystic, or both (Figure 5.2). Less commonly, metastases may involve the cortical surface or dura (Figure 5.3). In these cases, the MR image of the lesion may simulate that of a meningioma. Metastases may also affect the choroid plexus, particularly in patients

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Figure 5.3 Dural metastasis simulating meningioma in a 52-year-old woman with metastatic adenocarcinoma of unknown primary. (A) Axial T1-weighted; (B) contrast-enhanced axial T1-weighted; and, (C) axial T2-weighted MR images. MR imaging demonstrates a large extra-axial tumor (arrows in A, B, C), with homogeneous contrast enhancement within the left middle cranial fossa (arrow in B) showing edema (E in B, C) with mass effect upon the left cerebral peduncle (arrowheads in A, B, C). The open arrows in C identify prominent small vessels within the neoplasm.

Figure 5.4 50-year-old woman with renal cell carcinoma. Contrast-enhanced axial T1weighted MR image. Contrast-enhancing tumor metastatic to the left choroid plexus is shown (arrows). Also note a right temporal calvarial metastasis with an epidural tumor (arrowhead).

having renal cell cancer, and may invade the calvaria and affect bone with associated epidural growth (Figure 5.4). Metastases to bone may be osteolytic and thus appear hypointense on T1-weighted MR images, isointense or hyperintense on T2-weighted MR images, and enhanced following intravenous contrast administration. Calvarial metastases may also appear osteoblastic with marrow replacement and hypointense on all sequences without demonstrating contrast opaciﬁcation. Another important feature of metastases that must be considered is the shedding of cells and their spreading to the subarachnoid space, with the for-

Imaging of metastatic tumors of the brain 75

Figure 5.5 39-year-old woman with melanoma of the right axilla. (A) Axial ﬂuid-attenuatedinversion-recovery (FLAIR) image. (B) Contrast-enhanced axial T1-weighted MR image. Early detection of leptomeningeal metastatic disease on a FLAIR image as an area of increased signal intensity deep within the right sylvian ﬁssure (arrow in A) and within the frontotemporal sulci (arrowhead in A), whereas a contrast-enhanced scan (B) failed to reveal any abnormal enhancing lesions.

mation of leptomeningeal metastases16. These metastases may have a focal or diffuse appearance. In addition, ﬂuid-attenuated inversion-recovery (FLAIR) imaging may be used. FLAIR imaging is a T2-weighted MR sequence with an inversion pulse that causes mobile cerebrospinal ﬂuid (CSF) in the subarachnoid spaces or ventricles to be converted from having a hyperintense or bright signal to having a hypointense or dark signal17. Thus, subarachnoid collections of metastatic cells, elevated levels of protein, blood, or pus will convert the CSF on the FLAIR image from dark to bright (Figure 5.5). Also, metastasis to the dura may result in the development of subdural metastases (Figure 5.6). In addition, localized metastatic masses from shed tumor cells may occur anywhere within the reaches of the CSF. Moreover, a suprasellar mass may simulate a pituitary tumor (Figure 5.7) or a craniopharyngioma on MR images. Examining the patient’s medical history is important for making the appropriate diagnosis in such cases. Currently, metastatic lesions are treated using either surgical resection or focused radiation with or without subsequent whole-brain radiation therapy (WBRT). After radiation treatment, these tumors produce increased edema due to the reaction of the surrounding brain. Enlargement of the tumor may also develop as it responds to treatment with the formation of tumor necrosis. The lesions will gradually diminish in size as they respond to treatment, and they may even disappear with time or reveal only a small focus of enhancement after intravenous contrast administration, reﬂecting residual tumor necrosis (Figure 5.8).

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Figure 5.6 75-year-old man with gastric carcinoma. Contrast-enhanced axial T1weighted MR image. A left-sided crescentic peripherally enhancing metastatic tumor (arrows) partially excised and histologically proved to be subdural metastatic adenocarcinoma.

Figure 5.7 47-year-old woman who underwent surgery and radiation therapy in 1996 for adenocarcinoma of the parotid gland and displayed signs and symptoms of diabetes insipidus in 1997. Suprasellar metastasis simulating a pituitary adenoma. (A) Sagittal T1-weighted; (B) contrast-enhanced sagittal T1-weighted; and, (C) contrast-enhanced coronal T1-weighted MR images. A large suprasellar tumor (arrows in A, B, C) with a smaller intrasellar component (arrowheads in A, B) was surgically excised and histologically proved to be a metastasis.

In some cases, however, depending on the sensitivity of the brain structures in relation to that of the tumor being treated, a residual ring-enhancing lesion may be recognized after therapy, reﬂecting necrosis of the brain (Figure 5.9). Similarly, in other cases, radiation-induced necrosis may develop, but it may be difﬁcult to distinguish between a tumor recurrence in the treated area and radiation-induced necrosis of normal brain tissue18. Such radiation-induced necrosis develops over 3 to 16 months in the majority of cases; in some cases, it may be seen after several years. In these cases, increased edema is found, and

Imaging of metastatic tumors of the brain 77

Figure 5.8 74-year-old woman with metastasis to the brain from non-small cell lung carcinoma. (A), (B), (C), (D) Contrast-enhanced axial T1-weighted MR images. Gradual disappearance of a right parietal lobe metastasis (arrows in A, B, C, D) after stereotactic radiosurgery.

as in the case illustrated above, the focal area of contrast opaciﬁcation develops slowly, enlarges with time, and has a soap-bubble appearance (Figure 5.9). These lesions may actually produce a mass effect, making it even more difﬁcult to distinguish them from tumor recurrence as mass effect is uncommon with radiation-induced necrosis18. In these cases, additional examinations, including dynamic MR imaging scans19, 20, perfusion studies21, diffusionweighted MR imaging22, magnetic resonance spectroscopy23–25, and PET scanning may be used to aid in the differential diagnosis.

Differential diagnosis Some lesions may simulate metastases, as alluded to by Patchell et al.5, who recognized that in their series of metastases 10% of the cases of suspected metastases to the brain were, in fact, not metastases. These lesions included brain abscesses, which may be single or multiple. On T2-weighted MR images, a black rim is observed around a brain abscess (Figure 5.10); budding lesions

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Figure 5.9 64-year-old man with metastasis to the brain from colon adenocarcinoma. (A), (B), (C), (D) Contrast-enhanced axial T1-weighted MR images. (A) A peripherally enhancing metastatic mass (arrow) with a central area of less enhancing tumor tissue (arrowhead in A) is shown. The lesion increased in size despite stereotactic radiosurgery and hence was totally excised on 4/21/00. (B) A postoperative MR imaging scan on 4/24/00 revealed a large surgical cavity with no residual tumor. (C) An increase in peripheral enhancement (arrow) around the surgical cavity was noted 38 days after surgical excision of tumor. (D) Two months and 16 days later, a further increase in the degree of enhancement (arrow) with a decrease in size of the surgical cavity is noted. Surgical excision of the mass revealed only tissue necrosis from radiation with no evidence of tumor.

may also be recognized26. Furthermore, the use of diffusion-weighted MR imaging has been found to be helpful by demonstrating a hyperintense center in abscesses (Figure 5.11) as opposed to the central hypointensity seen in metastases (Figure 5.12)27, 28. The diffusion-weighted MR image is dependent on micromolecular motion, however. In cysts or regions of necrosis, the ﬂuid content is dark because of increased water content, whereas in an infection or abscess the ﬂuid content is bright because the pus and breakdown of leukocytes result in an increase in cellular material and restricted motion. In cases of suspected leptomeningeal metastases that are detected using FLAIR imaging, the possibility of meningitis must also be considered17. FLAIR imaging will demonstrate replacement of a hypointense CSF region with a

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Figure 5.10 59-year-old man with cerebral abscess simulating a metastasis. (A) Axial T1-weighted; (B) contrast-enhanced axial T1-weighted; (C) axial T2-weighted; and, (D) contrastenhanced sagittal T1-weighted MR images. A large peripherally enhancing mass (arrows in B and D) with a central area of low signal intensity. The diagnosis of abscess was entertained preoperatively due to the dark signal intensity of the abscess capsule as noted on the T2-weighted image (black arrowhead in C) and the daughter cyst (white arrowhead in D) attached to the parent cyst (arrow in D).

hyperintense signal in patients having meningitis (Figure 5.11). Granulomatous lesions, such as those of the sarcoid and histoplasmosis types, may also mimic metastatic lesions29. Additionally, MR imaging of glioblastoma multiforme with subarachnoid seeding may mimic that of metastases if the lesion’s site of origin is unrecognized (Figure 5.13). Other types of lesions that may mimic metastases because of their multiplicity include those from multiple sclerosis, multiple infarcts (particularly in a watershed distribution), glioblastomas that are multicentric, and multiple foci of radiation necrosis that appear as rings18, 29. However, the reverse may also be true: metastases may simulate meningiomas on MR images by arising in an extradural location and involving bone, with extension to the dura and development of a dural tail (Figure 5.14). Metastases may also simulate anaplastic astrocytoma or glioblastoma multiforme on MR images when they are solitary or cystic (Figure 5.2). Finally, a metastasis may simulate craniopharyngioma or a pituitary lesion by appearing as a solitary suprasellar subarachnoid lesion (Figure 5.7).

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Figure 5.11 47-year-old woman with acute lymphoblastic leukemia, 16 days after a bone marrow transplant. (A) Contrast-enhanced axial T1-weighted MR image; (B) axial FLAIR image; and, (C) diffusion-weighted MR image. An early abscess within the right frontal lobe is best shown on the diffusion-weighted image (black arrow in C) as an area of increased signal within the abscess cavity, with the abscess capsule not fully developed and thus poorly seen on postcontrast image (white arrow in A). A striking increase in signal intensity of the subarachnoid sulci from meningitis is best noted on the FLAIR image (arrowheads in B).

Figure 5.12 39-year-old woman with breast carcinoma. (A) Contrast-enhanced axial T1-weighted MR image; and, (B) axial diffusion-weighted image. A metastasis to the right occipital lobe (large arrow in A) with a central area of necrosis (arrowhead in A). Note that the necrotic component of the tumor is of low signal intensity on the diffusion-weighted image (black arrowhead in B). A small metastasis is also seen within the splenium of the corpus callosum (small arrow in A).

New imaging techniques may aid in differential diagnoses. For example, as described above, FLAIR imaging is very useful in revealing involvement of the subarachnoid space (Figure 5.5)17. On imaging studies, metastases often appear as solitary nodules or ring lesions (Figure 5.2), and edema is often present

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Figure 5.13 47-year-old woman with multifocal glioblastoma simulating metastatic lesions. (A), (B) Contrast-enhanced axial T1-weighted MR images. A contrast-enhancing glioblastoma multiforme of the right medial temporal lobe (arrow in A) and a small subarachnoid tumor within the sylvian tissue (arrowhead in B) from tumor extension is shown.

Figure 5.14 48-year-old woman with breast carcinoma. (A) Skull base axial; (B) coronal CT images in bone windows; and, (C) axial contrast-enhanced T1-weighted MR image. Sclerotic metastasis to the greater wing of the left sphenoid bone (arrows in A, B). The epidural tumor component is better appreciated in an MR image (arrowhead in C). The black arrow in C points to thickened metastatic bone.

around these lesions. The lesions may also have hemorrhaging in 5% of the cases, particularly with melanoma. Furthermore, cystic metastases may develop, particularly from lung and breast lesions (Figure 5.2). Speciﬁcally, a cystic appearance may be recognized in melanoma as a hemorrhage undergoes involution30. Additionally, the center of a lesion may be dark on T2weighted MR images in patients having adenocarcinoma because of the presence of mucoid material31. In patients having metastases from adenocarcinoma, calciﬁcation may also be observed.

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Advanced MR neuroimaging techniques applied to intracranial metastatic neoplasms In neuro-oncologic imaging, the typical set of MR images consists of T1weighted (with and without contrast agent enhancement), T2-weighted, and ﬂuid-attenuated inversion-recovery (FLAIR) images. However, recent improvements in the magnetic gradient ﬁeld subsystems of commercial scanners allow one to acquire images at rates as rapid as 50–100 msec/image. These rapid acquisition rates have resulted in the implementation of new neuroimaging techniques that not only provide exquisite anatomic detail but also allow for the assessment of tissue function. The following sections of this chapter discuss applications of some of this new high-speed imaging technology to neuro-oncologic imaging. In addition, advances in spectroscopic data acquisition and processing capabilities, which allow for noninvasive assessment of the local biochemical environment, are also brieﬂy reviewed.

Perfusion MR imaging techniques Tumors cannot grow beyond a few millimeters in diameter and are unlikely to metastasize, without altering the local vascular environment, i.e., increasing vascular permeability and density32. Treatment-related changes in tumors, on the other hand, are not typically associated with such dramatic increases in vascular density and permeability. Therefore, the ability to assess vascular volume, ﬂow, and permeability may provide a means of more reliably differentiating between tumor progression and treatment-related changes, a diagnosis that is often difﬁcult or impossible, even with the wide range of image contrasts provided by conventional MR imaging techniques. In addition, using such techniques to noninvasively monitor tissue vascularity may prove useful in assessing the efﬁcacy of the large number of antiangiogenic agents currently in clinical trials. Two different MR techniques have been proposed for mapping regional cerebral blood ﬂow (rCBF) and regional cerebral blood volume (rCBV). The most commonly used technique, sometimes referred to as dynamic susceptibility contrast (DSC) mapping, takes advantage of the local transient susceptibility change that occurs as a bolus of paramagnetic contrast agent passes through the microvasculature in any given volume of interest33 –37. The transient susceptibility changes result in transient, localized, inhomogeneities in the local magnetic ﬁeld, thereby causing enhanced dephasing of the local nuclear spins by decreasing the “apparent” T2 relaxation time (T2*). This dephasing results in a transient decrease in signal intensity on T2-weighted or T2*-weighted images as the bolus passes; the higher the rCBV, the greater the magnitude of the transient signal loss. Assuming that the contrast agent remains intravascular, i.e., there is no blood-brain barrier (BBB) breakdown, such images can be used to construct maps of rCBV. If, however, the BBB is highly fenestrated and contrast agent “leaks” from the vasculature to the inter-

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stitial space during the ﬁrst pass, the DSC mapping technique can underestimate the rCBV measurement due to loss of compartmentalization of the contrast agent and local decreases in the T1 relaxation times36. The chief advantage of the DSC technique is the favorable signal-to-noise ratio of the resulting rCBV maps, particularly if double-dose bolus injections are utilized. Furthermore, if the mean transit time (MTT) of the contrast agent can be determined (from signal intensity changes in an intracranial artery and vein, for example) then the rCBV measures can be converted to rCBF measures using the central volume theorem. An example of an rCBV map from a patient with recurrent brain metastasis from breast carcinoma is given in Plate 5.1 (facing p. 82) and demonstrates elevated but clearly demarcated regions of an rCBV. Primary brain tumors, such as anaplastic astrocytomas and glioblastomas multiforme, commonly demonstrate more diffuse regions of elevated rCBV than metastatic lesions. The second MR technique for assessing cerebral microvascular changes requires no exogenous contrast agent but, at this time, is still in the preclinical evaluation stage. This technique, known as arterial spin tagging (AST), relies on time-of-ﬂight signal loss in a chosen imaging section due to selective inversion of spins on nuclei ﬂowing in a section a few centimeters away38– 40. The inverted spins from the “tagged” section yield decreased signal intensity when imaged in the section of interest. Knowing the location of the tagging section, the T1 relaxation times in the section of interest, and the blood-tissue partition coefﬁcient (approximately constant with a value of ~0.9), rCBF can be computed in the section of interest. The totally noninvasive nature of the AST technique gives this approach a potential advantage relative to the DSC approach described above. However, the signal-to-noise ratio of the DSC technique is signiﬁcantly higher, and obtaining high quality AST measurement of rCBF from multiple sections is more difﬁcult. Furthermore, because of the lower signal-to-noise, AST acquisitions are currently more time consuming than DSC acquisitions. However, recently FDA-approved commercial ultrahigh ﬁeld systems (with 3 Tesla static magnetic ﬁelds) may provide adequate AST signal-to-noise ratios in scan times that begin to rival those required for current DSC techniques.

Dynamic contrast MR imaging techniques MR imaging with and without contrast agent enhancement has been commonly used in neuroimaging since the mid 1980s. Typically, the precontrast and postcontrast images are visually compared to determine areas of BBB fenestration. However, the recent development of the ability to rapidly acquire T1-weighted images before, during, and after the infusion of a bolus of paramagnetic contrast agent provides a means of quantitatively determining the rates of contrast agent uptake and washout within a lesion. In theory, simple two-compartment pharmacokinetic modeling of the contrast agent kinetics can then be used to map the fractional plasma volume (vascular volume),

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endothelial transfer coefﬁcient (permeability-surface area product in cases where contrast leakage is not ﬂow rate limited; extraction-ﬂow product when leakage is great enough to be ﬂow limited41), and the contrast agent reﬂux rate. Such noninvasive measures of vascular endothelial parameters might be useful in determining the penetration of chemotherapeutic agents, in assessing the efﬁcacy of antiangiogenic agents, and in more speciﬁcally characterizing lesions in a noninvasive manner, e.g., differentiating between tumor progression and treatment-related changes. Applications of dynamic contrast-agent-enhanced MR imaging to neuroimaging of patients with intracranial neoplasms have been previously reported. The utility of such scans in differentiating treatment-related changes from primary brain tumors, metastases, and meningiomas has been previously described42, and signiﬁcant correlations between outcome measures and dynamic contrast MR imaging measures in anaplastic astrocytoma and glioblastoma multiforme patients have been reported by Wong et al.43. In addition to these studies, which were based on empirical modeling of the dynamic data, several pharmacokinetic studies have been reported in which the endothelial transfer coefﬁcient, contrast reﬂux rate, and fractional plasma volume have been determined41, 44 – 46. When such calculations are performed on a pixel-by-pixel basis, the rapidly acquired source images can be used to generate maps of each of the above parameters47. Such parametric maps allow for improved assessment of lesion heterogeneity, thereby avoiding the potential for “sampling error”. An example of an endothelial transfer coefﬁcient (“permeability”) map from a patient with recurrent breast carcinoma metastasis is given in Plate 5.1c.

Diffusion MR imaging techniques If appropriate gradient pulses are applied within the echo time of a spin-echo echoplanar imaging (EPI) sequence, the resulting image contrast can be made to depend strongly on the rate of diffusion, or Brownian motion, of the nuclear spins of interest. The larger the area under the applied diffusion-sensitizing gradients, the greater the inﬂuence of diffusion on the image contrast. This area is directly related to the often-quoted “b factor” value. More speciﬁcally, the degree of attenuation of the signal from a given tissue in diffusionweighted images is proportional to e-bD, where b is the b factor value and D is the diffusion coefﬁcient. Thus, for a given b factor, larger diffusion coefﬁcient levels are associated with larger degrees of signal attenuation. Similarly, for a given diffusion coefﬁcient level, the degree of signal attenuation increases with increasing values of b. Therefore, in diffusion-weighted images, regions where diffusion is more restricted are hyperintense relative to regions of unrestricted diffusion. In general, to obtain the degree of diffusion sensitization necessary for acceptable image contrast, the b factor values must be rather large, e.g., 1,000 sec/mm2. Therefore, the areas of the diffusion-sensitizing gradient pulses are

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large, and the minimum echo time is relatively long, resulting in T2-weighted source image contrast. Since the images are T2-weighted, substances with long T2 values may not be as hypointense as expected based solely on the rate of diffusion, resulting in “T2 shine-through” of such substances in the diffusionweighted images. To remove such confounding shine-through effects, image contrast may be based on the “apparent diffusion coefﬁcient” or ADC33, 48, 49. The ADC images are computed from a set of diffusion-weighted images obtained with multiple (approximately 2 to 5) b factor values. Note that the contrast pattern on ADC-weighted images is the inverse of the contrast pattern obtained on diffusion-weighted images; regions where diffusion is restricted are hypointense and regions where diffusion is unrestricted are hyperintense. Water diffusion in some tissues is anisotropic50. For example, diffusion along white matter tracts of the brain is much less restricted than diffusion across the tracts. Therefore, if diffusion-sensitizing gradient pulses are applied only in one direction, it is difﬁcult to know if signal variations in the image plane are due to true differences in diffusion rates or due to white matter diffusion anisotropy. To remove this confusion, diffusion-sensitizing gradients are typically applied in each of the three orthogonal directions, and the results averaged together to yield the average or “trace” diffusion-weighted image in which the anisotropic diffusion rate information is suppressed. On the other hand, the fact that white matter tract diffusion is anisotropic does allow the use of diffusion tensor imaging techniques for noninvasively mapping the white matter tracts51–53, and the resulting “MR tractograms” may have utility in neurosurgical planning. Thus far, the primary clinical application of diffusion imaging has been the detection of acute stroke36, 54, 55. On diffusion-weighted images, areas of restricted extracellular water diffusion, secondary to increased cellular volume, appear hyperintense in acute ischemic injury. These signal changes have been shown to occur well before detectable changes are seen on T2-weighted or FLAIR images, and they have been useful in the detection and staging of ischemic injury. Furthermore, quantitative diffusion imaging, by providing a means of noninvasively assessing the degree of cellularity56, may prove useful in improved characterization of intracranial lesions. As with perfusion imaging techniques, diffusion imaging requires very high-speed imaging capabilities. In fact, of all the current advanced neuroimaging techniques, diffusion imaging is the most demanding of the MR scanner hardware. The large gradient ﬁeld pulses currently push the limit of even state-of-the-art scanners and typically require relatively long echo times, potentially increasing the T2 shine-through problem.

Functional MR imaging techniques for assessing neuronal activation Prior to recent developments in MR, the only imaging modality that was capable of imaging areas of neuronal function was positron emission tomography

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(PET). Other techniques for mapping areas of activation, e.g., electroencephalography (EEG) and magnetoencephalography (MEG), were not imagebased, and spatial localization of the activated areas was coarse at best. In 1991 and 1992, two new functional magnetic resonance imaging (fMRI) techniques were reported for indirectly mapping areas of neuronal activation in response to a visual stimulus57, 58. The underlying physiological principle for both techniques is that the neuronal activation that occurs in response to a stimulus, such as a visual task, results in local vasodilation and a concomitant local increase in rCBV and rCBF. The ﬁrst fMRI technique used to map this increase was the bolus contrast-agent-enhanced DSC perfusion imaging acquisition discussed previously. First, a resting rCBV map was acquired. Then, during a given functional task, a second bolus of contrast agent was administered, and a second rCBV map was obtained. The difference in the two images provided a map of areas of the brain that exhibited increased rCBV during the task. The advantage of the DSC fMRI techniques is that the signal intensity change between rest and activation is approximately 30% at 1.5 tesla. The disadvantage, however, is the required contrast agent infusion (twice per set of functional images), which limits the number of tasks that can be evaluated in a single imaging session and how soon such sessions can be repeated. The second fMRI technique is based on blood oxygen level dependent (BOLD) contrast and is currently the most commonly used approach for imaging areas of neuronal activation. In this technique, no exogenous contrast agent is administered. Instead, the fact that deoxyhemoglobin is a paramagnetic substance and oxyhemoglobin is a diamagnetic substance is taken advantage of. As noted in discussing the DSC perfusion imaging technique, paramagnetic substances cause increased dephasing of the MR signal (signal loss) on T2weighted or T2*-weighted images due to susceptibility effects. On the other hand, diamagnetic substances have minimal effect on signal dephasing. Therefore, a given amount of deoxyhemoglobin (paramagnetic) results in more signal loss relative to the same amount of oxyhemoglobin (diamagnetic). In regions of neuronal activation, local increases in rCBV and rCBF result in local increases in the oxyhemoglobin concentration, and as shown by previous PET studies59, the rate of oxygen extraction is signiﬁcantly less than the rate of oxyhemoglobin delivery. Therefore, in areas of activation, there is a net increase in the oxyhemoglobin-to-deoxyhemoglobin ratio and a concomitant increase in signal intensity on T2-weighted or T2*-weighted images. The key advantage of this technique is that it is totally noninvasive. However, the change in signal intensity at 1.5 tesla is only about 1 to 3%, requiring excellent stability of the MR scanner and well-designed test paradigms and signal processing strategies. (The BOLD signal increases with ﬁeld strength, and much of the recent interest in 3- and 4- tesla scanners stems from the improved BOLD signal response relative to 1.5- tesla scanners.) Since the publication of the ﬁrst fMRI studies of neuronal function in 1991, there have been many reports of BOLD fMRI studies for widely varying applications, including studies of visual stimulation, auditory stimulation,

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memory, language, sensorimotor stimulation, psychiatric disorders, and pain (see, for example, references 33, 36, 60–62, and references therein). Examples of fMRI mapping for presurgical planning purposes are given in Plate 5.2 (facing p. 82).

In vivo MR spectroscopic techniques One of the earliest practical applications of the nuclear magnetic resonance phenomenon was the determination of chemical structure based on MR spectral data. It is not surprising, therefore, that investigators began developing and attempting to apply in vivo MR spectroscopy (MRS) techniques to wholebody scanners as soon as they were commercially available in the mid 1980s. However, clinical MRS applications have lagged signiﬁcantly behind the rapidly advancing imaging capabilities. Nevertheless, the promise of being able to obtain biochemical information in a completely noninvasive manner continues to drive the transition of in vivo MRS from research use to clinical applications. It is beyond the scope of this section to provide detailed descriptions of the acquisition, processing, and clinical applications of in vivo MRS. Instead, a brief overview of each of these topics will be presented, and references will be made to the rather extensive literature available on these subjects. Three basic requirements exist for performing an in vivo MRS examination with a clinical imaging system. First, an appropriate non-zero spin nucleus must be selected, and the system must be capable of transmitting and receiving signals at the frequency appropriate for the chosen nucleus of interest. Although it is theoretically possible to obtain MRS data from a range of biologically interesting nuclei in the human body, natural abundance and relative MR sensitivity considerations generally limit current clinical applications to 1H and 31P studies. The second basic requirement is a means of accurately localizing the region from which the MRS data are to be obtained. Numerous localization schemes have been proposed, but the most commonly used techniques in clinical applications are the single voxel (SV) technique and the spectroscopic imaging (SI) technique. In the SV technique, spectral data are acquired from a single volume of interest (VOI) at a time (a single voxel 1H spectrum from a patient with glioblastoma multiforme is given in Figure 5.15). On the other hand, SI techniques acquire spectral data from a number of VOIs simultaneously, thereby allowing for assessment of lesion heterogeneity and/or comparison with surrounding “normal” tissue(s). In addition, SI techniques allow one to generate low-resolution images of the spatial distribution of chosen biochemicals. However, there are advantages and disadvantages of both SV and SI techniques63. Regardless of the chosen acquisition technique, an additional requirement, at least for 1H MRS acquisitions, is the ability to suppress the signal from water because the concentrations of the compounds of interest are typically 5,000–10,000 times less than the concentration of water.

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Figure 5.15 Single voxel spectrum (stimulated-echo acquisition mode [STEAM], echo time [TE] = 30 ms, repetition time [TR] = 2000 ms) from a glioblastoma multiforme in a patient. Relative to a normal brain spectrum acquired for this patient with the same parameters, there is a greatly decreased level of N-acetylaspartate (NAA), an elevated lactate level, and an elevated choline level.

The third basic requirement for clinical MRS examinations is a means of analyzing the spectral data. There are three primary ways that spectral data can be analyzed. The ﬁrst is by visual inspection of the spectral peaks; this is clearly the simplest, though highly subjective, method to implement. The second commonly used method is to form ratios of spectral peak heights, or areas, with respect to a chosen reference peak. For 1H brain spectra, the most commonly used reference peak is that of creatine/phosphocreatine resonance, which varies minimally with spatial position within the brain. This approach is clearly more quantitative and less subjective than the visual inspection method. However, in disease processes, changes in spectral peak ratios may reﬂect concentration changes in the compound of interest, in the reference compound, or both. The third method for analyzing spectral data is to obtain absolute metabolite concentrations from the associated spectral peak areas. Although clearly the most objective technique, this method of analysis is notoriously difﬁcult. To convert from peak areas to absolute concentration values requires a reference peak from a compound with known concentration. This reference compound may be either internal, most commonly water, or an external standard from which a spectrum is obtained just before or just after the in vivo MRS data acquisition. The internal standard approach may be problematic in disease states where the internal reference compound concentration changes, whereas in the external standard approach, it can be difﬁcult to position and obtain a spectrum from the reference standard under the same conditions that existed when the in vivo MRS acquisition occurred. Given the lack of objectivity of the visual inspection technique and the inherent difﬁculties of the absolute concentration technique, many investigators have chosen to use spectral peak ratios as the method of choice for routine analysis of spectral data. However, because the T1 and T2 relaxation times of the various compounds of interest vary, it should be noted that the spectral peak heights, areas, and ratios depend strongly on the echo time (TE) and, to a lesser degree, the repetition time (TR). Therefore, when comparing spectral data to literature

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values or between examinations or patients, it is important to take the TE and TR values into account. There are several review articles and texts describing the wide range of clinical applications of in vivo MRS63, 64 –72. In a normal human brain spectrum, the most prominent spectral peak is due to N-acetylaspartate (NAA). Although the exact biochemical role of NAA has yet to be fully elucidated, it is present in abundance only in viable neurons72. Reduction in the normal level of NAA is a sensitive indicator of neuronal degradation but is quite nonspeciﬁc. The next most prominent spectral peaks in the normal brain spectrum are produced by creatine/phosphocreatine and choline-containing compounds. Less prominent peaks from myoinositol and, for short TE spectra, glutamate/ glutamine, are also visible. Lactate peaks are typically below detection limits in a normal brain but may be visible in the case of disease states, including ischemic injury and the presence of some neoplasms. Spectral peaks from lipids, abundant in the myelin, are not seen in a normal brain due to the rigid structure of the lipids within the myelin. In some disease states, however, lipid peaks and peaks from macromolecular breakdown products may be present, particularly in spectra acquired with short echo times (The effective T2 relaxation times of these breakdown products are relatively short.). In patients with neoplastic lesions, the most common ﬁndings are elevated levels of cholinecontaining compounds, decreased levels of creatine/phosphocreatine, and decreased levels of NAA. Lactate may or may not be present. Therefore, using the spectral peak ratio method of analysis, the most common ﬁnding in neoplastic lesions is elevated choline-to-creatine and choline-to-NAA ratios relative to normal brain tissue levels. Treatment-related changes, such as radiation necrosis, do not typically demonstrate such highly elevated choline-tocreatine ratios and are often associated with the presence of peaks due to lipids and other macromolecular breakdown products (particularly in short TE spectra). Typical spectroscopic imaging technique results in patients with glioblastoma multiforme and breast carcinoma brain metastasis are given in Figure 5.16 and Plate 5.3 (facing p. 82), respectively.

Summary of advanced MR techniques In the last ﬁve years, signiﬁcant improvements in MR scanner technology have driven the implementation of new neuroimaging techniques that have produced a transition in MR imaging from a means of acquiring images with exquisite anatomical detail and soft tissue contrast to a means of acquiring images of tissue function. Although many of these functional imaging techniques are currently in a translational stage from basic research to clinical practice, several are poised to make a signiﬁcant impact on clinical patient management and outcome. Newer imaging techniques, including more speciﬁc contrast agents and novel image contrast mechanisms, will undoubtedly continue to propel the expanding use of MR imaging in neuroimaging applications. In addition, signiﬁcant improvements in automated SV and SI

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Figure 5.16 Spectroscopy imaging data from a patient with glioblastoma multiforme (pointresolved spectroscopy [PRESS]-spectroscopic imaging, TE = 144 ms, TR = 1,000 ms). (Left) FLAIR image with selected volumes of interest (VOIs, grey squares) within the large excited volume (grey rectangle). (Right) Spectra from the numbered VOIs. Notice the highly elevated choline levels in VOIs 9 and 10 (spectra indicated with H and VOIs highlighted in FLAIR image) compared with the relatively normal spectrum from VOI 28 (lower right spectrum, lower right VOI in image). (Peak assignments in VOI 28 spectrum are 1: choline; 2: creatine/phosphocreatine; 3: NAA.)

in vivo MRS data acquisition and processing techniques have allowed for “routine” acquisition of biochemical information that can be used, for example, to aid in the often difﬁcult differentiation of tumor progression from treatmentrelated changes.

References 1 Posner JB: Management of central system metastases. Semin Oncol 1977; 4: 81–91. 2 Posner JB: Management of brain metastases. Rev Neurol (Paris) 1992; 148: 477– 487. 3 Cappuzzo F, Mazzoni F, Maestri E, et al.: Medical treatment of brain metastases from solid tumors. Forum (Genova) 2000; 10: 137–148. 4 Delattre JY, Krol G, Thaler HT, et al.: Distribution of brain metastases. Arch Neurol 1988; 45: 741–748. 5 Patchell RA, Tibbs PA, Walsh JN, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 6 Blood CH, Zetter BR: Tumor interactions with vasculature angiogenesis and tumor metastasis. Acta Biochim Biophys 1990; 1032: 89–118. 7 Folkman J: Clinical application of research on angiogenesis. N Engl J Med 1995; 333: 1757–1763. 8 Frank JA, Girton M, Dwyer AJ, et al.: Ocular and cerebral metastases in the VX2 rabbit tumor model: contrast-enhanced MR imaging. Radiology 1987; 164: 527–530. 9 Risau W: Mechanisms of angiogenesis. Nature 1997; 386: 671– 674.

Imaging of metastatic tumors of the brain 91 10 Li W: Tumor angiogenesis: molecular pathology, therapeutic targeting and imaging. Acad Radiol 2000; 7: 800 – 811. 11 Rumana CS, Hess KR, Shi WM, et al.: Metastatic brain tumors with dural extension. J Neurosurg 1998; 89: 552–558. 12 Braun IR, Chambers E, Leeds NE, et al.: The value of unenhanced scans in differentiating lesions producing ring enhancement. AJNR Am J Neuroradiol 1982; 3: 643 – 647. 13 Davis PC, Hudgins PA, Peterman SB, et al.: Diagnosis of cerebral metastases: double dose delayed CT vs contrast-enhanced MR imaging. AJNR Am J Neuroradiol 1991; 12: 293–300. 14 Yuh WTC, Engelken JD, Muhonen MG, et al.: Experience with high-dose gadolinium MR imaging in the evaluation of brain metastases. AJNR Am J Neuroradiol 1992; 13: 335 –345. 15 Schörner W, Laniado M, Niendorf HP, et al.: Time-dependent changes in image contrast in brain tumors after gadolinium-DTPA. AJNR Am J Neuroradiol 1986; 7: 1013 –1020. 16 Sze G, Milano E, Johnson C, et al.: Detection of brain metastases: comparison of contrastenhanced MR with unenhanced MR and enhanced CT. AJNR Am J Neuoradiol 1990; 11: 785–791. 17 Singh SK, Agris JM, Leeds NE, et al.: Intracranial leptomeningeal metastases: comparison of depiction at FLAIR and contrast-enhanced MR imaging. Radiology 2000; 217: 50 –53. 18 Kumar AJ, Leeds NE, Fuller GN, et al.: Malignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapy-induced necrosis of the brain after treatment. Radiology 2000; 217: 377–384. 19 Hazle JD, Jackson EF, Schomer DF, et al.: Dynamic imaging of intracranial lesions using fast spin-echo imaging: differentiation of brain tumors and treatment effects. J Magn Reson Imaging 1997; 7: 1084 –1093. 20 Wong ET, Jackson EF, Hess KR, et al.: Correlation between dynamic MRI and outcome in patients with malignant gliomas. Neurology 1998; 50: 777–781. 21 Aronen JH, Gazit IE, Louis DN, et al.: Cerebral blood volume maps of gliomas: comparison with tumor grade and histologic ﬁndings. Radiology 1994; 191: 41–51. 22 Sugahara T, Korogi Y, Kochi M, et al.: Usefulness of diffusion-weighted MRI with echoplanar technique in the evaluation of cellularity in gliomas. J Magn Reson Imaging 1999; 9: 53 –60. 23 Burtscher IM, Skagerberg G, Geijer B, et al.: Protein MR spectroscopy and preoperative diagnostic accuracy: an evaluation of intracranial mass lesions characterized by stereotactic biopsy ﬁndings. AJNR Am J Neuroradiol 2000; 21: 84 –93. 24 Ott D, Hennig J, Ernst T: Human brain tumors: assessment with in vivo proton MR spectroscopy. Radiology 1993; 186: 745 –752. 25 Poptani H, Gupta RK, Roy R, et al.: Characterization of intracranial mass lesions with in vivo proton MR spectroscopy. AJNR Am J Neuroradiol 1995; 16: 1593 –1603. 26 Haimes AB, Zimmerman RD, Morgello S, et al.: MR imaging of brain abscesses. AJR Am J Roentgenol 1989; 152: 1073 –1085. 27 Desprechins B, Stadnik T, Koerts G, et al.: Use of diffusion weighted imaging in differential diagnoses between intracerebral necrotic tumors and cerebral abscesses. AJNR Am J Neuroradiol 1999; 20: 1252–1257. 28 Ebisu T, Tanak AC, Umeda M, et al.: Discrimination of brain abscess from necrotic or cystic tumors by diffusion-weighted echo planar imaging. J Magn Reson Imaging 1996; 14: 1113–1116. 29 Leeds NE: Pitfalls recognized in the magnetic resonance evaluation of patients with primary and secondary brain neoplasms. Neuroimaging Clin N Am 1993; 3: 755 –770.

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30 Isiklar I, Leeds NE, Fuller GN, et al.: Metastatic intracranial melanoma: correlation between MR imaging characteristics and melanin content. AJR Am J Roentgenol 1995; 165: 1503–1512. 31 Carrier DA, Mawad ME, Kirkpatrick JB, et al.: Metastatic adenocarcinoma to the brain: MR with pathologic correlation. AJNR Am J Neuroradiol 1994; 15: 155 –159. 32 Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1989; 82: 4–6. 33 Sanders JA, Orrison WWJ: Functional magnetic resonance imaging. In: Orrison WWJ, Lewine JD, Sanders JA, Hartshorne MF (eds): Functional Brain Imaging. St. Louis, MO, Mosby-Year Book, Inc, 1995, pp. 239–326. 34 Ostergaard L, Sorensen AG, Kwong KK, et al.: High resolution measurement of cerebral blood ﬂow using intravascular tracer bolus passages. Part II: Experimental comparison and preliminary results. Magn Reson Med 1996; 36: 726 –736. 35 Ostergaard L, Weisskoff RM, Chesler DA, et al.: High resolution measurement of cerebral blood ﬂow using intravascular tracer bolus passages. Part I: Mathematical approach and statistical analysis. Magn Reson Med 1996; 36: 715 –725. 36 Sorenson AG, Rosen BR: Functional MRI of the brain. In Atlas SW (ed): Magnetic Resonance Imaging of the Brain and Spine. Philadelphia, PA, Lippincott-Raven Publishers, 1996, pp. 1501–1545. 37 Sorenson AG, Tievsky AL, Ostergaard L, et al.: Contrast agents in functional MR imaging. J Magn Reson Imaging 1997; 7: 47–55. 38 Detre JA, Leigh JS, Williams DS, et al.: Perfusion imaging. Magn Reson Med 1992; 23: 37– 45. 39 Edelman RR, Siewert B, Darby DG, et al.: Qualitative mapping of cerebral blood ﬂow and functional localization with echo-planar MR imaging and signal targeting with alternating radio frequency. Radiology 1994; 192: 513 –520. 40 Alsop DC, Detre JA: Reduced transit-time sensitivity in noninvasive magnetic resonance imaging of human cerebral blood ﬂow. J Cereb Blood Flow Metab 1996; 16: 1236 –1249. 41 Tofts PS: Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging 1997; 7: 91–101. 42 Hazle JD, Jackson EF, Schomer DF, et al.: Dynamic imaging of intracranial lesions using fast spin-echo imaging: differentiation of brain tumors and treatment effects. J Magn Reson Imaging 1997; 7: 1084 –1093. 43 Wong ET, Jackson EF, Hess K, et al.: Correlations between dynamic MRI and outcome in patients with malignant glioma. Neurology 1998; 50: 777–781. 44 Larsson HBW, Stubgaard M, Frederiksen JL, et al.: Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors. Magn Reson Med 1990; 16: 117–131. 45 Tofts PS, Kermode AG: Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn Reson Med 1991; 17: 357–367. 46 Parker GJM, Tofts PS: Pharmacokinetic analysis of neoplasms using contrast-enhanced dynamic magnetic resonance imaging. Top Magn Reson Imaging 1999; 10: 130–142. 47 Parker GJM, Suckling J, Tanner SF, et al.: Probing tumor microvascularity by measurement, analysis and display of contrast agent uptake kinetics. J Magn Reson Imaging 1997; 7: 564–574. 48 Le Bihan D, Turner R, Douek P, et al.: Diffusion MR imaging: clinical applications. AJR Am J Roentgenol 1992; 159: 591–599. 49 Le Bihan D, Turner R: Diffusion and perfusion nuclear magnetic resonance imaging. In: Potchen EJ, Haacke EM, Siebert JE, Gottschalk A. (eds): Magnetic Resonance Angiography. Concepts & Applications. St Louis, Mosby-Year Book, Inc. 1993, pp. 323–342.

Imaging of metastatic tumors of the brain 93 50 Moseley ME, Cohen Y, Kucharczyk J, et al.: Diffusion-weighted MR imaging of anisotropic water diffusion in cat central nervous system. Radiology 1990; 176: 439 – 445. 51 Pierpaoli C, Jezzard P, Basser PJ, et al.: Diffusion tensor MR imaging of the human brain. Radiology 1996; 201: 637– 648. 52 Pajevic S, Pierpaoli C: Color schemes to represent the orientation of anisotropic tissues from diffusion tensor data: application to white matter ﬁber tract mapping in the human brain. Magn Reson Med 1999; 42: 526 –540. 53 Virta A, Barnett A, Pierpaoli C: Visualizing and characterizing white matter ﬁber structure and architecture in the human pyramidal tract using diffusion tensor MRI. Magn Reson Imaging 1999; 17: 1121–1133. 54 Van Gelderen P, de Vleeschouwer MHM, DesPres D, et al.: Water diffusion and acute stroke. Magn Reson Med 1994; 31: 154 –163. 55 Beauchamp NJJ, Ulug AM, Passe TJ, et al.: MR diffusion imaging in stroke: review and controversies. Radiographics 1998; 18: 1269 –1283. 56 Chenevert TL, McKeever PE, Ross BD: Monitoring early response of experimental brain tumors to therapy using diffusion magnetic resonance imaging. Clin Cancer Res 1997; 3: 1457–1466. 57 Belliveau JW, Kennedy DN, McKinstry RC, et al.: Functional mapping of the human cortex by magnetic resonance imaging. Science 1991; 254: 716 –719. 58 Kwong KK, Belliveau JW, Chesler DA, et al.: Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci USA 1992; 89: 5675–5679. 59 Fox P, Raichle M: Focal physiological uncoupling of cerebral blood ﬂow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci USA 1986; 83: 1140–1144. 60 Buckner RL, Koutstaal W: Functional neuroimaging studies of encoding, priming, and explicit memory retrieval. Proc Natl Acad Sci USA 1998; 95: 891– 898. 61 Tootell RB, Hadjikhani NK, Vanduffel W, et al.: Functional analysis of primary visual cortex (V1) in humans. Proc Natl Acad Sci USA 1998; 95: 811–817. 62 Turner R, Howseman A, Rees GE, et al.: Functional magnetic resonance imaging of the human brain: data acquisition and analysis. Exp Brain Res 1998; 123: 5 –12. 63 Jackson EF. Magnetic resonance spectroscopy: physical principles and applications. In: Kim EE, Jackson EF (eds): Molecular Imaging in Oncology. Berlin, Springer, 1999, pp. 47– 70. 64 Negendank W: Studies of human tumors by MRS: a review. NMR Biomed 1992; 5: 303 – 324. 65 Barker PB, Glickson JD, Bryan RN: In vivo magnetic resonance spectroscopy of human brain tumors. Top Magn Reson Imaging 1993; 5: 32– 45. 66 Howe FA, Maxwell RJ, Saunders DE, et al.: Proton spectroscopy in vivo. Magn Reson Q 1993; 9: 31–59. 67 Ross B, Michaelis T: Clinical applications of magnetic resonance spectroscopy. Magn Reson Q 1994; 10: 191–247. 68 Vion-Dury J, Meyerhoff DJ, Cozzone PJ, et al.: What might be the impact on neurology of the analysis of brain metabolism by in vivo magnetic resonance spectroscopy? J Neurol 1994; 241: 354–371. 69 Cox I: Development and applications of in vivo clinical magnetic resonance spectroscopy. Prog Biophys Mol Biol 1996; 65: 45 – 81. 70 Falini A, Calabrese G, Origgi D, et al.: Proton magnetic resonance spectroscopy and intracranial tumors: clinical perspectives. J Neurol 1996; 243: 706 –714.

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71 Ross B, Michaelis T: MR spectroscopy of the brain: neurospectroscopy. In: Edelman RR, Hesselink JR, Zlatkin MB (eds): Clinical Magnetic Resonance Imaging. Philadelphia, W.B. Saunders Co, 1996, pp. 928–981. 72 Castillo M, Kwock L: Proton MR spectroscopy of common brain tumors. Neuroimaging Clin N Am 1998; 8: 733 –752.

PA RT II

Principles of therapy

CHAPTER 6

Intracranial metastases: medical management and prognostic factors Susanne M Arnold, Roy A Patchell

Metastases to the brain are the most common type of intracranial tumor, occurring in over 100,000 patients per year in the United States1. As many as 25% of adults and 10% of children with systemic cancer will develop brain metastases during their lifetime2. Whereas signiﬁcant advancement has been made in the diagnosis and treatment of cerebral metastases, medical management of them has remained relatively constant for several decades. In this chapter, we will examine the medical treatment and prognosis of metastases to the brain. The appropriate medical management of brain metastases can aid in rapid stabilization of patients and improvement in quality and length of life.

Clinical presentation One of the most devastating complications of human cancer progression is the development of brain metastases. Because the brain lies within the rigid conﬁnes of the skull, even small brain lesions can have a perilous effect on neurological function and length of life. Metastases to the brain are usually symptomatic, with more than two-thirds of patients who have cancer developing some neurological symptoms during the course of their illness. The presentation is similar to that of any intracranial mass lesion. Seizures, either focal or generalized, occur in approximately 10% of patients at presentation and are more common in patients with multiple metastases1. Focal seizures can occasionally mimic symptoms of a transient ischemic attack. When focal seizures occur, they may provide localizing information. Five to ﬁfteen percent of patients may present with acute neurological symptoms caused by hemorrhage into the tumor or by cerebral infarction from embolic or compressive occlusion of a blood vessel3. Hemorrhage into a metastasis is particularly common with choriocarcinoma and melanoma4, 5. Intracranial hemorrhage may obscure a contrast-enhancing mass and complicate the diagnostic work up of brain metastases. In these cases, it is advisable to treat the patients as if they have brain metastases until the cause of the hemorrhage can be deﬁned. In summary, the signs and symptoms of cerebral lesions are often quite subtle; therefore, brain metastases should be suspected and

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aggressively pursued in all patients with known systemic cancer in whom new neurological ﬁndings develop.

Diagnostic testing The best diagnostic tests for brain metastases are contrast-enhanced magnetic resonance imaging (MRI) and, to a lesser extent, computed tomography (CT)6, 7. If the clinical history is typical and lesions are multiple, there is usually little doubt surrounding the diagnosis. However, it is important to distinguish metastases carefully from primary brain tumors, abscesses, cerebral infarction, and hemorrhages. Radiographic ﬁndings that favor metastases include: a gray/white matter junction location, relatively smooth margins, a small tumor nidus with a large amount of associated vasogenic edema, and the presence of multiple lesions8. It is also critical to accurately identify patients with single metastases, whose subsequent management and prognosis may be different. Brain metastases may be detected at the same time as the primary tumor (synchronous presentation) or, in over 80% of cases, after the primary tumor (metachronous presentation). When a brain mass is discovered on a patient’s CT images or by MRI and there is no prior history of cancer, it is difﬁcult to know how far to pursue investigation. In most cases of brain metastases, the primary tumor resides in the lungs or has metastasized there prior to disseminating to the brain. More than 60% of patients with brain metastases will have a mass demonstrated on a plain chest x-ray9 –11. When the chest x-ray fails to demonstrate a mass, CT imaging of the chest should be pursued because of its increased sensitivity in ﬁnding smaller lesions12. Colon cancer, renal cell cancer, and melanoma can present as brain metastases from an unknown primary site, and an abdominal CT scan and thorough skin exam may yield an occult primary tumor. Further evaluation is almost never productive without positive ﬁndings in the history or localizing signs on physical examination that suggest a speciﬁc primary tumor. When no identiﬁable lesion is found in the lung, the mechanism of metastatic extension to the brain may be via a patent foramen ovale (paradoxical embolus), tumor ﬁltration through the lungs without lung metastasis, or dissemination through Batson’s vertebral venous plexus from a pelvic or retroperitoneal mass.

Treatment The medical management of brain metastases primarily involves the treatment of cerebral edema and increased intracranial pressure, the control of seizures, and the management of intercurrent illnesses and conditions. Chemotherapy, when directed primarily against the brain metastases, may also be considered as medical management. Clearly, radiation and surgery are the primary modalities of treatment for brain metastases and are discussed at length in other chapters of this text.

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Treatment of cerebral edema and increased intracranial pressure Cerebral edema caused by brain tumors is primarily vasogenic in origin. It occurs when the blood-brain barrier (BBB) breaks down, allowing sodium and water to increase in the brain parenchyma. In response to this ﬂuid inﬂux, lactic acid increases and abnormal vascular autoregulation occurs. Corticosteroids help stabilize the BBB via endothelial cell interactions, although their mechanism of effect on brain edema is much more complex than this13. Almost all patients with brain metastases should be started on corticosteroid therapy at the time of diagnosis. Patients with small, completely asymptomatic lesions may not need steroids; however, steroids may reduce the side-effects of cranial irradiation through a reduction in brain edema14 and are rarely harmful to most patients for short periods of time. The beneﬁcial effects of steroids are noticeable within 6 to 24 hours after the ﬁrst dose and reach their maximum effect in 3 to 7 days15. The median survival time of patients treated with steroids alone is approximately two months16, 17, although much longer lengths of survival have been reported15, 18. Dexamethasone is the preferred form of corticosteroid for this purpose because it has a minimal mineralocorticoid effect and a relatively low tendency to induce psychosis12, 19. More than 70% of patients improve symptomatically after undergoing steroid administration14. Symptoms reﬂecting generalized neurological dysfunction or brain edema respond more consistently to steroids than do focal symptoms such as hemiparesis. The usual starting dose of dexamethasone is 4 mg four times daily, given either orally or intravenously. Occasionally, patients require higher doses. With stabilization of symptoms and the completion of more deﬁnitive treatment, the dose of dexamethasone should be reduced gradually over several weeks and then stopped in order to minimize long-term toxicity. About 10% of patients with brain metastases do not tolerate the reduction in steroids and redevelop the signs of brain edema. In these patients, the lowest effective dose should be continued indeﬁnitely. Concomitant use of histamine blockers or proton-pump inhibitors to prevent gastritis and peptic ulcer formation is commonplace, but no randomized trials have deﬁned efﬁcacy in this patient population. Acute decompensation from brain metastases may occur with any of the following: intratumoral hemorrhage, obstructive hydrocephalus, ﬂuid imbalances secondary to hyponatremia, hypotension, radiation necrosis, seizures, or brain infarct. The medical management of acutely increased intracranial pressure (ICP) has three components: 1 stabilization of the BBB 2 reversal of vasogenic swelling 3 coordination of surgical removal or emergent brain irradiation. Hyperventilation, head elevation, intracranial pressure monitoring, corticosteroids, osmotic diuretics, and cerebrospinal ﬂuid drainage via intraventricular catheters (IVC) are all measures that can acutely lower the patient’s ICP. The effect of hyperventilation is transient, and IVCs are associated with

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the risk of infection and bleeding20. Osmotic diuretics (e.g., mannitol) have the risk of rebound intracranial hypertension with repeated use20, 21. In most cases, it is advisable to begin corticosteroids, mannitol, and hyperventilation in the acutely decompensating patient. Once the patient is stable, surgery or irradiation should be undertaken as quickly as possible.

Management of seizures Seizures occur in about 25% of patients with brain metastases and are the presenting complaint in 10% of patients22–25. Two randomized trials25 have shown that prophylactic anticonvulsants do not reduce the frequency of the ﬁrst seizure in patients with newly diagnosed brain metastases. Therefore, anticonvulsants should not be given routinely at the time of the diagnosis of brain metastases but should only be given to patients who have actually had seizures25. In patients with seizures due to brain metastases, the choice of anticonvulsants is broad. Phenytoin has been a mainstay of anticonvulsant therapy. The drug is usually well tolerated and is effective against the most common seizure types. In addition, it can be given orally or parenterally. Phenytoin carries the risk of erythema multiforme, especially when given concomitantly with cranial irradiation26, and can induce increased clearance and decreased half-life of dexamethasone, as can phenobarbital. One alternative drug, carbamazepine, can be used in the nonurgent setting and gradually increased with time27. Valproic acid, although less effective in partial seizures, is another alternative, as are newer agents.

Deep venous thrombosis and anticoagulation Patients with systemic cancer are at an increased risk for developing deep venous thrombosis (DVT). As many as 20% of patients with brain metastases will develop DVT28. The management of DVT with anticoagulants in these patients can be especially difﬁcult because of the increased risk of intracranial hemorrhage. The concern for intracranial bleeding with anticoagulation therapy has led to the common practice of placing an inferior vena cava (IVC) ﬁlter in these patients. In a retrospective analysis of IVC ﬁlter complications in patients with brain neoplasms and DVT, 12% of patients developed a pulmonary embolism (PE) despite the IVC ﬁlter, with an overall complication rate of 62%29. A second study retrospectively reported the outcome of anticoagulation therapy in 42 patients who had brain metastases and DVT30. Seven percent of patients (3 of 42) experienced an intracranial hemorrhage (ICH); two patients who had a devastating ICH also were being treated with supratherapeutic anticoagulation at the time of the ICH. Furthermore, 40% of patients (4 of 10) treated with an IVC ﬁlter alone experienced recurrent, nonfatal thromboembolic events. No studies of patients with brain metastases and DVTs have examined the use of newer anticoagulants such as the low-molecular-weight heparins and heparinoids. It is therefore advisable to use warfarin in patients who have brain metastases and DVTs or PEs, with close monitoring of anti-

Intracranial metastases: medical management and prognostic factors 101

coagulation to avoid supratherapeutic levels. Use of low-molecular-weight heparin may help avoid producing supratherapeutic anticoagulant levels in these patients, but its use is unproven. In patients whose initial brain metastases were hemorrhagic, those at risk for falls or head trauma, those with poorly controlled seizures, or those with very large metastases, anticoagulation therapy is not advised.

Chemotherapy Unfortunately, most systemic chemotherapeutic agents that have proven efﬁcacy against primary cancers have little activity against cerebral metastases from the same cell population31, 32, because of inconsistent delivery of such drugs into the central nervous system (CNS). The entry of a drug into the brain depends on its molecular weight, lipid solubility, degree of ionization, protein or tissue binding properties, and local cerebral blood ﬂow. Prior to the development of brain metastases, an intact BBB may prevent dependable dispersion of chemotherapeutic agents into the brain parenchyma. Tsukada et al.33 have suggested that the BBB may increase the incidence of brain metastases after systemic chemotherapy by producing a kind of “pharmacological sanctuary” within the central nervous system. Although the BBB is disrupted both at the site of brain metastases and after cranial irradiation, other factors may play a role in the relative chemoresistance found within the brain34. Many drugs have been demonstrated to reach therapeutic levels in the brain (including methotrexate, cisplatin, vinblastine and carmustine)35 but then to dissipate rapidly or fail to attain a high enough concentration to ensure tumor cell death. The drugs appear to concentrate preferentially in necrotic areas rather than to spread uniformly throughout the tumor, diffusing away from tumor sites into the drug-free normal brain by a sink-like effect36. Furthermore, the BBB may be intact in one area and not in others within the brain, allowing inconsistent penetration of drugs rather than uniform exposure of the whole brain to chemotherapy. Chemotherapy has been used in the treatment of brain metastases from a variety of primary tumors; however, the results have generally been lackluster 32–39. The most impressive responses have been in patients with certain highly chemosensitive tumors (e.g., breast cancer, small cell lung cancer, germ cell tumors), but even in this setting, chemotherapy is not the primary therapy and is seldom the only therapy. In a recent study of 116 patients who had brain metastases from melanoma, breast cancer, and lung cancer, cisplatin and etoposide were given every three weeks until disease progression was observed40. Patients with breast cancer and non-small cell lung cancer had response rates (RRs) of 30% and 37%, respectively, whereas melanoma patients experienced no beneﬁt from therapy. Although it appears that chemotherapeutic drugs entered the CNS efﬁciently in one-third of the patients, it remains to be seen what the role of chemotherapy will be in the treatment of brain metastases. Another area in which chemotherapy has most recently been studied is in combination with whole-brain radiation therapy (WBRT) for brain metastases

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from non-small cell lung cancer41– 44. An improved response rate (in the brain) was seen when chemotherapy was added to WBRT, beyond that seen with WBRT alone44. In other nonrandomized trials, response rate (RR) was improved compared with historical controls when multiagent, cisplatin-based chemotherapy was used, and the intracranial RR ranged from 30 to 75%40, 42. In one study, no neurological sequellae were identiﬁed in the small subset of patients who survived for longer than 18 months42. Although radiosensitization appears to be no more toxic than irradiation alone, these are phase II studies, and it is unclear as to whether there is a survival advantage beyond that seen with WBRT alone. The concept of chemosensitizing brain metastases to radiation is intriguing; however, this therapy is clearly experimental and cannot be recommended without supporting data from randomized trials. At present, it is reasonable to give chemotherapy to patients with small, asymptomatic brain metastases from primaries that are known to be chemosensitive. If progression occurs with the patient receiving chemotherapy alone, more deﬁnitive treatment with surgery, radiosurgery, or radiotherapy must be given.

Prognosis The median survival time for untreated patients with brain metastases is less than two months1. Several favorable characteristics have been identiﬁed to help guide the level of aggressiveness with which to treat patients with brain metastases. For example, patients with single brain metastases and limited extracranial disease who are treated with surgery and WBRT have a median survival time of 10 to 16 months45 – 47. Improved survival is also seen in patients with brain metastases as the only manifestation of an undetected primary cancer, with overall median survival at 13.4 months48. Patients who have primary breast cancers who develop brain metastases appear to live longer, whereas those with colorectal cancers and melanomas tend to have a poorer prognosis49, 50. Signiﬁcant progress has been made in the last 5 years in deﬁning patient and disease characteristics that contribute to the prognosis of patients with brain metastases. The largest and most signiﬁcant analysis of prognostic factors was performed by Gaspar and colleagues51, using a recursive partitioning analysis (RPA) of three Radiation Therapy Oncology Group (RTOG) brain metastasis trials. The most favorable group (class 1 patients) had a Karnofsky Performance Scale (KPS) score of 70 or higher, an age of less than 65 years, and a controlled primary tumor with no extracranial metastases. These patients had a median survival time of 7.1 months. Class 3 patients had a KPS score of less than 70 and had a median survival time of 2.3 months. Class 2 patients were those who did not ﬁt into classes 1 or 3. These patients had a median survival time of 4.2 months. The validity of this RPA system for identifying prognostic factors in surgically resected patients has been conﬁrmed in 125 patients who

Intracranial metastases: medical management and prognostic factors 103

underwent surgery and WBRT for brain metastases52. Other independent prognostic factors that have been identiﬁed recently in a study of 1292 patients included: response to steroid therapy, systemic tumor activity, neurological performance status, and serum lactate dehydrogenase level (≤ 350 U/L)53. Clearly, neurological performance status (KPS score) at the time of treatment of brain metastases is the most important prognostic factor in the decisionmaking process.

Summary In summary, the medical management of brain metastases includes recognition of signs and symptoms of increased intracranial pressure, which mandates prompt initiation of corticosteroids in almost all cases. Anticonvulsants should be used only in patients who actually demonstrate seizure activity and should not be given prophylactically. Further therapies for acute increased ICP may include hyperventilation, osmotic diuresis, invasive ICP monitoring and emergency deﬁnitive therapy (i.e., surgery or irradiation). Chemotherapy may play an adjunctive role but is not considered a primary therapy and should be restricted to use in asymptomatic patients with primary tumors that show some degree of chemosensitivity.

References 1 Posner JB: Clinical manifestations of brain metastases. In Weiss L, Gilbert HA, Posner JB (eds): Brain Metastases. Boston, GK Hall, 1980, pp. 189–207. 2 Zimm S, Wampler GL, Stablein D, et al.: Intracranial metastases in solid tumor patients: natural history and results of treatment. Cancer 1981; 48: 384 –394. 3 Cairncross JG, Posner JB: The management of brain metastases. In Walker MD (ed): Oncology of the Nervous System. Boston, Martinus Nijhoff, 1983, pp. 341–377. 4 Mandybur TI: Intracranial hemorrhage caused by metastatic tumors. Neurology 1977; 27: 650–655. 5 Nutt SH, Patchell RA: Intracranial hemorrhage associated with primary and secondary tumors. Neurosurg Clin N Am 1992; 3: 591–599. 6 Davis PC, Hudgins PA, Peterman SB, et al.: Diagnosis of cerebral metastases: double dose delayed CT vs contrast enhanced MR imaging. AJNR 1991; 12: 293 –300. 7 Sze G, Milano E, Johnson C, et al.: Detection of brain metastases: comparison of contrastenhanced MR with unenhanced MR and enhanced CT. AJNR 1990; 1: 785 –791. 8 Williams AL: Tumors. In Williams AL, Haughton VM (eds): Cranial Computed Tomography: A Comprehensive Text. St. Louis, CV Mosby, 1985, pp. 17–29. 9 Bentson JR, Steckel RJ, Kagan AR: Diagnostic imaging in clinical cancer management: brain metastases. Invest Radiol 1988; 23: 335 –341. 10 Delattre JY, Krol G, Thaler HT, et al.: Distribution of brain metastases. Arch Neurol 1988; 45: 741–744. 11 Saphner TJ, Gallion HH, van Nagell JR, et al.: Neurologic complications of cervical cancer: a review of 2261 cases. Cancer 1989; 64: 1147–1151. 12 Latief KH, White CS, Protopapas Z, et al.: Search for a primary lung neoplasm in patients with brain metastases: is the chest radiograph sufﬁcient? AJR 1997; 168: 1339–1344.

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13 Shapiro W, Miesiger E, Cooney G, et al.: Temporal effects of dexamethasone on blood-tobrain and blood-to-tumor transport at 14C-alpha-aminoisobutyric acid in rat C6 glioma. J Neurooncol 1990; 8: 197–204. 14 Ehrenkranz JR, Posner JB: Adrenocorticosteroid hormones. In Weiss L, Gilbert HA, Posner JB (eds): Brain Metastases. Boston, G.K. Hall, 1980, pp. 340–363. 15 Gutin PH: Corticosteroid therapy in patients with cerebral tumor: beneﬁts, mechanisms, problems, practicalities. Semin Oncol 1975; 2: 49–56. 16 Chang DB, Yang PC, Luh KT, et al.: Late survival of non-small cell lung cancer patients with brain metastases. Chest 1992; 101: 1293 –1297. 17 Horton J, Baxter DH, Olson KB: The management of metastases to the brain by irradiation and corticosteroids. Am J Roentgenol Radium Ther Nucl Med 1971; 111: 334 –335. 18 Gottlieb JA, Frei E, Luce JK: An evaluation of the management of patients with cerebral metastases from malignant melanoma. Cancer 1972; 29: 701–705. 19 Fishman RA: Brain edema. N Engl J Med 1975; 293: 706 –711. 20 Bingaman W, Frank J: Malignant cerebral edema and intracranial hypertension. Neurol Clin 1995; 13: 479–509. 21 Smith M, Kelly D, McWhorter J, et al.: Comparison of mannitol regimens in patients with severe head injury undergoing intracranial monitoring. J Neurosurg 1986; 65: 820 – 824. 22 Posner JB: Diagnosis and treatment of metastases to the brain. Clin Bull 1974; 4: 47–57. 23 Posner JB: Management of brain metastases. Rev Neurol 1992; 148: 477– 487. 24 Dunlap FH. Metastatic malignant tumors of the brain. Ann Intern Med 1932; 5: 1274 –1288. 25 Glantz MJ, Cole BF, Forsyth PA, et al.: Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 54: 1886 –1893. 26 Delattre J, Safai B, Posner J: Erythema multiforme and Stevens-Johnson Syndrome in patients receiving cranial irradiation and phenytoin. Neurology 1988; 38: 194 –198. 27 Mattson R, Cramer J, Collins T, et al.: Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985; 313: 145 –151. 28 Sawaya R, Zuccarello M, Elkalliny M, et al.: Postoperative venous thromboembolism and brain tumors: Part I. Clinical proﬁle. J Neurooncol 1992; 14: 119 –125. 29 Levin JM, Schiff D, Loefﬂer JS, et al.: Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology 1993; 43: 1111–1114. 30 Schiff D, DeAngelis L: Therapy of venous thromboembolism in patients with brain metastases. Cancer 1994; 13: 453 –508. 31 Greig NH: Chemotherapy of brain metastases: current status. Cancer Treat Rev 1984; 11: 157–186. 32 Lesser, GJ: Chemotherapy of cerebral metastases from solid tumors. Neurosurg Clin N Am 1996; 7: 527–536. 33 Tsukada Y, Fouad A, Pickren JW, et al.: Central nervous system metastases from breast carcinoma. Autopsy study. Cancer 1983; 52: 2349–2354. 34 Korfel A, Thiel E: Chemotherapy of brain metastases. Front Radiat Ther Oncol 1999; 33: 343–348. 35 Buckner JC: The role of chemotherapy in the treatment of patients with brain metastases from solid tumors. Cancer Metastasis Rev 1991; 10: 335 –341. 36 Donelli MG: Zucchetti M, D’Incalci MD: Do anticancer agents reach the tumor target in the human brain? Cancer Chemother Pharmacol 1992; 30: 251–260. 37 Hazuka MB, Kinzie JJ: Brain metastases: results and effects of reirradiation. Int J Radiat Oncol Biol Phys 1988; 15: 433 – 437.

Intracranial metastases: medical management and prognostic factors 105 38 Hildebrand J: Chemotherapy of brain metastases. Eur J Cancer Clin Oncol 1988; 24: 1097–1098. 39 Seigers HP: Chemotherapy for brain metastases: recent developments and clinical considerations. Cancer Treat Rev 1990; 17: 63 –76. 40 Franciosi V, Cocconi G, Michiara M, et al.: Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast cancer, non-small cell lung cancer and malignant melanoma. Cancer 1999; 85: 1599 –1605. 41 Furuse K, Kamimori T, Kawahara M, et al.: A pilot study of concurrent whole-brain radiotherapy and chemotherapy combined with cisplatin, vindesine and mitomycin in non-small cell lung cancer brain metastasis. Br J Cancer 1997; 75: 614 – 618. 42 Quantin X, Khial F, Reme-Saumon, et al.: Concomitant brain radiotherapy and vinorelbine-ifosfamide-cisplatin chemotherapy in brain metastases of non-small cell lung cancer. Lung Cancer 1999; 26: 35 –39. 43 Quantin X, Pujol JL, Paris A, et al.: Concomitant brain radiotherapy and high-dose ifosfamide in brain relapses of lung cancer. Ann Oncol 1997; 8: 911–913. 44 Ushio Y, Arita N, Hayakawa, et al.: Chemotherapy of brain metastases from lung cancer carcinoma: a controlled randomized study. Neurosurgery 1991; 28: 201–205. 45 Wronski M, Arbit F, McCormick B, et al.: Surgical treatment of patients with brain metastases. Cancer 1992; 80: 1746 –1754. 46 Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 47 Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al.: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery. Ann Neurol 1993; 33: 583 – 590. 48 Nguyen L, Maor M, Oswald M: Brain metastases as the only manifestation of an undetected primary tumor. Cancer 1998; 83: 2181–2184. 49 Wronski M, Arbit E: Resection of brain metastases from colorectal carcinoma in 73 patients. Cancer 1999; 85: 1677–1685. 50 Sampson J, Carter J, Friedman A, et al.: Demographics, prognosis and therapy in 72 patients with brain metastases from malignant melanoma. J Neurosurg 1998; 88: 11–20. 51 Gaspar L, Scott C, Rotman M, et al.: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745–751. 52 Aghoula O, Benoit B, Cross P, et al.: Prognostic factors derived from recursive partitioning analysis (RPA) of Radiation Therapy Oncology Group (RTOG) brain metastases trials applied to surgically resected and irradiated brain metastases cases. Int J Radiat Oncol Biol Phys 1998; 42: 155 –159. 53 Lagerwaard F, Levendag P, Nowak P, et al.: Identiﬁcation of prognostic factors in patients with brain metastases: a review of 1252 patients. Int J Radiat Oncol Biol Phys 1999; 43: 755–803.

CHAPTER 7

Surgical management and techniques Frederick F Lang

Introduction Metastatic brain tumors are a signiﬁcant source of morbidity and mortality for patients with systemic cancer and are a common problem encountered by neurosurgeons. In the modern era, neurosurgical management of cancer patients with brain metastases has become progressively more complex for several reasons. First, treatment options have increased. Whereas in the past, therapy was limited to corticosteroids and whole-brain radiation therapy (WBRT), nowadays, surgical resection and stereotactic radiosurgery have become integral parts of the management armamentarium. Second, because operative techniques have progressively improved, there is an increasing potential for resecting lesions that in the past were considered unresectable. This has expanded the indications for surgical resection. Third, whereas in the past brain metastases were usually detected when they were large and symptomatic, screening by magnetic resonance (MR) imaging has resulted in the detection of brain metastases when they are asymptomatic and small. This early detection allows for “elective” and highly controlled surgical resections but has also raised questions as to whether less invasive interventions (e.g., radiosurgery) should be undertaken. Finally, there is an increasing trend toward aggressive systemic therapy that has led to the expectation that treatment of the brain should not excessively delay or interfere with treatment of the systemic disease. Modern neurosurgeons must therefore integrate surgical options into the overall treatment plan of the cancer patient. These complexities have led to a growing need for specialization in neurosurgical oncology, with speciﬁc training in the treatment of brain metastases. The purpose of this chapter is to provide an overview of the surgical management of brain metastases in order to deﬁne the role of neurosurgery in the overall management of the cancer patient. Thus, particular attention is given to patient selection and surgical techniques, as well as emphasizing surgical outcomes and potential complications.

Treatment goals: advantages of surgical resection The goals of treating brain metastases are to establish a histological diagnosis, relieve symptoms, and provide long-term local control. Compared with the 106

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other treatment options (i.e., corticosteroids, WBRT, and stereotactic radiosurgery) surgical resection has several advantages for achieving these aims. Surgery is the only treatment modality that can establish a histological diagnosis. Although in the future, imaging techniques such as spectroscopy may allow for determinations of tumor pathology, surgery is currently the only method for documenting the histological diagnosis. Thus, surgery is a critical part of the management of any patient in whom the diagnosis of brain metastasis is in question. This occurs most commonly for patients without a known primary cancer but may also arise in patients with cancer where the brain lesion may be of a noncancerous etiology. For patients with known systemic cancer, it must be remembered that failure to obtain histological conﬁrmation may lead to erroneous diagnoses in 5–11% of cases1–3. Relative to other modalities, surgery is most capable of rapidly relieving symptoms by eradicating the lesion and thereby reducing intracranial pressure, eliminating local compression, and abolishing the source of edema. Although corticosteroids reduce the effects of vasogenic edema, they do not alter the direct mass effect of the lesion itself, and their side-effects preclude long-term use. Conventional radiation therapy may reduce the tumor mass, but the effect is not immediate, and many metastases are radioresistant. Stereotactic radiosurgery is limited to treating small lesions (< 3 cm in greatest diameter) that are less likely to cause symptoms. Ultimately, local cure is the most important goal of surgery. Although WBRT and radiosurgery may provide local control, eradication of the lesion (deﬁned as no visible lesion on radiographic studies) is less predictable with these modalities than with surgery. With modern techniques, complete resection can be achieved in nearly all cases (see below). The ability to predict such an outcome is a major advantage over radiation-based modalities for which tumor response depends on the unpredictable intrinsic biological properties of a given tumor.

Clinical decision making Patient selection is the cornerstone of surgical management. Not all patients with brain metastases are candidates for resection, and decisions to operate should be based on a ﬁrm understanding of the variables inﬂuencing surgical outcomes. Determining whether surgical resection is best for a particular patient requires the physician to consider the number, location, and size of the lesion(s) in the context of the clinical features of the patient and the histology of the primary tumor. The value of surgery must be weighed against the role of other treatment options, including corticosteroids, WBRT, and stereotactic radiosurgery.

Radiographic assessment Radiographic studies, particularly MR imaging, are used to determine the number, location, and size of intracranial metastases. These tumor features are critical aspects of selecting patients for surgery.

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Number of lesions A primary factor in deciding whether to operate is the number of metastatic brain lesions present in a given patient. Patients should be grouped as those with single or with multiple brain metastases. Single brain metastases Patients with single brain metastases are the best candidates for surgery. It has been demonstrated by Class I evidence that surgical resection of single brain metastases is superior to treatment with WBRT alone1, 4. Although Minz et al.5 reported a randomized trial in which they observed no differences between patient subgroups receiving surgery plus WBRT and WBRT alone, two other prospective randomized trials1, 4 demonstrated that patients with single brain metastases, a Karnofsky Performance Scale (KPS) score of at least 70, and limited systemic disease who were treated with surgery lived signiﬁcantly longer, had fewer recurrences, and had a better quality of life than patients treated with WBRT alone. Therefore, for patients with single brain metastases, the standard of treatment is surgical resection. Although other treatment modalities, especially radiosurgery, are becoming increasingly popular, it must be remembered that, to date, there has been no randomized trial comparing radiosurgery with surgery for single brain metastases (see below). Thus, choosing radiosurgery instead of surgery as the primary treatment of a single brain metastasis is a decision based on conﬂicting results from retrospective studies (see below). Multiple brain metastases Traditionally, the presence of multiple metastases (Figure 7.1) has been considered a contraindication to surgery, even when the tumors are surgically accessible6 –9. However, a report from The University of Texas M. D. Anderson Cancer Center (M. D. Anderson)10 has suggested that there may be a role for surgery in the treatment of patients with multiple metastases. This study dealt with the outcome of 56 patients who underwent resection for multiple brain metastases. Patients were divided into those who had one or more lesions left unresected (Group A, N = 30) and those who had undergone resection of all lesions (Group B, N = 26). These patients were compared with a group of matched controls who had single brain metastases that were surgically resected (Group C). There was no difference in surgical mortality (3%, 4%, and 0% for groups A, B, and C, respectively) or morbidity (8%, 9%, and 8% for Groups A, B, and C, respectively) regardless of treatment group. Patients with multiple metastases who had all the lesions resected (Group B) survived signiﬁcantly longer (median, 14 months) than patients who had some lesions left unresected (Group A; median, 6 months, p = 0.003). The survival time of patients who had all lesions removed (group B) was similar to the survival of patients with resected single metastases (Group C; median, 14 months). Bindal et al.10 concluded that the removal of multiple metastatic brain lesions is as effective as resection of single metastases, as long as all lesions are removed.

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Figure 7.1 Multiple brain metastases. Preoperative (left) and postoperative (right) T1-weighted magnetic resonance images with gadolinium enhancement demonstrating two metastases in opposite hemispheres in a patient with non-small cell lung carcinoma. These lesions were resected via two separate craniotomies during the same operation. (Reproduced with permission from the American Association of Neurological Surgeons. Advanced Techniques in Central Nervous System Metastases Robert J. Maciunas, MD, Editor © 199811.)

Based on this study from M. D. Anderson10, patients with multiple metastases should not be excluded from surgery. Because the study only included patients with two to four lesions, it should be remembered that the “surgical deﬁnition” of “multiple” is < 4 lesions. In this context, we generally recommend surgery only if all lesions can be resected. However, surgery may also be used as part of a multitreatment approach that will result in the eradication of all the tumors. For example, resection of a large symptomatic lesion and treatment of several smaller lesions with radiosurgery may be a reasonable approach. Of course, all patients with multiple metastases should receive adjunctive WBRT.

Location Resectability, that is, whether a brain metastasis can be removed without morbidity, is dictated by its location. The most important features are whether the tumor’s location is deep or superﬁcial and whether the tumor is within or near eloquent brain. With modern microneurosurgical techniques, there is no location within the brain that is not accessible to the neurosurgeon. Stereotactic image-guided surgical techniques and skull-base exposures have made previously unreachable tumors resectable. A variety of techniques help preserve functionally important brain regions during resection. Nevertheless, lesions that are deep within the brain and within eloquent areas are associated with a slightly higher surgical morbidity than those found in noneloquent superﬁcial areas (see below). The potential morbidity (and hence, recovery time) associated with surgical removal of a metastasis must be weighed against the limited survival time of this patient population. Patients with metastases to the brain

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stem, thalamus, and basal ganglia are generally not considered surgical candidates, except in rare circumstances. Treatment of lesions in these locations with alternatives such as radiosurgery may be warranted. However, it must be remembered that there is no good study demonstrating that there is more morbidity from surgery than from radiosurgery when the lesion is located in eloquent brain.

Lesion size The size of the lesion is another factor that must be considered when choosing therapy. For lesions that are larger than 3 cm in greatest diameter, surgical resection is the primary option because surgery rapidly relieves the mass effect that commonly occurs with larger, often symptomatic lesions and because the large size precludes radiosurgery12, 13. For lesions of less than 1 cm in maximum diameter, radiosurgery may be more appropriate because localizing small lesions at surgery, even with MR imaging guidance, may be difﬁcult, especially when they are deep within the brain. The most complex lesions with regard to surgical decision making are those between 1 and 3 cm in maximum diameter. For these lesions, the decision may be complex because either surgery or radiosurgery can be applied and because no prospective randomized study has demonstrated the superiority of one treatment to the other. We believe that surgical resection, based on current evidence supporting it (see below) and its predictability, is the primary option for these patients and that radiosurgery should be reserved for patients with extensive systemic disease, poor neurological performance status, or medical problems that increase the risk of surgical intervention (see below).

Clinical assessment It is generally accepted that the status of a patient’s systemic disease (both the extent of the primary tumor and of noncerebral metastases) is the most important determinant of outcome in those undergoing surgery for cerebral metastases1, 7, 10, 14–16. This information is derived from Class I data, as up to 70% of patients undergoing surgery for single brain metastases were shown to die from progression of their systemic disease rather than from neurological causes in the randomized study of Patchell et al.1 The “status of the systemic disease” can be deﬁned as the growth pattern of the tumor at its primary site and the number and growth patterns of distant systemic metastases. Surgery is most appropriate for patients with absent, “controlled”, or “limited” systemic cancer. The decision to operate on patients with no systemic disease or not to operate on patients with widespread endstage disease is generally not problematic. Decision making in patients with “limited” or “controlled” systemic cancer may be quite difﬁcult, however, because the deﬁnitions of these terms are subjective. For example, patients with stable distant extracranial metastases or those with cancers that are responding well to systemic treatment may be considered surgical candidates to one surgeon but not to another. One practical approach is to determine the expected survival time for a patient,

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excluding the presence of cerebral metastases. This strategy is supported by studies suggesting that surgical resection of brain metastases in patients with lung cancer brings the overall prognosis back to what would be expected for a patient based on the thoracic stage of the disease alone17. At M. D. Anderson, patients who are expected to survive for more than 3 to 4 months are usually candidates for surgical resection. Patient selection is also inﬂuenced by the general health of the patient, a feature that is obviously affected by the status of their systemic disease but which also may be inﬂuenced by concurrent medical problems18. Patients with conditions that increase anesthesia risk must be carefully evaluated in terms of their expected survival. For example, patients with cardiac or respiratory conditions that are themselves life-threatening may better be treated with nonsurgical methods. The neurological status of the patient should also be considered. The potential for neurological recovery after surgical manipulation is dependent on the preoperative neurological status. Several studies have shown that patients with severe neurological deﬁcits have shorter postoperative survival times than patients with minimal deﬁcits16, 19. Poor neurological status, however, does not preclude a surgical option. In fact, surgery often radically improves function by decreasing mass effect on surrounding neurons, lowering intracranial pressure, and improving cerebral blood ﬂow. However, surgery will not improve function if the lesion has destroyed neurons. One way to assess the potential for recovery is to monitor the effect of preoperative steroid administration. Patients whose function improves after receiving steroids are more likely to recover after surgery.

Histological assessment It is important to consider the radiosensitivity and chemosensitivity of the primary tumor before proceeding with surgery. Metastases from small cell lung cancer, lymphoma, and germ cell tumors are particularly sensitive to conventional radiation therapy and chemotherapy. Patients with these tumors are probably best treated with radiation therapy or chemotherapy rather than surgery. Melanoma, renal cell carcinoma (RCC), and most sarcomas are essentially resistant to conventional radiation therapy and are better treated surgically. The most common brain metastases, i.e., those from non-small cell lung cancer and breast cancer, are intermediately sensitive to radiation therapy, and surgery should be considered as one part of a multidisciplinary treatment scheme. It is important to note that the responsiveness of tumors to conventional radiation therapy may not match their responsiveness to stereotactic radiosurgery because the biological effect of a single high dose (radiosurgery) is different from that of multiple fractionated doses (radiation therapy). The histology of a brain metastasis is also important because the type of primary tumor is an important indicator of survival. Thus, patients with melanoma have a consistently poorer survival time after surgery than do patients with other types of cancer. The fact that melanoma appears to have a

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very high propensity to spread to the brain may mean that these patients have a greater chance of harboring small, undetectable lesions at the time of surgery. In contrast, the few studies that report survival after surgical excision of brain metastases from renal cell cancer suggest that the prognosis is relatively good for these patients. Despite these generalizations, the effect of tumor histology on patient survival is actually poorly deﬁned, as few studies contain sufﬁcient numbers of patients to enable statistical examination of differences in prognosis attributable to this factor. Nevertheless, a general understanding of the inﬂuence of tumor histology on outcome may inﬂuence the decision to operate, particularly when other variables (such as the size and location of the lesion) do not suggest a deﬁnitive treatment regimen.

Surgical techniques Successful extirpation of cerebral metastases is based on good basic neurosurgical techniques in conjunction with technologies for tumor localization and functional brain mapping. A clear understanding of the surgical anatomy of these lesions results in safe and effective tumor removal.

Surgical anatomy Supratentorial metastases may be surgically deﬁned by their relationship to adjacent sulci and gyri20–22 (Plate 7.1, facing p. 82). Metastases may occur superﬁcially just below the cortex, ﬁlling a gyrus (subcortical); deep within a sulcus, either at the side of the sulcus (subgyral) or at its base (subsulcal); or deep within the white matter, independent of a single sulcus or gyrus (lobar). These same patterns may arise near the cerebral ﬁssures. For example, tumors in the subinsular cortex are located anatomically deep relative to the sylvian ﬁssure. Midline meta-stases, such as those in the cingulate gyrus, should be viewed in relation to the interhemispheric ﬁssure. Metastatic tumors arise less commonly within the ventricles. The cerebellar metastases can be categorized as those occurring in either deep or hemispheric locations. Hemispheric lesions can be considered as lateral and medial. A subset arises directly within the vermis. Cerebellar tumors may be further subdivided into those found in superior and inferior locations. Surgical approaches to a brain metastasis are based on its anatomic location20, 21. Supratentorial subcortical lesions are best resected by incision in the apex of the sulcus and circumferential dissection of the tumor (transcortical approach) (Plate 7.1). Removal of a cortical plug above the lesion improves exposure. This may be problematic when the lesion arises within the eloquent cortex. In such a situation, a longitudinal incision dictated by local functional mapping performed with direct brain stimulation (see below) may minimize injury to the surrounding brain. Lesions in the subgyral or subsulcal location are best approached by splitting the sulcus leading to the lesion. Subgyral tumors are removed by making an incision in the side of the split sulcus, while subsulcal lesions are entered at

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Figure 7.2 Intraventricular brain metastases. Preoperative (left) and postoperative (right) T1weighted magnetic resonance images with gadolinium enhancement demonstrating axial (upper) and saggital (lower) views of a large metastasis within the atrium of the lateral ventricle in a patient with renal cell carcinoma. Because of its location in the left hemisphere, the lesion was resected using a trajectory originating in the superior parietal gyrus.

the sulcal base (transsulcal approach) (see Plate 7.1). Metastases located deep within the white matter, independent of a single sulcus or gyrus (lobar), may be approached either transcortically or transsulcally (see Plate 7.1). Tumors in the subinsular cortex may be approached by splitting the sylvian ﬁssure. Midline metastases are best approached by splitting the interhemispheric ﬁssure. Tumors may then be resected by further splitting or entering a deep gyrus (Plate 7.1). Intraventricular lesions may be approached transcallosally or transcortically (Plate 7.1 and Figure 7.2). Cerebellar tumors are best approached along the shortest transparenchymal route to the lesion. Superior hemispheric lesions are approached via the supracerebellar cistern and incising the cerebellum at the closest point to the tumor. This requires a high suboccipital craniotomy with exposure of the transverse sinus. Lateral hemispheric lesions are approached directly from a posterior trajectory. Inferior cerebellar tumors require opening of the foramen magnum. Midline tumors can be resected after splitting the vermis. Once the lesion is reached, resection should be performed in a circumferential, en bloc fashion. This is because, as viewed microscopically, metastases are

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composed of a solid tumor mass without intervening brain tissue. There may be some degree of inﬁltration, but this does not typically extend more than 5 mm in depth beyond the circumference of the solid tumor 2, 12, 16. A gliotic pseudocapsule is often identiﬁable and deﬁnes a surgical plane. Circumferential dissection is carried out in this gliotic plane without violating the wall of the tumor. Such an approach ensures gross-total resection, as tumor cells rarely inﬁltrate beyond the gliotic plane, and also reduces spillage of cells into the surrounding area. When using such an approach, care must be taken to preserve main arteries that lie within sulci. Most tumors receive their blood supply from several small branches arising from the main vessel. It is critical to identify these branches and to individually coagulate and cut them. This reduces bleeding during resection and ensures that the main artery is not damaged. Likewise, signiﬁcant care should be taken to preserve all surface veins so that the drainage of the normal brain is not disrupted.

Technological adjuncts to surgery The two most important roles of current technological adjuncts to surgery are tumor localization and identiﬁcation of functional (eloquent) brain. Accurate identiﬁcation of a lesion and deﬁning the most appropriate surgical route to it are essential for safe and effective resection of a cerebral metastasis. These procedures are even more important when the tumor is deeply located, small, or within an eloquent region. Fortunately, several new technologies have emerged that improve a surgeon’s ability to locate the tumor and differentiate it from the surrounding anatomy23.

Ultrasound Tumors beneath the brain’s surface can be visualized with intraoperative ultrasound, using a self-contained portable unit with a sector scanner and a television monitor12, 24. Most metastatic lesions are echogenic and can be easily differentiated from surrounding edematous brain, which is nonechogenic, on ultrasound. Ultrasound also shows the lesion’s relationship to nearby anatomical landmarks such as adjacent sulci and the ventricles. A major advantage of ultrasound is its ability to portray an image of the tumor and operating ﬁeld in “real time,” allowing visual tracking of changes in the tumor and shifts in the surrounding brain during the operation, as well as assessment of resection extent. Ultrasound is limited by its inability to “penetrate” bone for craniotomy positioning or to visualize nonechogenic tumors.

Stereotactic devices Currently, the most technologically advanced means of metastasis localization and resection is by computer-assisted image-guided stereotaxis21, 25. In this technique, the surgeon is guided by three-dimensional reconstructions of the operative region generated from preoperative imaging studies. Speciﬁc coordinates on preoperative computed tomography (CT) or MR images are matched to landmarks on the patient’s head (stereotactic registration), allow-

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Figure 7.3 Functional mapping. Preoperative (upper left) and postoperative (upper right) T1-weighted magnetic resonance images with gadolinium enhancement showing a metastasis from non-small cell lung cancer near the central sulcus. Intraoperative phase reversal employing grid electrodes on the cortical surface of the brain (lower right) was used to identify the postcentral (sensory) and precentral (motor) gyri. To verify the position of the motor cortex, direct brain stimulation was used. Stimulation at a point marked Hst resulted in ﬂexion of the hand.

ing the surgeon to identify speciﬁc points on the image that correspond to identical points in the surgical ﬁeld. The advantages of this method are that it allows the path to deep lesions to be predetermined, it permits less exposure of normal brain because the cranial and dural openings are smaller, and it offers a more precise delineation of the tumor from edematous brain around it. Because this system is unable to provide the “real-time” imaging possible with ultrasound, many surgeons employ intraoperative ultrasound and these stereotactic devices simultaneously during the operation.

Functional mapping When preoperative studies suggest that the tumor is near or within the eloquent brain cortex, intraoperative functional mapping is essential. This can be accomplished using phase reversal (Figure 7.3) or by direct brain stimulation. Phase reversal Functional mapping of motor and sensory cortices can be performed by using somatosensory evoked potentials and recording the phase reversal between grid electrodes placed on the cortical surface 26. After exposure of the cortical

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surface, a strip electrode is placed on the surface of the brain, perpendicular to the long axis of the motor and sensory cortices. Stimulation of the median nerve results in recordable cortical potentials via the strip electrodes. Recordings from the motor cortex produce positive potentials, whereas simultaneous recording from the sensory cortex results in negative potentials. Identiﬁcation of the speciﬁc electrodes in which this reversal of phase occurs deﬁnes the central sulcus. Proximity of the lesion to the functionally identiﬁed motor gyrus can then be determined by visual inspection. Direct brain stimulation Functional mapping can also be performed by direct cortical stimulation. A hand-held bipolar electrode with 5-mm spacing is used to stimulate the cortical surface with a train of biphasic, square-wave, constant-current pulses at a frequency of 60 Hz and a 1-msec duration. The current is raised from 1 mA to 10 mA until a particular behavior is observed27. As with phase reversal, direct brain stimulation can be used to identify the motor cortex. Stimulation of the precentral gyrus produces movements in the contralateral face, arm, or leg. Direct brain stimulation may provide more information than phase reversal, as it can further subdivide functional and nonfunctional areas within the precentral gyrus itself. Thus, stimulation at one point in the motor gyrus may elicit arm movement while the neighboring area in the gyrus may be silent. This information can be used to guide the placement of the cortical incision required for removal of a tumor located directly within the precentral gyrus itself. A further advantage of direct brain stimulation relative to phase reversal is that it can be used to map language function. Determining the location of language areas usually involves observing speech arrest in a patient during speciﬁc functional paradigms. Whereas motor mapping may be performed with the patient under general anesthesia, language mapping requires awake craniotomy. This is rarely required in patients with cerebral metastases because most lesions are discrete and can be approached without disruption of eloquent brain by dissection along sulci.

Role of whole-brain radiation therapy as a postoperative adjuvant After resection of a single brain metastasis, patients are frequently given adjuvant whole-brain radiation therapy (WBRT) on a routine basis in an effort to eradicate residual cancer cells at the resection site as well as microscopic foci at other sites. Although some retrospective studies have shown this to beneﬁt patients28–30, others have not16, 31, 32. Moreover, irreversible neurotoxicities (dementia, etc.) often occur in long-term surviving patients given WBRT 33. Recently, Patchell et al.34 reported the results of a randomized prospective trial examining the beneﬁts of adjunctive WBRT in the surgical treatment of single brain metastases. After surgery, patients were randomly assigned either

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to treatment with 50.4 Gy over 5.5 weeks or to observation (median follow up = 43 weeks), and the patients were classiﬁed according to extent of disease and primary tumor type. The patients who received WBRT showed a striking reduction in tumor recurrence (distant and local) relative to the observation group (18% versus 70%, respectively; p < 0.001). The local recurrence rate was 20% in the surgery alone group and 3% in the surgery plus WBRT group, and patients in the radiotherapy group were less likely than those in the observation group to die of neurological causes (14% vs. 44%, respectively; p = 0.003). Nevertheless, overall patient survival was not improved by adjunctive WBRT. Moreover, the KPS scores for the patients undergoing WBRT declined at the same rate as for those in the surgery only (observation) group, raising the possibility that the toxicity of WBRT offset its beneﬁcial effect. An unexplained result was that among patients who died from systemic disease, those not receiving WBRT survived longer than those in the observation group. Although the authors concluded WBRT to be a valuable adjunct to surgical resection (partly on the basis of preventing deaths from neurological causes), the lack of overall survival improvement, their use of higher than standard radiation doses (50 Gy rather than the more common 30 Gy), and the potential for radiation toxicity, leave some unresolved concerns as to the best recommendations for treatment of patients with single brain metastases. Conﬁrmation of the ﬁndings of Patchell et al.34 with more careful assessments of cognitive function would be helpful. Moreover, in this study34, it is difﬁcult to draw conclusions for patients with RCC or melanoma (tumors that are considered radioresistant) because each arm of the study contained only one melanoma patient and an unspeciﬁed number of RCC patients. Thus, for patients having tumors with so-called radioresistant histologies, including metastatic melanoma and RCC, the need for adjunctive postoperative WBRT remains unclear. A randomized trial of postoperative WBRT exclusively for RCC or melanoma patients will be needed to help resolve the controversy.

Role of stereotactic radiosurgery Stereotactic radiosurgery via the gamma knife or linear accelerator uses small, multiple, well-collimated beams of ionizing radiation to destroy lesions localized by stereotaxy. An advantage of this technique over conventional surgery is that it lends itself to treatment of brain metastases that might be considered surgically inaccessible, especially where eloquent brain would be transgressed to reach the lesion. It is also less costly, less invasive (no incisions; requires placement of stereotactic headframe under local anesthesia), and necessitates shorter hospital stays because only a single-fraction radiation dose is given. Yet, radiosurgery is limited to treatment of small lesions, usually to those not exceeding 3 cm in maximum diameter (volume ≤ 10–12 cm3)12, 13. In addition, no histological veriﬁcation of the metastatic nature of the lesion can be obtained with radiosurgery, which is important considering that 5 to 11% of patients with systemic cancer are found to have nonmetastatic brain lesions

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Figure 7.4 T1-weighted (upper row) and T2-weighted (lower row) magnetic resonance images with gadolinium enhancement in a patient with a brain metastasis from renal cell cancer treated initially with radiosurgery. Five months after radiosurgery, the tumor had increased in size, and the considerable edema that surrounded it prior to radiosurgery had actually increased, necessitating surgical resection. Six months after surgery, the edema had totally resolved.

(i.e., primary brain tumors, abscesses, etc.)1–3. Furthermore, because radiosurgery does not have the immediate effect of conventional surgery (Figure 7.4), patients may have to remain on high steroid doses for longer intervals, and the compression effects of tumors (neurological deﬁcits, intracranial pressure elevation) are not quickly relieved. Primarily because radiosurgery is easy to perform and has a presumed lower cost, it has been suggested that conventional surgery should be replaced by radiosurgery for eradication of all small metastases (< 3 cm in greatest diameter). To date, no prospective randomized trial has been performed comparing treatment of brain metastases by craniotomy to treatment by radiosurgery. There have, however, been three retrospective studies attempting to evaluate the efﬁcacy of these modalities35–37; nevertheless, because the conclu-

Surgical management and techniques 119

sions of these reports are completely divergent, the controversy has not been resolved. Auchter et al.35 compared a group treated for single metastases by radiosurgery (n = 122), who were also deemed eligible for surgery, to a historical control group of patients who had undergone surgery followed by WBRT at other hospitals. Because the actuarial median survival time of the surgery patients was only 43 weeks compared with 56 weeks for the radiosurgery group, they concluded that radiosurgery plus WBRT was as good as, if not superior to, conventional surgery followed by WBRT. Our group at M. D. Anderson also conducted a retrospective study comparing surgery and radiosurgery. A group of 31 consecutive radiosurgically treated patients was matched to 62 patients treated by surgery during the same time interval according to sex, age, extent of systemic disease, primary tumor histology, pretreatment KPS score, number of brain metastases, and time to occurrence of brain metastases36. The median survival time was 16.4 months for the group undergoing surgery versus 7.5 months for the radiosurgery group; the difference was signiﬁcant using both multivariate (p = 0.0009) and univariate (p = 0.0041) analyses. Based on these ﬁndings, the authors concluded that surgery was superior to radiosurgery, and they favored surgical resection of single metastases as the treatment of choice when possible. More recently, Cho et al.37 evaluated their experience with 225 single brain metastases in patients who were treated with either WBRT alone, surgery plus WBRT, or radiosurgery plus WBRT. Patients in all three groups had similar distributions for prognostic factors including age, gender, KPS score, and location of metastasis, but not for extracranial disease, which was more prevalent in the group treated with radiosurgery plus WBRT than it was in the surgery group. The actuarial survival was the same for the surgery group and the radiosurgery group, and both of these groups fared better than those receiving WBRT alone. The authors37 concluded that “given that radiosurgery is minimally invasive, is able to treat lesions in surgically inaccessible locations, and is potentially more cost-effective than surgery, it is a reasonable and potentially more attractive alternative than surgery in the management of single brain metastases.” Overall, however, it is probably best to view surgery and radiosurgery as complementary rather than as competing therapies. In particular, the potential ability of radiosurgery to treat small, deep lesions with minimal morbidity is quite distinct from the ability of surgery to rapidly reverse neurological deﬁcits from larger symptomatic lesions. Currently at M. D. Anderson, surgery is our treatment of choice for single brain metastases. Radiosurgery is used primarily as an alternative to surgery. Radiosurgery is typically recommended in three situations: 1 For single lesions that are surgically inaccessible 2 In patients who are not surgical candidates because of advanced systemic disease or medical conditions that preclude surgery 3 As part of a multimodal attack on multiple brain lesions.

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Figure 7.5 Use of surgery and radiosurgery in a complementary fashion. T1-weighted magnetic resonance image with gadolinium enhancement in a patient with brain metastases from non-small cell lung cancer, demonstrating a large (3.3 cm in maximal diameter) symptomatic lesion located superﬁcially in the left parietal region and a small (8 mm in maximal diameter) (arrow) asymptomatic lesion in the deep white matter of the frontal lobe. The large lesion was excised surgically, resulting in relief of symptoms. The smaller lesion was treated with stereotactic radiosurgery.

For example, in patients with a single, large, symptomatic lesion and one small lesion (≤ 3 cm in maximum diameter), surgical resection of the large lesion is often followed by radiosurgery on the smaller, less accessible lesion (Figure 7.5).

Surgical outcomes Complete resection The goal of surgical resection is complete resection of the lesion without any residual tumor being seen on postoperative MR images. Thus, after surgery, all patients should undergo a gadolinium-enhanced MR imaging study to document the extent of resection. Despite this important concept, few studies in the literature examine the frequency of complete resection of brain metastases. We have recently analyzed the rates of complete resection of brain metastases in 194 consecutive craniotomies performed at M. D. Anderson38. Examination of postoperative MR images using volumetric measurements revealed that gross-total resection was achieved in 94% of cases. Interestingly, there was no difference in the extent of resection when the tumors were located within or near eloquent brain structures (such as Broca’s and Wernicke’s areas, or the motor strip) compared with when the tumor was located in noneloquent brain (Table 7.1).

Surgical mortality Most studies deﬁne surgical mortality as death that occurs within 30 days of operation, although some of the earlier surgeons used shorter intervals39– 41. Other series include deaths after 30 days if the patient did not leave the hospital15, 42. Surgical mortality has decreased dramatically since the earliest reports. For example, Cushing found that the mortality after resection of brain metastases (38%) was quite high42. In contrast, in the 1990s using modern techniques, surgical mortalities of 3% or less have often been reported. In fact, some of the more recent series report no mortality after surgery for brain metastases14, 36, 43, 44.

Surgical management and techniques 121 Table 7.1 Gross-total resections performed for metastatic tumors in different brain regions.

Metastasis location

No. of patients

GTR* (%)

Noneloquent Near eloquent Eloquent Total

79 61 54 194

75 (95) 55 (90) 52 (96) Avg = 94

*GTR, gross-total resections at The University of Texas M. D. Anderson Cancer Center, Department of Neurosurgery. Reproduced with permission from Sawaya R: Surgical treatment of brain metastases. Clin Neurosurg 1999; 45: 41–4738.

In the randomized trial of Patchell et al.1, the 30-day operative mortality and the 30-day postradiotherapy mortality were both 4%. In a very comprehensive analysis of 400 craniotomies from M. D. Anderson (1992–1994), 194 craniotomies were performed for resection of brain metastases45. The overall mortality for these patients was 2.0% (4/194), with the cause of death being sepsis in two patients and progressive leptomeningeal carcinomatosis in two others38, 45.

Postoperative complications and morbidity Postoperative morbidity after surgery for brain metastases includes those related to neurological changes and those related to nonneurological problems such as postoperative hematoma, wound infection, deep venous thrombosis, pneumonia, pulmonary embolism, etc. Some studies separate these two aspects of morbidity10, 14, 16, 20, others consider them together1, 4, 7, and a few report only neurological morbidity19, 39, 46– 48; many do not report morbidity9, 15, 18, 40, 41, 49–51. One of the most comprehensive recent analyses of postoperative complications for brain metastases was conducted by Sawaya et al.45 This series from M. D. Anderson reviewed the complications that occurred after 194 craniotomies for brain metastases performed using all the modern technologies described above. Importantly, complications were categorized as either neurological (directly producing neurological compromise), regional (at the surgical site), or systemic (more generalized medical problems). Complications were considered to be minor (not life-threatening and not prolonging the length of the hospital stay) when they resolved within a few days to 30 days without surgical intervention. They were considered to be major when they persisted for more than 30 days (reducing the quality of life) or required aggressive treatment because of their life-threatening nature. The rates of major neurological, regional, and systemic complications were 6%, 3%, and 6%, respectively. In a critical analysis of factors contributing to complications, the authors reported that the most important variable affecting the frequency of neurological complications was the juxtaposition of the tumor to functional (eloquent) brain (Table 7.2). Speciﬁcally, tumors located within or near eloquent brain had

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Metastasis location

No. of patients

No. of complications (%)

Noneloquent Near eloquent Eloquent Overall

79 61 54 194

1 (1) 6 (10) 4 (7) 6*

Table 7.2 Major neurological complications of surgery for metastases in different brain regions.

*Average. Adapted with permission from Sawaya R: Surgical treatment of brain metastases. Clin Neurosurg 1999; 45: 41–4738. Table 7.3 Predicted risk of any major complication with surgery for a brain metastasis according to patient age, preoperative Karnofsky Performance Scale score, and tumor functional grade. Patient category

Predicted risk of any major complicationa

Young,b good KPS, Grade I tumor Young, poor KPS, Grade I tumor Old, good KPS, Grade III tumor Old, poor KPS, Grade III tumor

5% (2.0%, 10.4%) 8% (2.8%, 22.7%) 13% (6.17%, 27.1%) 23% (12.0%, 38.6%)

risk = 1/(1 + exp(−logit)); logit = −1.739 + 0.004 • age − 0.013 • kps − 0.170 • metastases + 0.791 • grade II + 1.063 • grade III; metastases, grade II, and grade III are coded as 0 = no, 1 = yes; risk values have been rounded to integers. bYoung, age 40 years; old, age 65 years; good KPS, preoperative Karnofsky Performance Scale score of 100; poor KPS, preoperative Karnofsky Performance Scale score of 50; Grade I tumor, in noneloquent brain; Grade III tumor, in eloquent brain. c 95% conﬁdence interval for risk shown. Adapted with permission from Sawaya R, Hammoud M, Schoppa D, et al. Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery 1998; 42: 1044–105645. aPredicted

more neurological complications than those in noneloquent areas. Nevertheless, the risk of major neurological complications, even when the lesion was within eloquent areas, was low (only 10%). Based on their extensive data, the authors used a statistical model to predict the risk of major complications from any source. They found that patients who were relatively young (age 40 years), with a KPS score of 100 and a metastasis in noneloquent brain, had a 5% risk of a major complication, whereas at the opposite extreme, for a relatively old patient (age 65 years) with a low KPS score (of 50) and a tumor in eloquent brain, this risk was 23% (Table 7.3).

Recurrence Recurrence is fairly easily measured after resection because surgery typically removes the entire gadolinium contrast-enhancing tumor mass (as visualized by MR imaging) and causes regression of the secondary brain edema. Thus, reappearance of a contrast-enhancing mass and edema on an MR image can be fairly easily measured, although minimal postoperative contrast enhancement

Surgical management and techniques 123

may be present for up to three months after surgery. In addition, one must distinguish between recurrence at the surgical site (i.e., local recurrence) and the development of new lesions in the brain at sites outside the initial resection site (i.e., distant recurrence). These events represent two distinct biological processes. Local recurrence represents regrowth of microscopic residual disease after surgery, whereas distant recurrence is believed to arise from hematogenous dissemination of tumor cells to the brain from the primary site. When evaluating rates of local and distant tumor recurrence, it is important to know whether the patients received adjunctive WBRT. In the prospective study by Patchell and colleagues of patients with single brain metastases who were then randomized either to receive or not to receive WBRT after surgery34, the local recurrence rate after surgery alone was 46% (21 of 46 patients), whereas the distant recurrence rate was 37% (35 of 46 patients). This high rate of local recurrence is not consistent with the results of other studies, which suggest recurrence rates of 5 to 10%38. Veriﬁcation of the need for WBRT in all tumor types should be undertaken.

Survival Subsequent chapters of this text detail the survival of patients with tumors that metastasize to the brain from speciﬁc primary cancer types. In general, most series from the modern neurosurgical era that include metastases with different tumor histologies indicate a median patient survival time of 11 months (range, 6–16 months) and a one-year survival rate of 42% (range, 22–63%) of patients. Kelly et al.21 reported a one-year survival rate of 63% using computerassisted stereotactic craniotomy. Studies from M. D. Anderson report a median survival time of 14 months, with a one-year survival rate of 50% for patients with single brain metastases10, 14. Similar median (14 months) and one-year (55%) survival values were observed in patients with multiple metastases in whom all the lesions were removed10. In most studies, variables associated with poor survival are the presence of multiple metastases, extensive and progressive systemic cancer, and a poor KPS score.

Acknowledgment I thank David M. Wildrick, PhD, for assistance in the preparation of this chapter.

References 1 Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 2 Sawaya R, Bindal RK, Lang FF, et al.: Metastatic brain tumors. In Kaye AH, Laws ER (eds): Brain Tumors: An Encyclopedic Approach. 2nd ed. Edinburgh, Churchill Livingstone, 2001, pp. 999–1026. 3 Voorhies RM, Sundaresan N, Thaler HT: The single supratentorial lesion. An evaluation of preoperative diagnostic tests. J Neurosurg 1980; 53: 364 –368. 4 Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al.: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993; 33: 583 –590. 5 Mintz AH, Kestle J, Rathbone MP, et al.: A randomized trial to assess the efﬁcacy of

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7 8 9 10 11

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

27 28

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surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996; 78: 1470–1476. Elvidge AR, Baldwin M: Clinical analysis of eighty-eight cases of metastatic carcinoma involving the central nervous system. With an outline of therapeutic principles. J Neurosurg 1949; 6: 495 –502. Haar F, Patterson RHJ: Surgery for metastatic intracranial neoplasm. Cancer 1972; 30: 1241–1245. Oldberg E: Surgical considerations of carcinomatous metastases to the brain. JAMA 1933; 101: 1458–1461. Ransohoff J: Surgical management of metastatic tumors. Semin Oncol 1975; 2: 21–27. Bindal RK, Sawaya R, Leavens ME, et al.: Surgical treatment of multiple brain metastases. J Neurosurg 1993; 79: 210 –216. Lang FF, Sawaya R: Craniotomy for single and multiple cerebral metastases. In Maciunas RJ (ed): Advanced Techniques in Central Nervous System Metastases. Park Ridge, Illinois, The American Association of Neurological Surgeons, 1998, pp. 35–66. Kondziolka D, Lunsford LD: Brain metastases. In Apuzzo MLJ (ed): Brain Surgery: Complication Avoidance and Management. New York, Churchill Livingstone Inc., 1993, pp. 615–641. Sturm V, Kimmig B, Engenhardt R, et al.: Radiosurgical treatment of cerebral metastases. Method, indications and results. Stereotact Funct Neurosurg 1991; 57: 7–10. Bindal RK, Sawaya R, Leavens ME, et al.: Reoperation for recurrent metastatic brain tumors. J Neurosurg 1995; 83: 600 – 604. Galicich JH, Sundaresan N, Arbit E, et al.: Surgical treatment of single brain metastasis: factors associated with survival. Cancer 1980; 45: 381–386. Sundaresan N, Galicich JH: Surgical treatment of brain metastases. Clinical and computerized tomography evaluation of the results of treatment. Cancer 1985; 55: 1382–1388. Rizzi A, Tondini M, Rocco G, et al.: Lung cancer with a single brain metastasis: therapeutic options. Tumori 1990; 76: 579 –581. Richards P, McKissock W: Intracranial metastases. Br Med J 1963; 1:15 –18. Winston KR, Walsh JW, Fischer EG: Results of operative treatment of intracranial metastatic tumors. Cancer 1980; 45: 2639–2645. Kelly PJ: Nonglial mass lesions. In Tumor Stereotaxis. Philadelphia, W. B. Saunders Company, 1991, pp. 358–369. Kelly PJ, Kall BA, Goerss SJ: Results of computed tomography-based computer-assisted stereotactic resection of metastatic intracranial tumors. Neurosurgery 1988; 22: 7–17. Yasargil MG: Topographic anatomy for microsurgical approaches to intrinsic brain tumors. Microneurosurgery. New York, Thieme Medical Publishing Inc, 1994, pp. 2–114. Lang FF, Sawaya R: Surgical management of cerebral metastases. Neurosurg Clin N Am 1996; 7: 459–484. Landy HJ, Egnor M: Intraoperative ultrasonography and cortical mapping for removal of deep cerebral tumors. South Med J 1991; 84: 1323 –1326. Roberts DW, Strohbehn JW, Hatch JF: A frameless stereotaxic integration of computerized tomographic imaging and the operating microscope. J Neurosurg 1986; 65: 545 –549. Wood CC, Spencer DD, Allison T, et al.: Localization of human sensorimotor cortex during surgery by cortical surface recording of somatosensory evoked potentials. J Neurosurg 1988; 68: 99–111. Berger MS, Kincaid J, Ojemann GA, et al.: Brain mapping techniques to maximize resection, safety, and seizure control in children with brain tumors. Neurosurgery 1989; 25: 786 –792. DeAngelis LM, Mandell LR, Thaler HT, et al.: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 1989; 24: 798 – 805.

Surgical management and techniques 125 29 Hagen NA, Cirrincione C, Thaler HT, et al.: The role of radiation therapy following resection of single brain metastasis from melanoma. Neurology 1990; 40: 158 –160. 30 Smalley SR, Schray MF, Laws ER, Jr, et al.: Adjuvant radiation therapy after surgical resection of solitary brain metastasis: association with pattern of failure and survival. Int J Radiat Oncol Biol Phys 1987; 13: 1611–1616. 31 Dosoretz DE, Blitzer PH, Russell AH, et al.: Management of solitary metastasis to the brain: the role of elective brain irradiation following complete surgical resection. Int J Radiat Oncol Biol Phys 1980; 6: 1727–1730. 32 Wronski M, Arbit E, Burt M, et al.: Survival after surgical treatment of brain metastases from lung cancer: a follow-up study of 231 patients treated between 1976 and 1991. J Neurosurg 1995; 83: 605 – 616. 33 Sundaresan N, Galicich JH, Deck MD, et al.: Radiation necrosis after treatment of solitary intracranial metastases. Neurosurgery 1981; 8: 329 –333. 34 Patchell RA, Tibbs PA, Regine WF, et al.: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998; 280: 1485 –1489. 35 Auchter RM, Lamond JP, Alexander E, et al.: A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996; 35: 27–35. 36 Bindal AK, Bindal RK, Hess KR, et al.: Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg 1996; 84: 748 –754. 37 Cho KH, Hall WA, Lee AK, et al.: Stereotactic radiosurgery for patients with single brain metastasis. J Radiosurg 1998; 1: 79 – 85. 38 Sawaya R: Surgical treatment of brain metastases. Clin Neurosurg 1999; 45: 41– 47. 39 Raskind R, Weiss SR, Manning JJ, et al.: Survival after surgical excision of single metastatic brain tumors. AJR Am J Roentgenol 1971; 111: 323 –328. 40 Stortebecker TP: Metastatic tumors of the brain from a neurosurgical point of view. A follow-up study of 158 cases. J Neurosurg 1954; 11: 84 –111. 41 Vieth RG, Odom GL: Intracranial metastases and their neurosurgical treatment. J Neurosurg 1965; 23: 375 –383. 42 Cushing H: Notes upon a series of two thousand veriﬁed cases with surgical-mortality percentages pertaining thereto. Springﬁeld, IL, Charles C Thomas, 1932, 105pp. 43 Hammoud MA, McCutcheon IE, Elsouki R, et al.: Colorectal carcinoma and brain metastasis: distribution, treatment, and survival. Ann Surg Oncol 1996; 3: 453 – 463. 44 Brega K, Robinson WA, Winston K, et al.: Surgical treatment of brain metastases in malignant melanoma. Cancer 1990; 66: 2105 –2110. 45 Sawaya R, Hammoud M, Schoppa D, et al.: Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery 1998; 42: 1044 –1056. 46 Ferrara M, Bizzozzero L, Talamonti G, et al.: Surgical treatment of 100 single brain metastases. Analysis of the results. J Neurosurg Sci 1990; 34: 303–308. 47 Lang EF, Slater J: Metastatic brain tumors: results of surgical and nonsurgical treatment. Surg Clin North Am 1964; 44: 865 – 872. 48 Sause WT, Crowley JJ, Morantz R, et al.: Solitary brain metastasis: results of an RTOG/ SWOG protocol evaluation surgery + RT versus RT alone. Am J Clin Oncol 1990; 13: 427–432. 49 Grant FC: Concerning intracranial malignant metastases: their frequency and the value of surgery in their treatment. Ann Surg 1926; 84: 635 – 646. 50 Simionescu MD: Metastatic tumors of the brain: a follow-up study of 195 patients with neurosurgical considerations. J Neurosurg 1960; 17: 361–373. 51 White KT, Fleming TR, Laws ER, Jr: Single metastasis to the brain. Surgical treatment in 122 consecutive patients. Mayo Clin Proc 1981; 56: 424– 428.

CHAPTER 8

Whole-brain radiation therapy Ritsuko Komaki, Eric Chang

Introduction As diagnostic imaging (e.g., magnetic resonance imaging (MRI)) has advanced, occult brain metastasis has been discovered more frequently, especially in patients who survive long term after treatment of lung cancer1. Brain metastases are common in many solid tumors, not only in lung cancer but also in carcinoma of the breast, renal cell carcinoma, and malignant melanoma. It has been recognized that certain types of tumors such as small cell lung cancer, lung adenocarcinoma, and large cell lung carcinoma metastasize more frequently to the central nervous system (CNS) than squamous cell lung carcinoma2– 4. In this chapter, three topics will be discussed: 1 whole-brain radiation therapy (WBRT) for gross brain metastasis 2 the role of WBRT after surgical resection or radiosurgery of brain metastases, and 3 prophylactic cranial irradiation (PCI).

Whole-brain radiation therapy for gross brain metastasis Based on multiple trials5, the treatment of brain metastases with WBRT at a dose of 20 Gy to 40 Gy over one to four weeks resulted in a median patient survival time of four to six months (Table 8.1)5. More optimal dose-time fractionation for WBRT based on the multiple trials by the Radiation Therapy Oncology Group (RTOG) was investigated6. All treatment schedules were comparable with regard to frequency of treatment and the duration of improvement, time to progression, survival time of patients, and palliative index. According to RTOG 7361, approximately 900 patients were randomized to receive 20 Gy in ﬁve fractions over one week, 30 Gy in 10 fractions over two weeks, or 40 Gy in 15 fractions over three weeks. The results showed that median survival time was similar among the three arms of the study. The 20-Gy and 30-Gy arms showed 15 weeks of median survival time compared with 18 weeks of median survival time among the patients who received 40 Gy. WBRT improved neurological function for about half of those patients without much improvement of survival, depending on differences in dose or fractionation6. Also, a randomized study7 was performed to treat patients using an ultra-rapid high-dose radiation schedule (10 Gy in one fraction or 12 Gy in two fractions). There was 126

Whole-brain radiation therapy 127 Table 8.1 Postoperative Radiation Therapy Oncology Group (RTOG) studies of brain metastases. No. Patients

Scheme

Median Survival Time

1971–1973

233 217 233 227

30 Gy/10 Fx/2 weeks 30 Gy/15 Fx/3 weeks 40 Gy/15 Fx/3 weeks 40 Gy/20 Fx/4 weeks

21 Weeks 18 Weeks 18 Weeks 16 Weeks

RTOG 7361 (Gelber et al. 198157)

1973–1976

447 228 227

20 Gy/5 Fx/1 week 30 Gy/10 Fx/2 weeks 40 Gy/15 Fx/3 weeks

15 Weeks 15 Weeks 18 Weeks

RTOG 6901 ultra-rapid (Borgelt et al. 19817 )

1971–1973

26

10 Gy/1 Fx/1 day

15 Weeks

RTOG 7361 ultra-rapid (Borgelt et al. 19817 )

1973–1976

33

12 Gy/2Fx/2 days

13 Weeks

RTOG 7606 favorable patients (Kurtz et al. 198158)

1976–1979

130 125

30 Gy/10 Fx/2 weeks 50 Gy/20 Fx/4 weeks

18 Weeks 17 Weeks

RTOG 8528 accelerated fractionation (Sause et al. 19938 )

1986–1989

30 53 44 36

48 Gy/1.6 Gy bid 54.5 Gy/1.6 Gy bid 64 Gy/1.6 Gy bid 70.4 Gy/1.6 Gy bid

4.8 Months 5.4 Months 7.2 Months 8.2 Months

RTOG 9104 (Murray et al. 19979 )

1991–1995

213 216

30 Gy/10 Fx 54.4 Gy/1.6 bid

4.5 Months 4.5 Months

RTOG 7916 Misonidazole (Komarnicky et al. 199110 )

1979–1983

193 200 196 190

30 Gy/10 Fx/2 weeks 5 Gy/6 Fx/3 weeks 30 Gy/10 Fx + Miso 5 Gy/6 Fx + Miso

4.5 Months 4.1 Months 3.1 Months 3.9 Months

RTOG 8905 BrdU (Phillips et al. 199511)

1989–1993

36 34

37.5 Gy/15 Fx/3 weeks 37.5 Gy/15 Fx + BrdU

6.1 Months 4.3 Months

Protocol (reference)

Years

RTOG 6901 (Borgelt et al. 19806 )

Fx, fraction(s); bid, twice daily; Miso, misonidazole; BrdU, bromodeoxyuridine. From Sneed PK, Larson DA, Wara WM. Neurosurg Clin N Am 1996; 7: 505–515.5

not much difference between the median survival of these patients and that of those in RTOG 7361; however, patients who received ultra-rapid high-dose WBRT manifested more neurological toxicities from the treatment. The rapidity of the response of patients to therapy was also similar between the two arms of this study. However, the duration of the improvement, time to worsening of neurological status, and rate of complete disappearance of neurological

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symptoms were generally less for patients receiving 10–12 Gy in one or two fractions than for those receiving more prolonged treatment schedules such as 30 Gy in 10 fractions. The RTOG 8528 trial8 applied accelerated hyperfractionated radiation therapy for brain metastases, and patients received 1.6 Gy twice-daily fractionation to a total dose of 48 Gy, 54.4 Gy, 64 Gy, or 70.4 Gy. There was a steady increase in patient median survival time favoring higher dose, 4.8 months, 5.4 months, 7.2 months, and 8.2 months, respectively. However, this difference in the median survival time improvement was not statistically signiﬁcant. A follow-up randomized RTOG phase III study9 included 445 patients with Karnofsky Performance Scale (KPS) scores of 60 or higher who were treated either using hyperfractionated radiation therapy (1.2 Gy twice-daily fractionation) with a total tumor dose of 54.4 Gy or using 30 Gy in 10 fractions, as a control. The median survival time obtained was 4.5 months, in both arms of the study. The RTOG 7916 trial10 was initiated to evaluate the radiosensitizer misonidazole for brain metastasis patients. This study included 779 patients who were randomized to receive either 30 Gy in 10 fractions over two weeks with or without administration of 1 gm/m2 of misonidazole or 30 Gy in six fractions over three weeks with or without 2 gm/m2 of misonidazole. The median survival times obtained ranged between 3.1 months and 4.5 months, without any signiﬁcant difference for patients treated with or without misonidazole. The median survival time observed for patients who received misonidazole was slightly inferior in both groups. Other sensitizers tested were bromodeoxyuridine (BrdU), a halogenated pyrimidine, and gadolinium texaphyrins. The RTOG trial11 that was established to investigate survival beneﬁt from BrdU enrolled 72 patients. The WBRT dose employed was 37.5 Gy delivered in 15 fractions over three weeks. The dose of BrdU was 0.8 gm/m2 per day for four days, given each week for three weeks. Five patients who received BrdU manifested signiﬁcant grade 4 and 5 hematologic and/or skin toxicities. There was no signiﬁcant survival beneﬁt for patients receiving BrdU. Gadolinium texaphyrins have also been under investigation as radiosensitizers for WBRT12. The most common lung cancer to metastasize to the brain is small cell lung cancer (SCLC). Baglan and Marks13 examined data from multiple retrospective studies using therapeutic WBRT to treat such metastases. The radiotherapy dose to the brain ranged from 20 Gy to 40 Gy delivered over one to four weeks, and the overall tumor response rates ranged from 30% to 75%, with complete response rates ranging from 21% to 46%. The median survival time of these patients after WBRT was four months, and their symptomatic responses were not often durable. More than half of the patients who received WBRT for brain metastasis from SCLC died of progressive CNS disease, although Baglan and Marks13 claimed signiﬁcant symptomatic and functional improvement from WBRT for short durations, a matter of a few months.

Complications from therapeutic whole-brain radiation therapy Acute effects of WBRT have been documented as mild fatigue, reversible hair loss, mild scalp erythema, and hyperpigmentation. Somnolence syndrome,

Whole-brain radiation therapy 129

described as persistent fatigue, anorexia, and irritability (especially in children), may occur three to ten weeks after WBRT but usually resolves within six months14, 15. Among the patients who survived long-term after WBRT (along with multiple drug chemotherapy) were those who manifested progressive dementia, ataxia, and urinary incontinence, causing severe disability that resulted in death in seven of 12 patients, as reported by DeAngelis16. The computed tomography (CT) scans of the brains of these patients showed cortical atrophy, and hypodense white matter was identiﬁed. A total WBRT dose of 25 to 39 Gy, using a large daily fraction of 3 to 6 Gy per day, may have contributed to the increased incidence of late toxicities. These children also received multiple chemotherapeutic drugs, which might have contributed to the toxicity. It is not clear if these patients had any recurrent tumors, with or without paraneoplastic syndromes. Based on this review, it is reasonable to give smaller radiation dose fractions, 1.8 to 2 Gy per day for a total of 40–45 Gy, to reduce long-term sequellae in patients with more favorable prognostic factors, which have been analyzed by the RTOG17. According to this analysis, patients having a favorable outcome were younger than 65 years old, had a KPS score of 70 or higher, and had a primary tumor that was controlled, with the brain being the only site of distant metastasis. Median survival in the favorable group was 7.1 months compared with 2.3 months in the least favorable group.

Whole-brain radiation therapy after surgical resection or radiosurgery Postoperative radiation therapy The role of postoperative radiation therapy delivered to the whole brain is to make sure micro-metastatic lesions do not occur in the brain outside the vicinity of the resected lesion and to prevent local recurrence at the site of tumor removal. Most studies shown in Table 8.218 –23 are retrospective except for the study of Patchell et al.23, which randomized patients to receive either WBRT or observation alone after the resection of the single metastatic lesion. This randomized study, based on 95 patients with single brain metastases, showed a signiﬁcant reduction of tumor recurrence in the brain when patients received WBRT (18%) after the resection of the single brain metastasis compared with the observation group where 70% of them developed recurrence (p < 0.001). Postoperative radiation therapy reduced the recurrence rate in the brain (in the original tumor bed) to 10% after WBRT compared with a 46% recurrence rate without WBRT (p < 0.001). Also, WBRT reduced the recurrence rate outside of the tumor sites from 44% without WBRT to 14% with WBRT (p = 0.003). However, there was no signiﬁcant difference in median survival between patients who received postoperative WBRT and those who did not. The majority of the retrospective studies in Table 8.218 –22 did not show any signiﬁcant reduction of brain tumor recurrence by administering postoperative WBRT, except for that of DeAngelis et al.16 who demonstrated a signiﬁcant reduction of brain tumor recurrence using WBRT (p = 0.03). Only

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Table 8.2 Postoperative whole-brain radiation therapy for brain metastases. Brain tumor recurrence (%) Authors/year Primary tumor location Doseretz et al. 198018 Any Site Smalley et al. 198719 Any Site DeAngelis et al. 198916 Any Site Hagen et al. 199020 Melanoma Armstrong et al. 199421 Lung Skibber et al. 199622 Melanoma Patchell et al. 199823 Any Site

Median survival (months)

#Patients RT

#Patients No RT

RT

No RT

p-value

RT

No RT

p-value

12

21

50

52

NS

8

10

NS

34

51

21

85

NA

21

12

.02

79

19

45

65

.03

21

4

NS

12

21

50

52

NS

8

10

NS

32

32

47

38

NS

10

14

NS

22

12

32

72

NA

18

6

.002

49

46

18

70

.001

11

10

NS

NS, not signiﬁcant; NA, not available; RT, postoperative whole-brain radiation therapy.

two retrospective studies showed that median survival was signiﬁcantly increased by using postoperative WBRT (p = 0.02)19, 22. Reduction in deaths from neurological causes was not observed for patients who did not receive WBRT in the immediate postoperative period but were instead given WBRT at the time of tumor recurrence, arguing for immediate postoperative delivery of WBRT. On the basis of preventing deaths from neurological causes, it is reasonable to support the routine use of postoperative radiotherapy. However, this subject has become controversial because of growing concern regarding long-term toxicities of WBRT including neurocognitive decline and dementia. It must be remembered that the risk of withholding postoperative WBRT is increased neurological morbidity due to tumor recurrence in the brain. The postoperative WBRT needs to be given in a timely manner, usually within a few weeks of resection, depending on the aggressiveness of the surgical procedure and the patient’s rate of postoperative recovery.

The role of whole-brain radiation therapy after radiosurgery Researchers at the University of California at San Francisco reported 106 patients with single or multiple brain metastases that were managed initially with WBRT or radiosurgery (RS) + WBRT.24 Median survival times were 11.3 and 11.1 months, respectively, and the 1-year values for local freedom from progression (FFP) of the tumor were 71% versus 79%, respectively. FFP of the tumor was signiﬁcantly worse for RS alone than for RS + WBRT (28% vs. 69%, respectively, at 1 year). However, analysis of tumor control in the brain,

Whole-brain radiation therapy 131

allowing for successful salvage of a ﬁrst tumor control failure, was not signiﬁcantly different for RS alone relative to RS + WBRT (62% and 73%, respectively, at 1 year; p = 0.56). A randomized trial comparing the effects of RS and RS plus WBRT will be needed to better assess survival, brain tumor FFP, and quality of life24.

Prophylactic cranial irradiation Prophylactic cranial irradiation (PCI) has been recognized to be beneﬁcial in improving the survival of pediatric patients with acute lymphocytic leukemia (ALL) by preventing the disease from involving the CNS25. As systemic chemotherapy has become more efﬁcacious, isolation of the malignancy in the CNS has been recognized more frequently among the patients with ALL. This phenomenon has also been noted in patients with SCLC26. More recently, a high incidence of brain metastasis in patients with lung adenocarcinoma and undifferentiated large cell carcinoma of the lung has also been observed3. Patients with SCLC present with obvious brain metastases at the time of diagnosis, and an additional 10% of the patients usually have occult metastases. Approximately half of the SCLC patients who do not undergo PCI will develop clinical brain metastasis2. However, the incidence of microscopic brain metastasis and extracranial CNS metastasis has been underestimated when the duration of the survival has been considered27. PCI became more important when the survival rates of SCLC patients with limited disease started to increase due to improvement of systemic treatment as well as earlier application of thoracic radiation therapy during the course of the treatment9. Because of the fear of neurotoxicity related to PCI and PCI’s lack of effect on overall survival time, for many years PCI was not considered for routine use in spite of the observed reduction in number of brain metastases after its application, until neuropsychological testing of patients before and after the PCI did not show signiﬁcant mental deterioration. In addition, a recent meta-analysis28 has shown improvement of the overall and brain metastasis-free survival by the application of PCI in patients who had achieved a complete response to the systemic cancer treatment and thoracic radiation therapy29. Table 8.3 shows that early trials of PCI have demonstrated reduction of brain metastasis, although there was no improvement in overall patient survival. Cox et al.30 from the Veterans Affairs Lung Study Group (using 20 Gy in ﬁve fractions) did not show signiﬁcant reduction of brain metastasis. This was thought to be due to a low total dose of radiation therapy, 20 Gy, although fraction size was considerably larger than that used in a more recent PCI study (2–3 Gy/fraction). Beiler et al.31 applied 24 Gy in their study, which showed no patient developing a brain tumor relapse after the administration of PCI compared with 16% of the 54 patients who did not receive PCI developing brain recurrence (1979). The difference in brain tumor recurrence between those receiving and not receiving PCI was statistically signiﬁcant (p < 0.05).

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Table 8.3 Early trials of prophylactic cranial irradiation in small cell lung cancer. % Brain tumor relapse No. of patients

Radiation dose

PCI+

PCI−

Reference

45 54 163 110 30 38 29 217 51

20 Gy/5 Fx 24 Gy/8 Fx 30 Gy/10 Fx 40 Gy/20 Fx 36 Gy/10 Fx 40 Gy/10 Fx 30 Gy/10 Fx 30 Gy/10 Fx 40 Gy/20 Fx

17 0 4 9 13 12 0 5 0

20 16 18 12 73 44 27 22 27

Cox et al. (1978)30 Beiler et al. (1979)31 Maurer et al. (1980)32 Hansen et al. (1980)26 Eagan et al. (1981)33 Katensis et al. (1982)35 Jackson et al. (1977)34 Seydel et al. (1985)36 Niiranen et al. (1989)37

PCI+, receiving prophylactic cranial irradiation; PCI−, not receiving prophylactic cranial irradiation; FX, fractions. Modiﬁed from Gregor A, Cull A: Role of prophylactic cranial irradiation: beneﬁts and late effects. In Van Houtte P, Klastersk J, Rocmans P (eds): Progress and Perspectives in the Treatment of Lung Cancer. Berlin, Springer-Verlag, 1999, pp. 139–149.38

Maurer et al.32 randomized 163 patients to receive or not to receive PCI at a total dose of 30 Gy in ten fractions. There was a signiﬁcant reduction of brain metastasis (4%) in patients receiving PCI compared with those not receiving it (18% brain recurrence; p < 0.009). Egan et al., Jackson et al., Katensis et al., Seydel et al., and Niiranen et al.33 –37 showed a statistically signiﬁcant reduction of brain metastases by giving patients PCI, but they saw no signiﬁcant difference in their overall survival. According to Table 8.3, in more recent studies, and with the use of radiation therapy doses of 30 Gy or more, there was less brain tumor recurrence, which might be related to the more precise metastatic work-up and improvement of the systemic chemotherapy and additional thoracic radiation therapy38. Hirsch et al.39 randomized 111 patients to receive or not to receive PCI, with a total tumor dose of 40 Gy, and they did not show signiﬁcant improvement of the incidence of brain metastases (9% with PCI versus 13% without PCI). This was considered to be related to the late application of the PCI, which started at week 12 after completion of the prolonged systemic treatment. More recent randomized studies40 – 45 have been accumulated and reported as a meta-analysis28 on 987 patients with small cell lung cancer who achieved complete remission in seven randomized trials comparing PCI with no PCI to determine if there was any survival beneﬁt (Table 8.4). According to the metaanalysis28, these randomized studies were performed between 1977 and 1994. The relative risk of death in the treatment group compared with the control group was 0.84 (95% conﬁdence interval, 0.73–0.97; p = 0.01). This corresponded to a 5.4% increase in the rate of survival at three years, which meant 15.3% in the control group without PCI compared with a 20.7% three-year survival among the patients who received PCI. PCI also signiﬁcantly increased

Table 8.4 Characteristics of seven prophylactic cranial irradiation trials included in a meta-analysis.

Trial UMCC40 Okayama41 PCI-8542 Danish-NCI (unpublished) UKCCR-EORTC43 PCI-8844 ECOG-RTOG45

Induction therapy

Total PCI dose/ No. of fractions (dose/fraction)

Median time between start of induction therapy & enrollment (months)

No. of patients

No. of patients surviving

18.5 11.7 8.4 8.8

CT CT or CT + RT CT or CT + RT CT

30 Gy/10 (3 Gy) 40 Gy/20 (2 Gy) 24 Gy/8 (3 Gy) 24 Gy/8 (3 Gy)

3.6 2.5 5.3 4.4

29 46 300 55

2 4 32 7

3.5 5.1 3.9

CT or CT + RT CT or CT + RT CT or CT + RT

8–36 Gy/1–18* 24 Gy/8 (3 Gy) 25 Gy/10 (2.5 Gy)

NA 5.1 NA

314 211 32

54 37 5

Enrollment period

Median follow up (years)

“77-”80 “81-”86 “85-”93 “85-”91 “87-”95 “88-”94 “91-”94

UMCC, University of Maryland Cancer Center; PCI-85, prophylactic cranial irradiation trial started in 1985; UKCCR-EORTC, United Kingdom Clinical Cancer Research-European Organization for Research and Treatment of Cancer; PCI-88, prophylactic cranial irradiation trial started in 1988; ECOG-RTOG, Eastern Cooperative Oncology Group-Radiation Therapy Oncology Group; CT, chemotherapy; RT, thoracic radiotherapy; PCI, prophylactic cranial irradiation; NA, not available. *During the ﬁrst period of the trial, there were three treatment groups: no PCI, PCI at a total dose of 24 Gy in 12 fractions, and PCI at a total dose of 36 Gy in 18 fractions. During the second period of the trial, there were only two treatment groups: no PCI and PCI at various doses. Modiﬁed from Auperin A, Arriagada R, Pignon JP, et al. N Engl J Med 1999; 341: 476–484.28

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the rate of patient survival free of brain metastases (p < 0.001). At 3 years, it was 13.5% in control patients versus 22.3% in those receiving PCI. The cumulative incidence of brain metastases was reduced from 58.6% to 33.3% at three years (p < 0.001). Larger doses of radiation led to a greater decrease in the risk of brain metastasis according to an analysis of four total doses, 8 Gy, 24–25 Gy, 30 Gy, and 36–40 Gy (p = 0.02). However, the effect on survival time was not proportional to the dose administered. Also they have recognized a trend toward a decrease in the risk of brain metastasis with early application of PCI after the initiation of induction chemotherapy comparing results from PCI administered less than 4 months, 4–6 months, or longer than 6 months (p = 0.01) after chemotherapy. There was no signiﬁcant neuropsychological deterioration in patients after the application of PCI, although there was no systematic evaluation of patients by neuropsychological testing before and after PCI administration in the majority of these randomized studies. In addition to the use of PCI with SCLC patients, randomized studies have been performed to administer PCI to patients with non-small cell lung cancer (NSCLC)46 by the Radiation Therapy Oncology Group. Patients whose primary cancer was controlled and whose tumors had adeno- or large cell carcinoma histology were randomized to receive or not to receive PCI, with a total brain dose of 30 Gy in ten fractions. The results showed that patients who received PCI had a signiﬁcant reduction of brain metastases without any signiﬁcant improvement in overall survival, an outcome that might be correlated with the lack of efﬁcacious systemic chemotherapy or timing of the PCI. Another study47, although this was not a randomized one, compared patients with locally advanced NSCLC who received PCI, with similar patients who elected not to receive PCI after undergoing multimodality treatment of the primary malignancy in the lung. Long-term follow up of the patients did not ﬁnd any late neuropsychological effects from the PCI . There were 75 patients with stage IIIA or stage IIIB NSCLC treated with induction chemotherapy and preoperative chemoradiation therapy followed by surgery. PCI was offered to the patients during the second period of study accrual. The total dose of 30 Gy with 2 Gy per daily fraction was administered to patients who accepted PCI. Forty-seven patients underwent PCI, and 28 patients refused to have PCI. The rate of brain metastasis was reduced from 30% to 8% at four years by PCI (p = 0.005). Those patients who had good prognostic factors (47 patients) and who had a partial or complete response to induction chemotherapy achieved reduction of brain tumor relapse as a ﬁrst site of failure from 23% to 0% at four years (p = 0.01) relative to controls. The main concern in using PCI relates to neuropsychological toxicity from the radiation in addition to systemic treatment of the patient’s cancer, which also inﬂuences neurological toxicities. Sheline et al., Leibel and Sheline, and Gregor et al.48 –50 have documented the effect of ionizing radiation on the CNS. Johnson et al.51 have described the frequency of such neuropsychological deﬁcits in orientation, memory, and language function, which occurred among 86% of patients with SCLC who survived six to 13 years after treatment.

Whole-brain radiation therapy 135

The factors underlying these impairments include immunologic dysfunction, opportunistic infection, microscopic brain metastasis, and treatment toxicity, which includes large size of the area irradiated, the combination of a neurotropic chemotherapeutic agent with PCI, as well as the total dose of radiation therapy. Concern has been expressed for pediatric patients with ALL52 who undergo PCI while receiving methotrexate, and also, for patients with SCLC who undergo PCI combined with CCNU and methotrexate53. However, Catane et al.54 found that there was a lack of clinical ﬁndings corresponding to CT abnormalities among the patients who received prophylactic CNS radiation and unexplained late neurologic sequellae. We have investigated the lowest effective biological dose for PCI and found that 25 Gy in 10 fractions was as effective as 30 Gy in 10 fractions and possibly less toxic55. Subsequently, patients with limited SCLC were evaluated by neuropsychological testing before any treatment, which was then followed by post-PCI neuropsychological testing. This prospective study revealed that 29 of 30 patients with limited SCLC and without clinical evidence of brain metastasis showed minor cognitive dysfunction prior to PCI. The most frequent impairment was of verbal memory, followed by frontal lobe dysfunction, and ﬁne-motor incoordination. After PCI, no signiﬁcant deterioration was found related to PCI. It has been speculated that the cognitive deﬁciency found among the patients with limited SCLC before any treatment might be related to the paraneoplastic syndrome29. Cognitive deﬁciency related to paraneoplastic syndrome has been described by Dalmau and associates at Memorial Sloan Kettering56. Anti-Hu antibody has been detected in the serum of patients with SCLC and might be correlated with paraneoplastic encephalopathy, although anti-Hu has been demonstrated in up to 16% of SCLC patients without paraneoplastic neurologic disease. This antibody detection is important for future investigations in order to ﬁnd any patient who might develop neurological deterioration or, possibly, for early detection of small cell lung cancer. In summary, PCI is effective in signiﬁcantly reducing brain metastases without evidence of serious complications related to the PCI, if it is given appropriately. A recent meta-analysis28 revealed that the administration of PCI improved the survival time among the patients who achieved a complete response and that determination of the optimal radiation therapy dose and timing of PCI needs to be pursued in the future. Objective testing of patients for neuropsychological toxicities and detection of serum markers will be important future research areas. Of course, advancement in imaging methods that will allow early detection of brain metastasis or recurrence of brain metastases is warranted.

References 1 Komaki R, Cox JD, Start R: Frequency of brain metastasis in adenocarcinoma and large cell carcinoma of the lung: correlation with survival. Int J Radiat Oncol Biol Phys 1983; 9: 1467–1470.

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2 Komaki, R: Prophylactic cranial irradiation for small cell carcinoma of the lung. Cancer Treat Symp 1985; 2: 35 –39. 3 Komaki R, Derus SB, Perez-Tamayo C, et al.: Brain metastasis in patients with superior sulcus tumors. Cancer 1987; 59: 1649 –1653. 4 Komaki R, Seiferheld W, Curran W, et al.: Sequential vs. concurrent chemotherapy and radiation therapy for inoperable non-small cell lung cancer (NSCLC): analysis of failures in a phase III study (RTOG 9410). Int J Radiat Oncol Biol Phys 2000; 48: 113. 5 Sneed PK, Larson DA, Wara WM: Radiotherapy for cerebral metastasis. Neurosurg Clin N Am 1996; 7: 505–515. 6 Borgelt B, Gelber R, Kramer S, et al.: The palliation of brain metastases: ﬁnal results of the ﬁrst two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980; 6: 1–9. 7 Borgelt B, Gelber R, Larson M, et al.: Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: ﬁnal results of the ﬁrst two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981; 7: 1633 –1638. 8 Sause WT, Scott C, Krisch R, et al.: Phase I/II trial of accelerated fractionation in brain metastasis RTOG 85–28. Int J Radiat Oncol Biol Phys 1993; 26: 653 – 657. 9 Murray KJ, Scott C, Greenberg HM, et al.: A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 1997; 39: 571–574. 10 Komarnicky LT, Phillips TL, Martz K, et al.: A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG 7916). Int J Radiat Oncol Biol Phys 1991; 20: 53 –58. 11 Phillips TL, Scott CB, Leibel et al.: Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89–05. Int J Radiat Oncol Biol Phys 1995; 33: 339 –348. 12 Wen PY, Loefﬂer JS: Management of brain metastasis. Oncology 1999; 13: 941–961. 13 Baglan RJ, Marks JE: Comparison of symptomatic and prophylactic irradiation of brain metastases from oat cell carcinoma of the lung. Cancer 1981; 47: 41– 45. 14 Boldrey ES, Sheline GE: Delayed transitory clinical manifestations after radiation treatment of intracranial tumors. Acta Radiol 1966; 5: 5 –10. 15 Littman P, Rosenstock J, Gale G, et al.: The somnolence syndrome in leukemic children following reduced daily dose fractions of cranial radiation. Int J Radiat Oncol Biol Phys 1984; 10: 1851–1853. 16 DeAngelis LM, Delattre JY, Posner JB.: Radiation-induced dementia in patients cured of brain metastases. Neurology 1989; 39: 789–796. 17 Gaspar L, Scott C, Rotman M, et al.: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745 –751. 18 Dosoretz DE, Blitzer PH, Russell AH, et al.: Management of solitary metastasis to the brain: the role of elective brain irradiation following complete surgical resection. Int J Radiat Oncol Biol Phys 1980; 6: 1727–1730. 19 Smalley SR, Schray MF, Laws ER, et al.: Adjuvant radiation therapy after surgical resection of solitary brain metastasis: association with patterns of failure and survival. Int J Radiat Oncol Biol Phys 1987; 13: 1611–1616. 20 Hagen NA, Cirrincione C, Thaler HT, et al.: The role of radiation therapy after resection of single brain metastasis for melanoma. Neurology 1990; 40: 158 –160. 21 Armstrong JG, Wronski M, Galicich JH, et al.: Postoperative radiation for lung cancer metastatic to the brain. J Clin Oncol 1994; 12: 2340 –2344.

Whole-brain radiation therapy 137 22 Skibber JM, Soong S, Austin L, et al.: Cranial irradiation after surgical excision of brain metastases in melanoma patients. Ann Surg Oncol 1996; 3: 118 –123. 23 Patchell RA, Tibbs PA, Regine WF, et al.: Postoperative radiotherapy in the treatment of single metastases to the brain. JAMA 1998; 280: 1485 –1489. 24 Sneed PK, Lamborn KR, Forstner JM, et al.: Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 1999; 43: 549 –558. 25 Bleyer WA, Poplack DG: Prophylaxis and treatment of leukaemia in the central nervous system and other sanctuaries. Semin Oncol 1985; 12: 131–148. 26 Hansen HH, Dombernowsky P, Hirsch FR, et al.: Prophylactic irradiation in bronchogenic small cell anaplastic carcinoma. A comparative trial of localized versus extensive radiotherapy including prophylactic brain irradiation in patients receiving combination chemotherapy. Cancer 1980; 46: 279 –284. 27 Nugent JL, Bunn PA, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma. Cancer 1979; 44: 1885 –1893. 28 Auperin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 1999; 341: 476 – 484. 29 Komaki R, Myers CA, Shin DM, et al.: Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 1995; 33: 179 –182. 30 Cox JD, Petrovich Z, Paig C, et al.: Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung. Cancer 1978; 42: 1135 –1140. 31 Beiler DD, Kane RC, Bernath AM, et al.: Low dose elective brain irradiation in small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1979; 5: 941–945. 32 Maurer LH, Tulloh M, Weiss RB, et al.: A randomized combined modality trial in small cell carcinoma of the lung: comparison of combination chemotherapy-radiation therapy versus cyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactic whole brain irradiation. Cancer 1980; 45: 30 –39. 33 Eagan RT, Frytak S, Lee RE, et al.: A case for preplanned thoracic and prophylactic whole brain radiation therapy in limited small cell lung cancer. Cancer Clin Trials 1981; 4: 261–266. 34 Jackson DV, Richards F II, Cooper MR, et al.: Prophylactic cranial irradiation in small cell lung cancer. JAMA 1977; 237: 2730–2733. 35 Katensis AT, Karpastis N, Giannakakis D, et al.: Elective brain irradiation in patients with small cell carcinoma of the lung: a preliminary report. Excerpta Medica, Amsterdam, (Lung Cancer International Congress series no. 558), 1982, pp. 277–284. 36 Seydel HG, Creech R, Pagano M: Prophylactic versus no brain irradiation in regional small cell lung carcinoma. Am J Clin Oncol 1985; 8: 218 –223. 37 Niiranen A, Holsti P, Salmo M: Treatment of small cell lung cancer. Two-drug versus four-drug chemotherapy and loco-regional irradiation with or without prophylactic cranial irradiation. Acta Oncol 1989; 28: s501–505. 38 Gregor A, Cull A: Role of prophylactic cranial irradiation: beneﬁts and late effects. In Van Houtte P, Klastersk J, Rocmans P (eds): Progress and Perspectives in the Treatment of Lung Cancer. Berlin, Springer-Verlag, 1999, pp. 139–149. 39 Hirsch FR, Hansen HH, Paulson OB, et al.: Development of brain metastasis in small cell anaplastic carcinoma of the lung. In Kay J, Whitehouse J (eds). CNS Complications of Malignant Disease. New York, MacMillan, 1979, pp. 175–184. 40 Aroney RS, Aisner J, Wesley MN, et al.: Value of prophylactic cranial irradiation given at complete remission in small cell lung cancer. Cancer Treat Rep 1983; 67: 675 – 682. 41 Ohonoshi T, Ueoka H, Kawahara S, et al.: Comparative study of prophylactic cranial irradiation in patients with small cell lung cancer achieving a complete response: a longterm follow-up result. Lung Cancer 1993; 10: 47–54.

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42 Arriagada R, LeChevalier T, Borie F, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 1995; 87: 183–190. 43 Gregor A, Cull A, Stephens RJ, et al.: Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomized trial. Eur J Cancer 1997; 33: 1752–1758. 44 Laplanche A, Monnet I, Santos-Miranda JA, et al.: Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Lung Cancer 1998; 21: 193–201. 45 Wagner H, Kim K, Turrisi A: A randomized phase III study of prophylactic cranial irradiation versus observation in patients with small cell lung cancer achieving a complete response: ﬁnal report of an incomplete trial by the Eastern Cooperative Oncology Group and Radiation Therapy Oncology Group (E3589/R92–01). Proc Am Soc Clin Oncol 1996; 15: 376 (abstract). 46 Russell AH, Pajak TE, Selim HM, et al.: Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1991; 637–643. 47 Stuschke M, Eberhardt W, Pottgen C, et al.: Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects. J Clin Oncol 1999; 17: 2700 –2709. 48 Sheline GE, Wara WM, Smith V: Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 1980; 6: 1215 –1228. 49 Leibel SA, Sheline GE: Tolerance of the central and peripheral nervous system to therapeutic irradiation. In Lett JT, Altman KI (eds): Advances in Radiation Biology, New York, Academic Press, 1987, pp. 257–288. 50 Gregor A, Cull A, Traynor E, et al.: Neuropsychometric evaluation of long-term survivors of adult brain tumours: relationship with tumour and treatment parameters. Radiother Oncol 1996; 41: 55–59. 51 Johnson BE, Patronas N, Hayes W, et al.: Neurologic computed cranial tomographic and magnetic resonance imaging of abnormalities in patients with small cell lung cancer: further follow-up of 6- to 13-year survivors. J Clin Oncol 1990; 8: 48–56. 52 Blyer WA: Neurogenic sequellae of methotrexate and ionizing radiation: a new classiﬁcation. Cancer Treat Rep 1981; 65: 89 –98. 53 Ellison N, Bernath A, Kane R, et al.: Disturbing problems of success: clinical status of long term survivors of small cell lung cancer (SCLC). Annual Conference of the American Society of Clinical Oncology abstract C-579, 1982; 149. 54 Catane R, Schwade JG, Yarr I, et al.: Follow-up neurological evaluation in patients with small cell lung carcinoma treated with prophylactic cranial irradiation and chemotherapy. Int J Radiat Oncol Biol Phys 1981; 7: 105 –109. 55 Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 1985; 8: 362–370. 56 Dalmau J, Furneaux HM, Rosenblum MK, et al.: Detection of the anti-Hu antibody in speciﬁc regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy. Neurology 1991; 41: 1757–1764. 57 Gelber RD, Larson M, Borgelt BB, et al.: Equivalence of radiation schedules for the palliative treatment of brain metastases in patients with favorable prognosis. Cancer 1981; 48: 1749–1753. 58 Kurtz JM, Gelber R, Brady LW, et al.: The palliation fo brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981; 7: 891– 895.

CHAPTER 9

Radiosurgery for single and multiple brain metastases Minesh P Mehta, Ivo Tremont-Lukats

Introduction Cancer represents the second commonest cause of mortality in the United States, accounting for approximately a quarter of all deaths. Although primary central nervous system (CNS) cancers are relatively uncommon, the annual incidence of brain metastases in the United States has been estimated to be as high as 170,000 cases1. Large autopsy series have found intracranial metastases in about 25% of patients who die of cancer2. Most brain metastases are associated with moderate to extensive peritumoral edema, and symptoms of increased intracranial pressure dominate the clinical picture. Routine use of steroids to treat or prevent symptoms of brain metastases can extend median survival up to approximately two months3, 4. The vast majority of these patients die within a few months of diagnosis, making metastatic disease of the brain one of the commonest immediate causes of death in the United States. These tumors therefore represent an extremely important cause of morbidity and mortality, particularly in light of the disappointing results from conventional treatment.

Rationale for stereotactic radiosurgery 1 The vast majority of brain metastases are pseudospherical and therefore ideal targets for radiosurgery, because most radiosurgical systems can generate spherical dose distributions. 2 The grey-white matter junction, an area of the brain often thought to be relatively “noneloquent”, is a common location for these lesions, thus permitting the delivery of a single large fraction of radiation without excessive toxicity. Even complex, large lesions in such a location can be treated radiosurgically, using multiple isocenters. 3 In the era of modern diagnostic techniques, computed tomography (CT) and magnetic resonance (MR) imaging detect most brain metastases while still relatively small, i.e., less than 3 cm in maximum diameter. Radiosurgical techniques can easily target such volumes. The limited treatment volumes help to reduce long-term morbidity. 139

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Table 9.1 Contemporary randomized trials of resection and whole-brain radiotherapy. Investigators using WBRT alone

N

MS (wk)

KPS > 70

CNS death (%)

LC (%)

Patchell et al. (1990) Noordijk et al. (1994) Mintz et al. (1996)

23 31 43

15 26 25

8 15 39

50 33 28

52 N/A N/A

Investigators using surgery + WBRT Patchell et al. (1998) 25 Noordijk et al. (1994) 32 Mintz et al. (1996) 41

40 43 22

38 33 41

29 35 14

80 N/A N/A

N, number of patients; MS (wk), median survival in weeks; KPS, functional independence as deﬁned by duration of maintenance of a Karnofsky Performance Scale score of > 70; CNS death, death from central nervous system causes; LC, local control; N/A, not assessed; WBRT, whole-brain radiotherapy.

4 Many brain metastases remain pseudoencapsulated without substantial microscopic peripheral extension, thus permitting the use of “tight” margins. Engebraaten et al. have provided an elegant demonstration of this relative lack of invasion by metastases into brain parenchyma, with experiments using fetal rat brain aggregates and brain metastasis spheroids5. 5 Most of the evidence based on controlled clinical trials supports the hypothesis that achieving local control of tumors in the brain may improve survival. To establish whether improved intracranial control would reduce morbidity, improve the quality of life, prolong survival and alter mortality patterns, two trials were conducted comparing surgery followed by whole-brain external beam radiotherapy (WBRT) with WBRT alone in patients with single brain metastases (Table 9.1)6, 7; the addition of surgery produced an improvement in median survival from 26 to 43 weeks and from 15 to 40 weeks, respectively6, 7. These trials also demonstrated that functional independence, as deﬁned by maintenance of the Karnofsky Performance Scale score (KPS) at or above a level of 70 following therapy, was superior for patients who had WBRT and surgical resection. Additional data from another randomized clinical trial showed that the combination of surgery and postoperative WBRT improves tumor local control over that produced by surgery alone, although it did not prolong overall survival or functional independence8. Therefore, surgical resection of single intracranial metastases in selected patients is gaining acceptance as a treatment modality. In contrast, the results of a Canadian multicenter, randomized controlled trial did not demonstrate a survival advantage from resection9. These results are summarized in Table 9.1 and lend credence to the notion that aggressive management strategies directed at improved local control are beneﬁcial for selected patients with brain metastases. 6 A dose-response relationship exists for local control, and it has been suggested that better local control improves survival of patients with brain metastases10, 11. Based on the extensive trials conducted by the Radiation Therapy

Radiosurgery for single and multiple brain metastases 141

Oncology Group (RTOG), the standard recommendation for most patients with brain metastases for the last two decades has been conventional external beam radiation to a dose of 30 Gy in 10 fractions delivered to the whole brain. In previous RTOG studies, 50% or more of the patients died from neurological deterioration. It is logical to assume that if there is better control of intracranial disease, survival may improve. To test this hypothesis, an RTOG study evaluated the role of dose escalation using accelerated hyperfractionation (1.6 Gy b.i.d. to total doses ranging from 48 to 70.4 Gy). This trial demonstrated a signiﬁcant advantage in survival and neurological improvement with higher doses, providing early evidence that there is a relationship between control of intracranial disease and dose and that such control actually translates into neurological improvement and survival advantage. However, when tested in a randomized controlled trial, this strategy did not yield survival improvement12. Nieder et al. analyzed CT scans of 322 patients with brain metastases to evaluate the best local result after radiotherapy and the time to local progression as a function of dose13. Patients were treated with doses ranging from 25 to 60 Gy; these doses were distilled to a single comparative parameter called the biologically effective dose (BED), using the linear-quadratic model assuming an alpha/beta value of 10 Gy. The BED ranged from 37.5 Gy to 72 Gy. Partial response rates of metastatic brain tumors signiﬁcantly increased with increased BED. The 1-year-failure rate of tumor local control decreased with higher BED. Based on this analysis, the authors predicted that for brain metastases from squamous-cell carcinoma and adenocarcinoma, a BED of at least 72 Gy seems to be necessary for local control. For small cell lung cancer and breast carcinoma, a BED between 48 Gy and 60 Gy might be sufﬁcient.

Does radiosurgery improve local control? An increasing number of reported series of patients who have been treated with radiosurgery in the United States and abroad during the last 10 years supports the hypothesis that this modality may be at least as effective as surgery or conventional WBRT for local control of intracranial metastases. In spite of the heterogeneity of these reports (different methodologies; lack of a standard deﬁnition of local control; different tumor types; different numbers of metastases; radiosurgery in combination with WBRT; differing radiosurgery techniques, and dose schedules), the tumor response and local control rates are uniform for these retrospective studies. Table 9.2 contains a list of the most relevant series published in the English language for a total of 40 nonrandomized or retrospective studies, including 2,697 patients and > 3,922 metastatic lesions. Several institutions have published multiple manuscripts on this topic on the same patients, and in some instances, multi-institutional reports have included patients reported in other single-institution publications. To eliminate this duplication, only the largest published series from single institutions were included in this table14 –53.

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Table 9.2 Treatment of brain metastases with radiosurgery. Authors (reference)

Method

Year

n

#

Dose (Gy)

RR%

LC%

MS, mo

Sturm et al.14 Mehta et al.15 Caron et al.16 Engenhart et al.17 DeSalles et al.18 Kihlstrom et al.19 Voges et al.20 Davey et al.21 Flickinger et al.22 Jokura et al.23 Alexander et al.24 Valentino25 Kida et al.26 Whang et al.27 Bindal et al.28 Joseph et al.29 Chamberlain et al.30 Breneman et al.31 Shiau et al.32 Shirato et al.33 Fernández-Vicioso et al.34 Williams et al.35 Grob et al.36 Cho et al.37 Muacevic et al.38 Lavine et al.39 Sneed et al.40 Huang et al.41 Hayashi et al.42 Kaiser et al.43 Matsuo et al.44 Schoeggl et al.45 Goyal et al.46 Maor et al.47 Weltman et al.48 Shaw et al.49 Maesawa et al.50 Simonova et al.51 Firlik et al.52 Li et al.53

L L L L L G L L G G L L G G L L L L G L L L G GL G G G G L L L G GL G L LG G G G L

91 92 92 93 93 93 94 94 94 94 95 95 95 95 96 96 96 97 97 97 97 98 98 98 99 99 99 99 99 99 99 99 00 00 00 00 00 00 00 00

39 40 9 69 19 160 46 12 116 25 248 139 20 28 31 120 50 84 100 39 48 30 35 73 56 45 105 26 38 57 92 97 29 84 65 100 15 237 30 41

54 58 11 102 34 235 66 20 116 77 421 139 55 60 > 31 189 > 50 145 219 39 48 > 30 56 136 56 93 > 175 27 57 > 57 162 266 66 > 84 125 > 78 31 237 58 41

MPD 18 MPD 18 MPD 20 MCD 21.5 MPD 21.4 MPD 29 MPD 20 MPD 25 MPD 17.5 MPD 26.1 MPD 15 MCD 50 MPD 18.9 MPD 30 MPD 18.7 MPD 26.6 Median 20 MPD 16 MPD 18.5 MCD 25 MPD 17 MPD 16.2 MPD 14–40 MPD 6–50 MPD 22 – MPD 18 MPD 16 MPD 25 – MPD 20–25 MPD 20 MPD 18 MPD 19 MPD 18 MPD 15–24 MPD 16.2 MPD 20 MPD 12–20 MPD 15–35

86 71 100 55 72 N/A 53 47 N/A N/A N/A 86 53 88 N/A N/A N/A N/A 47 92 81 53 25.7 N/A N/A 78 N/A 81 N/A 96.5 77 N/A 32 63 N/A 52 29.6 81.4 N/A 87

93 82 N/A 95 92 94 85 25 85 99 85 N/A 97 N/A 60 96 N/A 25 77 84 73 71 87.5 80 83 97 75 95 68.4 N/A N/A 94 91 N/A N/A 40 85 95 93 100

6.5 6.5 5.0 6.0 N/A N/A 6.0 6.0 11 8.5 9.4 13.5 6.4 15 8 8.0 6.5 11 12 8.7 8 8.4 7 7.8 9 8 11 9 9.3 10 11 6 6.7 7 6.8 8.8 15 9 13 40

L, LINAC; G, Gamma Knife; n, number of patients; #, number of metastases; MPD, median/mean peripheral dose; MCD, median/mean central dose; RR%, % response rate; LC%, % local control (when actuarial, the 1-year ﬁgure is used); MS, mo, median survival in months from date of radiosurgery; N/A, data not available.

Radiosurgery for single and multiple brain metastases 143

A review of the 40 series in Table 9.2 reveals local control rates varying from 25% to 100%, for a mean local control rate of 81%. Response rates range from 30% to 100%, with a series average of 69%. In comparison, local control rates after WBRT alone are generally around 50%, suggesting an approximately 20% relative increase in local control with the addition of radiosurgery. In fact, these local control values are very comparable to those achieved with surgical resection. Unfortunately, few reports provide actuarial data, and many local control ﬁgures represent assessment at a single point in time. In one of the largest reviews to date, Alexander et al. reported on a series of 421 lesions in 248 patients and indicated one- and two-year actuarial local control rates of 85% and 65%, respectively24. Similarly, the multi-institutional trial by Flickinger provides actuarial data suggesting a local control rate of 67% at 2 years22. In the report by Shiau, actuarial local control (deﬁned as freedom from progression) rates were 82% and 77% at 6 and 12 months, respectively32. These data substantially validate the clinical observation of improved local control after radiosurgery in comparison to WBRT.

Does radiosurgery improve survival? The entire hypothesis that radiosurgery yields a survival beneﬁt hinges on the paradigm that, in spite of a high rate of mortality from systemic disease, deaths from neurological causes contribute to a substantial degree in accelerating the mortality pattern. Therefore, improved local control from any strategy should have at least some impact on survival. The median survival following radiosurgery ranges from 5 to 40 months in the patient series reported in Table 9.2, for an overall mean survival of 10 months. To better address the question of whether local control improves survival, we performed a multi-institutional analysis of the radiosurgery databases from four treatment centers and selected patients with single, newly diagnosed brain metastases who had a KPS score ≥ 70%. We accepted the determination by CT that single lesions were present, and radiosensitive histological types of tumors were excluded54. This group of 122 patients was compared with a similar group of 54 patients receiving WBRT alone that constituted a modern well-selected control group from two randomized trials6, 7. The median survival for the patients in this study and rates of local tumor control are presented in Table 9.3. Although retrospective, this study suggested that a survival advantage was conferred when radiosurgery was incorporated as a boost in selected patients who had single brain metastases. This survival gain could have been due to a reduction in local control failures and hence, deaths from neurological causes.

Expanded multicenter radiosurgery review We have further expanded this retrospective analysis by reviewing the radiosurgery databases from 10 institutions, including 541 eligible patients treated from 1/4/88 to 5/21/98, relative to predetermined criteria, including the

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Table 9.3 Whole-brain radiation alone or with radiosurgery. Study (reference)

N

WBRT

SRS

MS wk

LC %

CNS deaths %

Patchell et al.7 Noordijk et al.6 Mintz et al.9 Auchter et al.54

23 31 43 122

Yes Yes Yes Yes

No No No Yes

15 26 25 56

48 NA NA 86

50 35 28 25

N, number of patients; WBRT, whole-brain radiation therapy; SRS, stereotactic radiosurgery; MS wk, median survival in weeks; LC %, percent local control; NA, not available; CNS deaths %, percent deaths due to central nervous system causes.

utilization of both WBRT and radiosurgery for newly diagnosed brain metastases55. The median follow-up period in this study was 37 months (range 2– 133 months). The median age of patients at diagnosis of brain metastases was 59 years (range 26–83). There were 241 (48%) women and 261 men (52%), and the median KPS was 80, with a range of < 70 to 100. The majority of the primary tumor types observed were lung cancer (n = 279), breast cancer (n = 63), and melanoma (n = 109). Three hundred and twenty patients had stable disease at the primary site whereas 182 had progressive disease at the time of diagnosis of brain metastases. In addition, 285 patients had known extracranial metastases, and 217 had no other extracranial metastases when a diagnosis of brain metastases was established. These patients were categorized into one of three prognostic classes, as deﬁned by the RTOG recursive partitioning analysis (RPA) method. There were 112 (22%) in class I, 356 (71%) in class II, and 34 (7%) in class III. This distribution demonstrates the preponderance of class II patients, which clearly dominate most recent trials. For the entire cohort of patients, the median survival was 10.7 months. Patients in RPA class I had the best prognosis, with the longest median overall survival (16.1 months). RPA class III patients had the lowest median overall survival (8.7 months). For RPA class II patients, the median overall survival was 10.3 months. When prognostic groups in the current study were compared with their counterparts in previous RTOG studies, median survival statistically improved for each RPA class. For RPA class I, the median survival was 16.1 months for the patients treated with radiosurgery and 7.1 months in the RTOG studies (95% CI = 6.3–8.5 months, p < 0.05). For RPA class II, the median survival was 10.3 months (95% CI = 8.9–11.2 months) compared with 4.2 months (95% CI = 3.8–4.7 months, p < 0.05) for the RTOG analysis. For class III, the median survival was 8.7 months (95% CI = 5.7–11.5 months) compared with 2.3 months for the RTOG database (95% CI = 1.9–2.8 months, p < 0.05). Overall, radiosurgery with WBRT provided a signiﬁcant survival advantage compared with WBRT alone, irrespective of RTOG RPA class56.

Analysis from a multicenter gamma-knife radiosurgery review In a multi-institutional report of brain metastases treated with the Gamma Knife, Flickinger et al.22 reviewed the results from ﬁve institutions and identi-

Radiosurgery for single and multiple brain metastases 145

ﬁed 116 patients with solitary brain metastases, 39% of which were tumors recurring after whole-brain radiation. The median survival time of patients was 11 months. For the patients with newly diagnosed brain metastases, median survival was 14 months22. A report from the University of California at San Francisco (UCSF) also analyzed the survival of patients comparable to those in Patchell’s series7 and found a rather impressive median survival of 70 weeks57.

Randomized trials (preliminary results) To date, results from three randomized radiosurgery trials are available, and the preliminary results provide mixed evidence for improved survival. The ﬁrst of these was a small trial of WBRT versus WBRT plus radiosurgery in patients with two to four brain metastases (all of less than 25 mm in maximum diameter and of known primary tumor type)58. Twenty-seven patients were randomized to initial brain tumor management with either WBRT alone (30 Gy in 12 fractions) or WBRT plus radiosurgery. The study was stopped at an interim evaluation point after 60% accrual, at which time 14 patients had received WBRT alone and 13 had undergone additional radiosurgery. The groups were well-matched according to age, sex, tumor type, number of tumors, and extent of extracranial disease. The rate of local control failure at 1 year was 100% in patients receiving WBRT alone but only 8% in those who received boost radiosurgery. The median time to local control failure was six months after WBRT alone compared with 36 months after WBRT plus radiosurgery. The median time to any tumor local control failure in the brain improved in the radiosurgery group. Patients who received WBRT alone lived for a median of 7.5 months, whereas those who received WBRT plus radiosurgery lived for 11 months58. Although these results are promising, the small trial size is a concern. In addition, the lack of allocation concealment may have introduced selection bias, easily distorting the results of an otherwise wellrandomized trial. Chougule et al., reported a three-armed, prospective randomized clinical trial comparing treatment of brain metastases using Gamma Knife radiosurgery, WBRT, or both59. Ninety-six patients received protocol therapy: radiosurgery alone (n = 36), WBRT plus radiosurgery (n = 37), and WBRT (n = 31). Fifty-one patients underwent surgical resection of large, symptomatic lesions before randomization; the distribution of these participants was not even among the three treatment arms. The overall median survival times were 7 months, 5 months, and 9 months for the radiosurgery alone, WBRT plus radiosurgery, and WBRT arms, respectively; the local control was 87%, 91%, and 62%, respectively, for these three arms. The occurrence of new brain lesions was lower in the two arms receiving WBRT 19% and 23%, respectively than in the radiosurgery only group (43%). The authors concluded that the local control was superior in the radiosurgery arms of the study. However, the risk of developing new brain lesions was higher for patients not receiving WBRT. There were no differences in overall survival times among the three study arms. The major variable limiting the interpretation of these data is the

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uneven distribution of patients who underwent surgical resection in the various arms, introducing a major treatment bias. In the largest randomized trial conducted to date, Sperduto et al. reported the data from the randomized Phase III trial, RTOG 950860. These investigators randomized 139 evaluable patients who each had two or three brain metastases to receive WBRT (n = 70) or WBRT plus radiotherapy (n = 69). They analyzed survival, local control, treatment technique (linear accelerator versus Gamma Knife), cause of death, toxicity, and quality of life (QOL). QOL indicators included the mini-mental status exam (MMSE), KPS, Neurologic Function Score (NFS), and steroid dose. There was no difference between the two patient groups in overall survival (5.8 months with WBRT versus 6.7 months with WBRT and radiosurgery). Local control at 1 year improved in the radiosurgery group (88% versus 63% with WBRT alone, p < 0.01). There was no difference in local control or survival time according to treatment technique (linear accelerator versus Gamma Knife). Death from neurological causes decreased in the radiosurgery group (26% versus 35% with WBRT alone). Regarding QOL, the radiosurgery patient group experienced signiﬁcant beneﬁt at 6 months based on KPS (p = 0.01) and steroid dose requirements (p = 0.02), and at 9 months in terms of NFS (p < 0.01) and required steroid dose (p = 0.03). At 9 months, 73% of patients in the radiosurgery group were steroid-independent whereas only 33% in the whole brain radiotherapy group were. MMSE data are still under analysis, and the study arm containing patients with single brain metastases is still open to accrual. Although dismissed by purists as a negative trial, these data deserve very careful analysis. Clearly, in a randomized context, radiosurgery has demonstrated an improved local intracranial tumor control (88% versus 63% for WBRT alone at 1 year) and consequently, a decreased death rate from neurological causes. Treatment by radiosurgery also resulted in less steroid dependence among patients (73% versus 33% with WBRT alone at 9 months), as well as an improvement in KPS and NFS, all measures of superior intracranial outcome. However, treatment by radiosurgery did not demonstrate improvement in patient survival, which cannot logically be due to the presumed lack of therapeutic efﬁcacy but rather, to two other variables, patient selection and study design. Because rigorous efforts were not undertaken to assess systemic disease during patient randomization, it is quite possible that an imbalance in this variable could have occurred, accounting for the higher rate of death from systemic disease in the radiosurgery arm. In addition, some patients listed as not receiving radiosurgery actually crossed over to receive it when they experienced tumor progression, thereby gaining an advantage that would dilute the overall results. In summary, both prospective and retrospective data conﬁrm that radiosurgery enhances local control of brain metastases. Consequently, it decreases death from neurological causes, increases steroid dependence, and enhances QOL as measured by the NFS and KPS61. In well-selected patients, a survival advantage found in retrospective studies needs conﬁrmation in appropriately

Radiosurgery for single and multiple brain metastases 147

designed and powered randomized controlled clinical trials. The lack of a survival beneﬁt in the RTOG trial cannot be easily ascribed to a presumed lack of therapeutic efﬁcacy, especially if one is to believe that another local modality, surgery, produces a survival beneﬁt through the same mechanism of improved local control, as demonstrated in two much smaller randomized surgical trials. Survival beneﬁt, therefore, must be a function of appropriate patient selection and thereby, a function of identifying appropriate prognostic variables.

Prognostic factors for response, local control, and survival Prognostic factors for response, local control, and survival after radiosurgery are still undergoing deﬁnition. We recently deﬁned some of the most important of these variables in a multi-institutional analysis. Additionally, a few recent single institutional reports have also added to this knowledge base.

Prognostic factors from the four-center LINAC-radiosurgery review In our multi-institutional report, with a potential median follow-up time for all patients of 123 weeks, the overall local response rate was 59% (complete responses [CR] = 25%, partial responses [PR] = 34%, no responses [NR] = 36%, and progressive disease [PD] = 6%). In-ﬁeld local recurrence, including PD, occurred in 17 patients (14%), for an overall local control rate of 86%54. Intracranial recurrence outside the radiosurgery volume occurred in 27 patients (22%). Univariate analysis of potential predictors of response to radiosurgery was performed on the following factors: age, time interval from diagnosis of the primary tumor to detection of the brain metastasis, gender, baseline KPS, site of the primary tumor, radiosurgery dose, tumor volume, and the presence of non-CNS metastases. Only the site of the primary tumor was a statistically signiﬁcant predictor of local response (p = 0.047). Patients with breast cancer showed the highest response rate (CR = 38% and PR = 31%). Colorectal cancer patients had the poorest response (CR = 0% and PR = 33%). The same factors were analyzed as predictors of in-ﬁeld tumor recurrence. For this endpoint, the presence of metastasis outside the CNS was signiﬁcantly associated with a lower risk of in-ﬁeld recurrence (p = 0.02). This may be due to the increased risk that early death would occur from systemic progression before the development of local control failure. Melanoma and renal cell carcinoma, which are generally considered more “radioresistant” tumor types, showed remarkable levels of local control (only one failure in 27 patients, a 96% control rate). Breast cancer patients and the few patients with unknown primary tumors also experienced excellent local control (92% in breast cancer patients; 100% in those with an unknown primary). In our multi-institutional analysis54, we performed both a univariate and a multivariate analysis of predictors of survival, as well as prediction of “quality survival” deﬁned as a KPS ≥ 70. The following factors were evaluated: age, time interval from diagnosis of the primary tumor to detection of brain

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metastases, gender, baseline KPS, site of primary tumor, location of the metastases, in-ﬁeld and out-of-ﬁeld brain recurrence. The most signiﬁcant predictor of survival and functional independence was baseline KPS (p < 0.0001). For patients with a KPS = 100, median survival had not been reached with a follow up of > 123 weeks; for those with a KPS = 90, median survival was 54 weeks, and for those with a KPS of 70–80, median survival was only 28 weeks. In the multivariate analysis, baseline KPS remained the strongest predictor of survival time. The only other predictive factor that reached statistical signiﬁcance in the multivariate model was the presence of extracranial metastases at the time of radiosurgery, with a relative risk (RR) of death of 1.96 (median survival of 78 weeks if absent, and 42 weeks if present; p = 0.008). Primary tumor site was a variable that showed a predictive trend for survival that did not reach statistical signiﬁcance (p = 0.13). Breast cancer patients had the longest survival time, with a RR of 0.42 when compared with all other patients, and a median survival of 115 weeks. The shortest median survival times were for patients with lung (47 weeks) and renal cell (29 weeks) cancers. The status of the primary tumor was signiﬁcant as determined by univariate analysis, with patients having active disease at the primary site showing a relative risk of death of 2.74 (p = 0.04), compared with the patients with controlled primary tumors; however, this factor did not reach signiﬁcance upon multivariate analysis. A patient’s sex was a signiﬁcant predictor of survival in the univariate model but not in the multivariate model because of its colinearity with breast cancer.

Prognostic factors from the expanded radiosurgery review In a series of 541 patients55, we performed both uni- and multivariate analyses for survival variables. Using univariate analysis, performance status, controlled primary disease, and absence of extracranial metastases were shown to affect overall survival signiﬁcantly (p = 0.00011, 0.0023, and 0.0001, respectively). The median survival time for patients with a KPS of 100 was 17.4 months; it was 12.0 months for those with a KPS of 90, 9.5 months for a KPS of 80, 7.4 months for a KPS of 70, and 8.7 months for a KPS of < 70. Patients with controlled primary tumors had a median survival time of 11.6 months compared with 8.8 months when the primary tumor was not controlled. Finally, patients without extracranial metastases realized a longer median survival of 13.4 months compared with 9.1 months for those with known metastases outside the central nervous system. When multivariate analysis was used, the same variables were prognostically signiﬁcant; the RR of death was 0.77 (p < 0.0001) for patients who had higher KPS values (above 70), 1.18 (p = 0.0014) for an uncontrolled primary tumor versus a controlled one, and 1.22 (p = 0.00019) for those with extracranial metastases relative to those lacking them. Women had a slightly higher median overall survival (11.5 months) than men, who had a median overall survival of 10.2 months, but this difference based on gender was not statistically signiﬁcant. The median overall survival was 11.7 months for breast cancer patients, 11.4 months for lung cancer pati-

Radiosurgery for single and multiple brain metastases 149

ents, 8.6 months for skin cancer patients, and 10.3 months for patients with tumors at other sites (p = 0.34). Furthermore, there was a trend towards improvement (that did not statistically impact on survival) for patients who were 65 years old or younger (p = 0.33). When multivariate analysis was employed, gender (p = 0.056), primary tumor type (p = 0.44), and age (p = 0.25) remained nonsigniﬁcant variables. Overall, patient survival times from institution to institution ranged from 7.5 months to 14.9 months (p = 0.016). After adjusting for RPA class, the p-value for differences in patient survival times among institutions is 0.091. Interestingly, the type of radiosurgical procedure, Gamma Knife or linear-accelerator-(LINAC)-based, did not affect overall survival signiﬁcantly. One hundred and seventy-seven patients from four institutions who were treated with the Gamma Knife had a median survival time of 11.5 months, which was not statistically different from the 10.6-month median survival for the 325 patients from the six institutions using a LINACbased system.

Prognostic factors from other radiosurgery studies Other radiosurgery studies have attempted to perform more detailed univariate and multivariate analyses of prognostic factors. A summary of some of these variables is presented in Table 9.4.

Inﬂuence of number of intracranial metastases Several radiosurgery trials have consistently found that patients with one or two lesions fare equally well, but those with three or more metastases have a uniformly poor outcome in terms of survival24, 29, 31, 37. The presence of three or more metastases at the time of radiosurgery was signiﬁcantly associated with decreased survival, with a relative risk of 1.69 in the study by Alexander et al.24 Perhaps due to the different methodologies used in various studies, it is not surprising that some investigators have found no difference in median survival after treatment of single or multiple brain metastases and that number of metastases is of no prognostic value45, 48, 60. It appears that a patient’s having a KPS > 70 and controlled or absent systemic disease accounts at least partially for this lack of difference in survival. In fact, an analysis of data from a study in Miami found that there was no correlation between lesion number and survival, even in patients with eight or more lesions62. Wronski et al. used fractionated radiosurgery on patients with 5–10 brain metastases from different tumor types, including lung cancer (n = 31), melanoma (n = 7), and breast cancer (n = 15). The median survival was 18.4 weeks, comparable to the median survival obtained from series with single intracranial metastases63. In a study at Stanford University, multivariate analysis was done to test the independence of the number of metastases (one or two versus three or four) as a prognostic factor29. The best-ﬁt model showed independent prognostic value for the number of lesions, with a p = 0.0001. In addition, the results of this study showed that patients with up to two brain metastases identiﬁed on CT or MRI scans who were treated with radiosurgery had a median survival time identical

Table 9.4 Variables prognostic for survival. Study (reference)

Variable # Metastases ECD KPS ≤ 70 Tumor histology Patient age Patient gender Tumor size Radiosurgery dose WBRT

Auchter et al.54

-ve -ve ± none none

Engenhart et al.17

Alexander et al.24

Joseph et al.29

Breneman et al.31

none ±

≥ 3 -ve -ve

≥ 3 -ve -ve

none

none > 60 -ve none

≥ 3 -ve ± -ve none none none

none none none

Flickinger et al.22

breast none none none none

Shu et al.57 none -ve -ve none > 70 -ve none -ve

ECD, extracranial disease; -ve, variable predicts signiﬁcantly for decreased survival; ±, variable has borderline signiﬁcance; none, variable is not signiﬁcant; KPS, Karnofsky Performance Scale score; WBRT, whole-brain radiation therapy. Blank cells denote variables not applicable or not analyzed.

Shirato et al.33

-ve none none none none none

Radiosurgery for single and multiple brain metastases 151

to that of patients with a solitary lesion. Similarly, Breneman et al. found that patients with one or two lesions had identical survival times after radiosurgery (44 weeks) but that patients with more than two lesions had signiﬁcantly shorter survival (p = 0.02)31. One report suggested that the overall total volume of intracranial metastatic burden, rather than the number of metastases, was a prognostic variable for survival64. In this retrospective review, 55 patients with single or multiple intracranial melanoma metastases were treated at the UCSF: 16 for recurrence after radiation therapy, 11 receiving radiosurgery as a boost to WBRT, and 28 treated with radiosurgery alone for initial management of brain metastases. The median total target volume per patient was 6.1 cc (range: 0.25–28.3 cc). With a median follow-up time of 75 weeks in these patients, the median survival time was 35 weeks overall; it was 35 weeks for patients with solitary metastases and 33 weeks for those with multiple metastases. In uni- and multivariate analyses of survival, the total target volume treated remained a signiﬁcant prognosticator.

Inﬂuence of active extracranial disease Of the eight studies summarized in Table 9.4, one did not include the presence of active extracranial disease in the analysis, ﬁve found it to be a negative prognostic factor for survival, and in the remaining two, it reached borderline signiﬁcance, suggesting that this factor is probably one of the most important prognostic variables to consider. In the study by Alexander et al., the presence of known systemic disease at the time of radiosurgery was markedly unfavorable for survival, with a RR of death of 4.424. Breneman et al. found that patients without active extracranial disease at the time of radiosurgery had a superior survival time (45 versus 35 weeks; p = 0.03)31. In the study by Shirato et al., the actuarial survival rate was higher in patients without active extracranial disease (p = 0.0411)33. In the report of Shu et al., absence of known extracranial disease at the time of radiosurgery was the second most signiﬁcant factor associated with improvement in overall survival (p = 0.006)57. Subsequent studies of prognostic factors reinforce the idea that extracranial disease is one of the most robust prognosticators for outcome44, 47, 48, 51, 65.

Inﬂuence of Karnofsky Performance Scale score In a report from Stanford University by Joseph et al., when several clinical factors potentially associated with a prolonged survival time after radiosurgery were examined by univariate and multivariate analysis, a pretreatment KPS of ≥ 70 was signiﬁcant as a continuous variable29. This is in agreement with our ﬁnding in the multi-institutional analysis54. In the UCSF study, a decreasing KPS was the third most important factor in predicting decreased survival (p = 0.009)57. Other studies have highlighted the importance of the KPS as a consistent, robust prognostic factor for treatment response and survival34. In general, a KPS of greater than 70 is a favorable factor in the assessment of prognosis.

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Inﬂuence of tumor histological type Although “conventional wisdom” categorizes tumors as radiosensitive or radioresistant, there are no signiﬁcant differences in patient survival with respect to the primary tumor histological types in any of the major trials of radiosurgical treatment for brain metastases. There was initially some speculation that radioresistant tumors such as melanoma would be less responsive to radiosurgery. In a volumetric analysis, Voges et al. showed that the mean relative volume reduction in brain metastases was 23% for melanoma, 27% for renal cell carcinoma, 53% for breast cancer, 60% for lung adenocarcinoma and 77% for squamous cell carcinoma20. In one of our trials, we evaluated complete response rates in terms of tumor histology15. Whereas 100% of patients with brain metastases from lymphomas achieved a CR, the rates for brain metastases from other histological types were 67% for melanoma/ sarcoma, 50% for non-small cell lung cancer, 33% for breast cancer, and 11% for renal cell carcinoma15. A more detailed analysis of this phenomenon shows some intriguing results. Exquisitely radiosensitive tumors, such as small cell lung carcinoma, indeed show a marked radiographic regression in comparison with radioresistant tumors such as melanomas, which are typically slower to respond and tend not to undergo complete radiographic resolution. These response rates, however, do not necessarily correlate with local control. In fact, it appears that the so-called radioresistant tumors may be better controlled than the radiosensitive lesions. Somaza et al. reported on 32 melanoma metastases in 23 patients treated radiosurgically, with local control in 31 of 32 (97%) lesions in spite of an imaging response rate of 13 of 32 (41%)66. In Breneman’s series, all 12 melanoma patients had brain metastases that remained locally controlled for the duration of the study31. Loefﬂer et al. reported one of the largest LINAC-based series, with 330 metastatic lesions treated in 217 patients and a local control rate of 94%67. The most common tumor histological subtypes were lung carcinoma (134), small cell lung cancer (22), melanoma (60), renal cell cancer (25), breast cancer (44), sarcoma (18), colon cancer (10), germ cell cancer (7), and others (10). The so-called “radioresistant tumors” actually had higher local control rates. In the more recent update by Alexander et al., this trend continued without statistical signiﬁcance24. In several studies that used univariate and multivariate analyses, there were no signiﬁcant differences in survival time of patients with respect to the primary tumor histological types29, 31, 33, 47. In contrast, Flickinger found the presence of brain metastases from breast cancer to be the only signiﬁcant predictor for survival (p = 0.0002)22. Patients with brain metastases from breast cancer had a median survival of approximately 18 months in comparison to less than 12 months for metastases from other histologic tumor types. In terms of local control, however, multivariate analysis revealed improved control for brain lesions from melanoma and renal cell carcinoma, as opposed to other histologies (p = 0.0006)22. Other investigators have independently reported good local control rates in patients with brain metastases from melanoma using radiosurgery alone36, 39.

Radiosurgery for single and multiple brain metastases 153

Inﬂuence of age and gender The most relevant studies in which the age of patients has had prognostic importance for survival are those of Alexander et al., Shu et al., and FernandezVicioso24, 34, 57. In the ﬁrst two studies, an age of greater than 60 years at the time of radiosurgery was signiﬁcantly associated with decreased survival, with a RR increasing by 18% per decade. There were no signiﬁcant differences in survival with patient age in any of the other major series. Similarly, gender was not prognostic for survival in any of the trials.

Inﬂuence of radiation dose Intuitively, one would expect radiation dose to have a major inﬂuence on local control of brain metastases, and, possibly, on survival. However, there is no uniform agreement about the doses to use for lesions of various sizes. In general, larger tumors receive lower doses, resulting in some size-dependent loss of local control. Alexander et al. reviewed the effect of dose and found that it did not inﬂuence local control24. Shirato et al. reported no effect of dose on survival33. Flickinger did not ﬁnd a correlation between dose and survival22. However, Breneman et al. found a signiﬁcant improvement in local control with a radiation dose ≥ 1,800 cGy (median time to failure 52 weeks versus 25 weeks for those treated with < 1,800 cGy; p = 0.008)31. The RTOG completed a Phase I dose-seeking trial and recommended a dose prescription based on tumor maximum diameter as follows: 24 Gy for tumors of ≤ 20 mm in diameter, 18 Gy for tumors 21–30 mm in diameter, and 15 Gy for those 31–40 mm in diameter68. In a separate report analyzing data from the UCSF, Shiau et al. speciﬁcally evaluated the effect of radiation dose and found that increased doses led to improved local control and freedom from progression, with lesions treated with ≥ 18 Gy being controlled for a substantially longer time than those treated with < 18 Gy32. Breneman and colleagues reported on eighty-four patients undergoing stereotactic radiosurgery for brain metastases, 79 of whom (93%) were treated at recurrence after previous whole brain radiotherapy31. Patients had between one and six lesions treated with a median minimum tumor dose of 16 Gy. Local control was signiﬁcantly improved for radiosurgery doses of > 18 Gy31.

Inﬂuence of lesion size In a volumetric analysis of 54 recurrent and newly diagnosed brain metastases treated with LINAC-based stereotactic radiosurgery from one of our earlier studies, some insight into the relationship between size and response can be discerned15. As expected, the rate of complete responses declined dramatically with increasing tumor size (Table 9.5). Kida and colleagues from Japan also noted that smaller tumors tend to respond faster than larger tumors25. In the report by Alexander and coworkers, lesions having a volume greater than 3 cm3 approached borderline signiﬁcance in a multivariate analysis for variables affecting local control24. Shirato and Flickinger found no signiﬁcant differences in survival time of patients with respect to the size of their primary

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Table 9.5 Tumor size versus response analysis. Tumor size (cm3)

#

Mean volume (mm3)

Mean dose (Gy)

Number of CR (%CR)

Number of PR (%PR)

% CR + % PR

<2 >2<6 > 6 < 10 > 10

23 16 5 10

0.97 3.27 7.89 19.94

22.4 17 13.2 13.2

14 (61) 7 (43) 1 (20) 1 (10)

4 (17) 5 (32) 2 (40) 4 (40)

78 75 60 50

Gy, Gray; CR, complete responses; PR, partial responses; #, number of metastases.

tumors33, 69. Shu et al. found that tumor volume was the most important predictive factor for survival (p = 0.0005)57. Therefore, whereas smaller tumors may be more effectively controlled, the data are unclear as to how lesion size inﬂuences survival.

Inﬂuence of WBRT The issue of WBRT and its effect on survival remains contentious despite data from at least three randomized clinical trials. In some studies, a minority of patients did not receive WBRT. A comparison of this subgroup with the remaining cohort ends invariably with indeterminate or misleading conclusions. For example, Joseph et al. compared 20 patients who did not receive WBRT with 100 who did; there was no difference in survival time between the two groups29. Shirato et al. reported a series of 44 patients with single metastases treated with single fraction or fractionated radiosurgery who did not receive WBRT33. The intracranial relapse rate for tumors occurring outside the radiosurgical volume was 39%. No patients receiving WBRT as a salvage treatment required further therapy, but 36% of those salvaged by repeat radiosurgery needed additional treatment. This ﬁnding indicates that some patients with single metastases may receive radiosurgery without WBRT but with the expectation of a high rate of intracranial tumor relapse. The nonrandomized study by Flickinger et al. included 51 patients treated with radiosurgery alone who were compared with 65 patients treated with radiosurgery plus fractionated WBRT22. In their multivariate analysis, they found that actuarial local control at 24 months after radiosurgery was 50%, compared with 80% for radiosurgery plus fractionated WBRT (p = 0.011). However, this did not translate into a survival advantage, possibly because of a mixture of patients having recurrent and newly diagnosed tumors. Pirzkall and colleagues reported their experience with 311 brain metastases in 236 patients at the University Hospital of Heidelberg and compared 158 patients receiving radiosurgery alone with 78 patients receiving radiosurgery with WBRT. They found no difference between the two treatments in terms of survival outcome or local tumor control. However, in patients without evidence of extracranial disease, median survival increased for those who received WBRT (15.4 versus 8.3 months with no WBRT; p = 0.08)70. A retrospective

Radiosurgery for single and multiple brain metastases 155

review by Sneed et al. of 105 patients with newly diagnosed brain metastases comparing radiosurgery alone with radiosurgery plus WBRT showed no survival time difference (median survival after diagnosis of brain metastases, 11.3 versus 11.1 months, respectively)40. There was a two-fold increased risk of developing new brain metastases in the 62 patients managed initially with radiosurgery alone, but local control of brain metastases (after allowing for successful salvage therapy) was the same for patients managed with radiosurgery alone versus radiosurgery plus WBRT. Interestingly, Li et al. found that radiosurgery plus WBRT was no better than radiosurgery alone in terms of survival time, local control, post-treatment KPS, or cause of death in 70 patients with single brain metastases from lung cancer 53. A retrospective study done in Germany compared surgery plus WBRT (n = 52) with radiosurgery alone (n = 56)38. The 1-year survival times, local control rates, and death rates from neurological causes were not statistically different between the two groups. Another retrospective review of patients with newly diagnosed brain metastases by Chidel et al. showed a trend toward longer survival among the 78 patients managed initially with radiosurgery alone versus 57 patients treated with radiosurgery plus WBRT (median survival times, 10.5 versus 6.4 months, respectively)71. Similarly to the study by Sneed et al.40, intracranial disease-free survival was signiﬁcantly worse for patients managed initially with radiosurgery alone relative to those receiving radiosurgery plus WBRT (60% versus 34% at 2 years). Data collected from our ten-institution analysis permitted a more in-depth analysis of this question56. We reviewed these data to compare survival probabilities of patients with newly diagnosed brain metastases managed initially with radiosurgery alone or with radiosurgery plus WBRT. We created a database with raw data submitted from these ten institutions on patients treated with radiosurgery for brain metastases. Of the 660 evaluable patients, 272 had radiosurgery alone initially (24% of whom ultimately had salvage WBRT) and 388 had radiosurgery immediately followed by WBRT. The median survival times for patients treated initially with radiosurgery alone versus those receiving radiosurgery plus WBRT were 16.3 versus 16.2 months, respectively, for RPA class 1 patients, 8.6 versus 7.9 months, respectively, for class 2, and 5.1 versus 5.5 months, respectively, for class 3. With adjustment by RPA class, there was no survival difference comparing patients treated initially by radiosurgery alone with those treated with radiosurgery plus WBRT shortly thereafter. Omission of WBRT administered shortly after radiosurgery did not appear to compromise survival of patients treated with radiosurgery for newly diagnosed brain metastases. An important caveat is that this concept has not been adequately tested in a randomized context.

Inﬂuence of technique There are two primary technical radiosurgery modalities, Gamma Knife and linear accelerator systems. The Gamma Knife consists of multiple Cobalt sources (201) focused on a central point using tiny collimators ranging in size

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from 8 to 18 mm. Typically, such multiple “shots” are stacked together to produce a heterogenous distribution of radiation dose within the tumor with a very large gradient, commonly approaching 50%; that is, the central portion of the tumor could easily have twice the radiation dose seen at the periphery. This could have both theoretical advantages as well as disadvantages. LINAC systems typically have a larger range of collimator size choices (for example, 4 to 40 mm) and hence, typically require fewer “shots” to conform the radiation dose around a target, resulting in a more homogenous dose distribution. These different dose distributions have become the subject of much discussion without any reasonable data to support one point of view as being superior to the other. At times, these debates take on commercial rather than scientiﬁc undertones. A direct randomized comparison of the two approaches has never been undertaken. A recent report has focused considerable attention on this issue. In a Phase I RTOG trial (90–05), primarily designed to establish the maximum tolerated dose of radiosurgery, a post-facto data analysis suggested that local control was improved (mostly for recurrent glioma) with the Gamma Knife technique49. An accompanying editorial identiﬁed the major methodological pitfalls that lead to ﬂaws in the study’s conclusion. First, the trial did not have the design, power, or stratiﬁcation to answer such a question. For example, the Gamma Knife technique contributed only 37 patients compared with 131 from the linear accelerator technique, a 3.5-fold discrepancy. The number of institutions contributing linear accelerator cases was 15 (average case/institution = 8.7), compared with the two Gamma Knife users (average case/institution = 18.5, a 2.1-fold variance). There was a considerable imbalance between the tumor types (primary versus metastatic) considered. Clearly, because of these major clinical imbalances, the data cannot be statistically convolved into a meaningful conclusion regarding comparative efﬁcacy. Additional concerns raised by the editorial addressed the lack of central review for what is essentially a neuroradiological end point: local control. “However, the actual reported methodology of central review by two non-neuroradiologists, who parenthetically represented one of the two Gamma Knife centers and at least one of which was intimately involved with the study, negates objectivity and eliminates the likelihood of necessary ‘blinding’ for interpretation”72. Data from much larger trials do not support the contention that technique makes a difference in local tumor control. Both in the randomized Phase III RTOG trial (n = 139)60 and our ten-center review (n = 541)56, technique was not predictive for superior outcome, and in fact, the results were identical. These ﬁndings validate the well-known scientiﬁc observation that individual cells are unable to determine the source (Gamma Knife or LINAC) when faced with a stream of photons. The concept of “differential boosting” engendered by dose heterogeneity needs far more proof.

A comparison of radiosurgery and surgery The median survival time of well-selected patients with single brain metastases treated with WBRT and resection or radiosurgery is comparable, although

Radiosurgery for single and multiple brain metastases 157 Table 9.6 Comparison of resection with radiosurgery. Surgery + WBRT Series (reference) Patchell et al.7 Noordijk et al.6 Patchell et al.8 SRS + WBRT Series (reference): Auchter et al.54 Shu et al.57

MS (wk)

KPS ≥ 70

CNS death (%)

LC (%)

25 32 49

40 43 48

38 33 48

29 35 14

80 NS 90

122 23

56 70

51

25

87

N

WBRT, whole-brain radiotherapy; SRS, stereotactic radiosurgery; N, number of patients; MS (wk), median survival in weeks; KPS ≥ 70, median duration of survival with Karnofsky Performance Scale score > 70; CNS death, death from neurological causes; LC, local control.

there are no randomized trials directly comparing resection and radiosurgery. This observation for linear-accelerator radiosurgery has support from a major multi-institutional outcome and prognostic factor analysis54. In this study, we reviewed the stereotactic radiosurgery databases of four institutions and identiﬁed so-called surgical patients as deﬁned by the criteria used by Patchell et al.7 These patients had to have a single brain metastasis (as determined by CT or MR imaging), be > 18 years old, have a lesion located in a surgically resectable area, have a KPS ≥ 70, have a tumor with nonradiosensitive histology, and have undergone no prior cranial surgery or WBRT. We identiﬁed 122 patients who met these criteria and compared these patients with matched controls enrolled in the surgical arms of two randomized trials6, 7. The patients in the radiosurgery category received a median dose of 37.5 Gy of WBRT followed by a median dose of 17 Gy radiosurgery boost. With a potential median follow-up period of 123 weeks for all patients, the actuarial median survival time after radiosurgery was 56 weeks. In comparison, the median survival times in the two surgical arms were 43 and 40 weeks, respectively (although a second randomized trial carried out by Patchell and coworkers reported a median survival of 48 weeks)8. Pending ﬁrm evidence from other randomized trials, these data, as well as the subset analysis reported by Shu (selecting only those patients who met Patchell’s criteria) lend support to the contention that aggressive management of well-selected patients yields superior survival, and no remarkable differences are noted between surgery and radiosurgery (Table 9.6)57. In this era of cost containment, it is imperative that healthcare professionals make ﬁscally prudent decisions. The present environment necessitates a critical appraisal of apparently equi-efﬁcacious therapeutic modalities, and within this context, we recently performed and reported on a cost-effectiveness and cost-utility analysis of radiosurgery versus resection for single brain metastases73. Survival and quality of life data for radiation alone or with surgery were obtained from the above-mentioned two randomized trials, and radiosurgical results were obtained from our multi-institutional analysis, considering only

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Table 9.7 Cost-effectiveness and cost-utility analysis. Parameter

WBRT

WBRT + RS

WBRT + surgery

Effectiveness: median survival (years) Utility: median QALYs Median cost ($) Average C/E ($/median survival) Average C/U ($/median QALYs) Average cost/week of survival ($)

0.4 0.2 6,500 16,250 32,500 310

1.1 1 15,102 13,729 15,102 270

0.8 0.7 22,018 27,523 31,454 524

WBRT, whole-brain radiotherapy; RS, radiosurgery; QALYs, quality-adjusted life-years.

linear accelerator radiosurgery data. Cost analysis was performed from a societal viewpoint, and the relative cost ratios of resection and radiosurgery were compared using the Wilcoxon rank sum test. The cost-effectiveness of each modality was deﬁned as the cost per year of median survival time. The cost-utility of each modality was deﬁned as the cost per quality year (KPS ≥ 70) of median survival. Our analysis showed that both resection and radiosurgery yielded superior survival and functional independence compared with WBRT. Surgical resection resulted in a 1.8-fold increase in cost compared with radiosurgery. These data are presented in Table 9.7 and strongly suggest that radiosurgery is the more cost-effective modality, with an average cost per week of survival of $270 compared with $310 for radiotherapy alone and $524 for resection plus radiation.

Complications Acute There are very few signiﬁcant acute complications reported for patients within the ﬁrst week after radiosurgery. Loefﬂer has reported episodes of nausea in 22 of 196 patients (11.2%) during the ﬁrst 24 hours after radiosurgery (all of them received a dose of > 2.75 Gy to the area postrema); 12 of 196 patients (6.1%) had seizures within 24 hours and within 36 hours transient motor weakness occurred in four patients (2%), all of whom had motor cortex lesions67. Alexander’s update suggests that in order to reduce or eliminate radiosurgeryinduced nausea/vomiting, all patients who receive a dose of more than 375 cGy to the area postrema should receive antiemetic therapy before treatment24. Ten of the patients experiencing post-radiosurgery seizures had a history of seizure disorder and in retrospect, had subtherapeutic levels of anticonvulsants. Since 1990, the Boston group has recommended that all patients with cortical lesions should be prophylactically premedicated for seizures before the radiosurgery procedure, regardless of their seizure history. The study by Breneman et al. reported an 8.3% (7 of 84 patients) acute complication rate31. Three patients experienced transient worsening of their neurological symptoms within the ﬁrst two weeks after radiosurgery that resolved

Radiosurgery for single and multiple brain metastases 159

after a short course of steroids. Three patients with lesions in the motor cortex experienced generalized tonic-clonic seizures within the ﬁrst 72 hours after radiosurgery, but all had subtherapeutic anticonvulsant levels. Likewise, Joseph et al. reported a low incidence of severe headaches or nausea and a 2.3% (3 of 120 patients) incidence of seizures within twelve hours of completing the radiosurgery treatment29. Each of these patients had a subtherapeutic anticonvulsant level at the time of treatment. Shiau et al. from UCSF reported complications in 100 evaluable patients and found that six patients (6%) experienced acute worsening of pre-existing neurological deﬁcits such as aphasia or hemiparesis within two weeks of radiosurgery, with 5 out of 6 responding to steroids32. Therefore, it is prudent to consider premedicating patients who have lesions near the posterior fossa with antiemetics and to routinely check serum anticonvulsant levels in those with a seizure history.

Subacute Complications occurring within the ﬁrst 6 months after radiosurgery are considered subacute. The data from the major trials suggest the following as possible subacute complications22, 24, 32, 67: 1 Alopecia in 11 patients (5.6%), all of whom received a dose of at least 4.4 Gy to the scalp, as reported in the Joint Center for Radiation Therapy (JCRT) series. 2 Necessity for steroid reinstitution and/or continuation in 21% of survivors at six months after radiosurgery in the JCRT series, probably reﬂecting vascular changes rather than tumor recurrence. In the multicenter Gamma Knife report by Flickinger22, steroid reinitiation at < 6 months was necessitated in < 3% of patients. 3 Neurological deterioration: The UCSF series32 reported 6 cases of neurological deterioration between 2 weeks and 3 months after radiosurgery, including 4 cases of increased hemiparesis and/or confusion in which the patients were treated with steroids, and 2 cases of necrosis that were documented by MR spectroscopy/autopsy.

Chronic The major chronic complications of radiosurgery are radiation necrosis, cranial nerve palsies, and chronic steroid dependence.

1. Radiation necrosis In studies conducted in Boston, symptomatic radiation necrosis was detected in 17 of 217 patients (8%) between 2 and 22 months after therapy, all of whom eventually required resection. Ten of these patients had also received methotrexate, which could have contributed to the necrosis24, 67. Breneman et al. reported that 2 of 84 patients (2.3%) developed worsening neurological symptoms associated with increasing mass effect after radiosurgery, requiring surgical decompression31. Both of these patients had radiation necrosis.

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Delayed local necrosis within the treated volume was the major complication in 16.6% (20 of 120) of patients in the Stanford study29. The risk of necrosis was a function of tumor volume and prior or concurrent WBRT. Symptomatic and pathologically conﬁrmed necrosis with no viable tumor developed in 1 of 116 patients 11 months after radiosurgery in Flickinger’s report, yielding a 2-year actuarial risk of developing necrosis of 4%22. However, reoperation was required in 10 of 116 patients (8.6%) because of hemorrhage, necrosis, or recurrence22. In the UCSF report, there were four late complications occurring more than three months after radiosurgery, including one case of increased hemiparesis, one of increased confusion, and two of brain necrosis documented by positron emission tomography (PET) scan32.

2. Cranial nerve palsies Only about one percent of patients (2 of 196) in the Boston series developed permanent cranial nerve palsies67. This phenomenon was observed at seven and eight months after treatment. One incidence involved the ﬁfth nerve, which received a dose of 16.5 Gy, and the other involved the eighth nerve, which received 15 Gy.

3. Chronic steroid dependence One of the potential complications ascribed to radiosurgery is persistent edema requiring chronic steroid usage, with all of its attendant problems. At the University of Wisconsin, the need for steroids beyond six months was documented in 4/54 (7%) of radiosurgery patients, a ﬁgure very comparable to the 8% steroid dependence at 12 months seen in the Boston series15, 66. In a report by Flickinger et al., the 2-year actuarial rate of developing delayed symptomatic edema was 11%22. Radiosurgery can result in the dramatic resolution of edema rather than a persistence of this phenomenon. Jokura et al. provide further conﬁrmatory evidence for this, ﬁnding “dramatic improvement of perifocal edema with regression of tumors”23.

Conclusions 1 Recent data support the notion that there is a radiation dose-response relationship and that improved local control of brain metastases translates into improved survival. 2 Published data in peer-reviewed journals indicate that radiosurgery has been used to treat brain metastases in over 2,500 patients with local control rates of approximately 70%, although the deﬁnition of local control is not consistent in all reports. 3 Retrospective comparisons suggest that there is a survival time gain from radiosurgery that is comparable to that from surgical resection of brain metastases. 4 Factors important to the prognosis of patients undergoing radiosurgery are still being deﬁned, but independent prognostic variables consistent among

Radiosurgery for single and multiple brain metastases 161

studies include KPS, extent of extracranial disease, size and number of brain metastases, and possibly, radiation dose and patient age. There is debate as to whether the number of brain lesions is prognostically important. 5 The role and timing of WBRT with respect to radiosurgery for brain metastases are not completely clear. It appears that local control of brain metastases increases with WBRT, but its effect on patient survival time is still unclear. 6 Radiosurgery appears to be more cost-effective than surgical resection in treatment of brain metastases. 7 The morbidity of radiosurgery is low; the most serious risks from it are a low probability of necrosis (4%) and cranial nerve damage (1%). Brain metastasis tumor volume and prior WBRT may be important predictors for late damage.

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14 Sturm V, Kimmig B, Engenhardt R, et al.: Radiosurgical treatment of cerebral metastases. Method, indications and results. Stereotact Funct Neurosurg 1991; 57: 7–10. 15 Mehta MP, Rozental JM, Levin AB, et al.: Deﬁning the role of radiosurgery in the management of brain metastases. Int J Radiat Oncol Biol Phys 1992; 24: 619 –625. 16 Caron JL, Souhami L, Podgorsak EB: Dynamic stereotactic radiosurgery in the palliative treatment of cerebral metastatic tumors. J Neurooncol 1992; 12: 173 –179. 17 Engenhart R, Kimmig BN, Hover KH, et al.: Long-term follow-up for brain metastases treated by percutaneous stereotactic single high-dose irradiation. Cancer 1993; 71: 1353–1361. 18 DeSalles AA, Hariz M, Bajada CL, et al.: Comparison between radiosurgery and stereotactic fractionated radiation for the treatment of brain metastases. Acta Neurochir (Suppl) 1993; 58: 1353–1361. 19 Kihlstrom L, Karlsson B, Lindquist C: Gamma Knife surgery for cerebral metastases. Implications for survival based on 16 years experience. Stereotact Funct Neurosurg 1993; 61: 45–50. 20 Voges J, Treuer H, Erdmann J, et al.: Linac radiosurgery in brain metastases. Acta Neurochir (Suppl) 1994; 62: 72–76. 21 Davey P, O’Brien PF, Schwartz ML, et al.: A phase I/II study of salvage radiosurgery in the treatment of recurrent brain metastases. Br J Neurosurg 1994; 8: 717–723. 22 Flickinger JC, Kondziolka D, Lunsford LD, et al.: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994; 28: 797–802. 23 Jokura H, Takahashi K, Kayama T, et al.: Gamma knife radiosurgery of a series of only minimally selected metastatic brain tumours. Acta Neurochir (Suppl) 1994; 62: 77– 82. 24 Alexander E, 3rd, Moriarty TM, Davis RB, et al.: Stereotactic radiosurgery for the deﬁnitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995; 87: 34 – 40. 25 Valentino V: The results of radiosurgical management of 139 single cerebral metastases. Acta Neurochir (Suppl) 1995; 63: 95–100. 26 Kida Y, Kobayashi T, Tanaka T: Radiosurgery of the metastatic brain tumours with gamma-knife. Acta Neurochir (Suppl) 1995; 63: 89 –94. 27 Whang CJ, Kwon Y: Gamma knife radiosurgery for malignant tumors. J Korean Med Sci 1995; 10: 379–387. 28 Bindal AK, Bindal RK, Hess KR, et al.: Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg 1996; 84: 748 –754. 29 Joseph J, Adler JR, Cox RS, et al.: Linear accelerator-based stereotaxic radiosurgery for brain metastases: the inﬂuence of number of lesions on survival. J Clin Oncol 1996; 14: 1085–1092. 30 Chamberlain MC, Kormanik P, Barba D, et al.: Stereotactic radiosurgery for metastatic brain tumors. Int J Oncol 1996; 1996: 617– 624. 31 Breneman JC, Warnick RE, Albright RE, Jr., et al.: Stereotactic radiosurgery for the treatment of brain metastases. Results of a single institution series. Cancer 1997; 79: 551–557. 32 Shiau CY, Sneed PK, Shu HK, et al.: Radiosurgery for brain metastases: relationship of dose and pattern of enhancement to local control. Int J Radiat Oncol Biol Phys 1997; 37: 375–383. 33 Shirato H, Takamura A, Tomita M, et al.: Stereotactic irradiation without whole brain irradiation for single brain metastases. Int J Radiat Oncol Biol Phys 1997; 37: 385 –391. 34 Fernandez-Vicioso E, Suh JH, Kupelian PA, et al.: Analysis of prognostic factors for patients with single brain metastasis treated with stereotactic radiosurgery. Radiat Oncol Investigat 1997; 5: 31–37.

Radiosurgery for single and multiple brain metastases 163 35 Williams J, Enger C, Wharam M, et al.: Stereotactic radiosurgery for brain metastases: comparison of lung carcinoma vs. non-lung tumors. J Neurooncol 1998; 37: 79 – 85. 36 Grob JJ, Regis J, Laurans R, et al.: Radiosurgery without whole brain radiotherapy in melanoma brain metastases. Club de Cancerologie Cutanee. Eur J Cancer 1998; 34: 1187–1192. 37 Cho KH, Hall WA, Gerbi BJ, et al.: Patient selection criteria for the treatment of brain metastases with stereotactic radiosurgery. J Neurooncol 1998; 40: 73 – 86. 38 Muacevic A, Kreth FW, Horstmann GA, et al.: Surgery and radiotherapy compared with gamma knife radiosurgery in the treatment of solitary cerebral metastases of small diameter. J Neurosurg 1999; 91: 35 – 43. 39 Lavine SD, Petrovich Z, Cohen-Gadol AA, et al.: Gamma knife radiosurgery for metastatic melanoma: an analysis of survival, outcome, and complications. Neurosurgery 1999; 44: 59–64. 40 Sneed PK, Lamborn KR, Forstner JM, et al.: Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 1999; 43: 549 –558. 41 Huang CF, Kondziolka D, Flickinger JC, et al.: Stereotactic radiosurgery for brainstem metastases. J Neurosurg 1999; 91: 563 –568. 42 Hayashi N, Uchida T, Okimoto T, et al.: Linear accelerator based stereotactic radiosurgery (SRS) as an initial treatment for brain metastases: We can control the tumors 2 cm or less with SRS alone. Eur J Cancer 1999; 35 (Suppl 4): S119. 43 Kaiser A, Bohmer D, Fitzek M, et al.: Stereotactic radiosurgery for solitary brain metastases as alternative to surgery. Eur J Cancer 1999; 35 (Suppl 4): S120. 44 Matsuo T, Shibata S, Yasunaga A, et al.: Dose optimization and indication of Linac radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 1999; 45: 931–939. 45 Schoeggl A, Kitz K, Ertl A, et al.: Prognostic factor analysis for multiple brain metastases after gamma knife radiosurgery: results in 97 patients. J Neurooncol 1999; 42: 169 –175. 46 Goyal LK, Suh JH, Reddy CA, et al.: The role of whole brain radiotherapy and stereotactic radiosurgery on brain metastases from renal cell carcinoma. Int J Radiat Oncol Biol Phys 2000; 47: 1007–1012. 47 Maor MH, Dubey P, Tucker SL, et al.: Stereotactic radiosurgery for brain metastases: results and prognostic factors. Int J Cancer 2000; 90: 157–162. 48 Weltman E, Salvajoli JV, Brandt RA, et al.: Radiosurgery for brain metastases: a score index for predicting prognosis. Int J Radiat Oncol Biol Phys 2000; 46: 1155–1161. 49 Shaw E, Scott C, Souhami L, et al.: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: ﬁnal report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys 2000; 47: 291–298. 50 Maesawa S, Kondziolka D, Thompson TP, et al.: Brain metastases in patients with no known primary tumor. Cancer 2000; 89: 1095 –1101. 51 Simonova G, Liscak R, Novotny J: Solitary brain metastases treated with the Leksell gamma knife: prognostic factors for patients. Radiother Oncol 2000; 57: 207–213. 52 Firlik KS, Kondziolka D, Flickinger JC, Lunsford LD: Stereotactic radiosurgery for brain metastases from breast cancer. Ann Surg Oncol 2000; 7: 333 –338. 53 Li B, Yu J, Suntharalingam M, et al.: Comparison of three treatment options for single brain metastasis from lung cancer. Int J Cancer 2000; 90: 37–45. 54 Auchter RM, Lamond JP, Alexander E, et al.: A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996; 35: 27–35. 55 Gaspar L, Scott C, Rotman M, et al.: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745–751.

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56 Sanghavi SN, Miranpuri SS, Chappell R, et al.: Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratiﬁed by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys 2001; 51: 426 – 434. 57 Shu HKG, Sneed PK, Shiau CY, et al.: Factors inﬂuencing survival after gamma knife radiosurgery for patients with single and multiple brain metastases. Cancer J Sci Am 1996; 2: 335. 58 Kondziolka D, Patel A, Lunsford LD, et al.: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999; 45: 427– 434. 59 Chougule P, Burton-Williams M, Saris S, et al.: Randomized treatment of brain metastasis with Gamma Knife radiosurgery, whole brain radiotherapy or both. Int J Radiat Oncol Biol Phys 2000; 48 (Suppl): 114. 60 Sperduto P, Scott C, Andrews D, et al.: Preliminary report of RTOG 9508: A phase III trial comparing whole brain irradiation alone versus whole brain irradiation plus stereotactic radiosurgery for patients with two or three unresected brain metastases. Int J Radiat Oncol Biol Phys 2000; 48 (Suppl): 113. 61 Young RF: The role of the gamma knife in the treatment of malignant primary and metastatic brain tumors. CA Cancer J Clin 1998; 48: 177–188. 62 Amendola BE, Wolf AL, Coy SR, et al.: Gamma knife radiosurgery in the treatment of patients with single and multiple brain metastases from carcinoma of the breast. Cancer J 2000; 6: 88–92. 63 Wronski M, Lombardi E, Volpicella F, et al.: Survival of patients with multiple (5–10) brain metastases after fractionated stereotactic radiosurgery. Proc Annu Meet Am Soc Clin Oncol 1999; 18: A596. 64 Seung SK, Sneed PK, McDermott MW, et al.: Gamma knife radiosurgery for malignant melanoma brain metastases. Cancer J Sci Am 1998; 4: 103 –109. 65 Schoggl A, Kitz K, Reddy M, et al.: Deﬁning the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases. Acta Neurochir 2000; 142: 621–626. 66 Somaza S, Kondziolka D, Lunsford LD, et al.: Stereotactic radiosurgery for cerebral metastatic melanoma. J Neurosurg 1993; 79: 661– 666. 67 Loefﬂer J, Alexander E: Radiosurgery for the treatment of intracranial metastases. In Alexander E, Loefﬂer JS, Lunsford LD, (eds): Stereotactic Radiosurgery. New York: McGraw-Hill, 1993, 254pp. 68 Shaw E, Scott C, Souhami L, et al.: Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of radiation therapy oncology group protocol (90–05). Int J Radiat Oncol Biol Phys 1996; 34: 647– 654. 69 Flickinger JC, Loefﬂer JS, Larson DA: Stereotactic radiosurgery for intracranial malignancies. Oncology (Huntingt) 1994; 8: 81– 86. 70 Pirzkall A, Debus J, Lohr F, et al.: Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol 1998; 16: 3563 –3569. 71 Chidel MA, Suh JH, Reddy CA, et al.: Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases. Int J Radiat Oncol Biol Phys 2000; 47: 993–999. 72 Buatti JM, Friedman WA, Meeks SL, et al.: RTOG 90–05: The real conclusion. Int J Radiat Oncol Biol Phys 2000; 47: 269 –271. 73 Mehta M, Noyes W, Craig B, et al.: A cost-effectiveness and cost-utility analysis of radiosurgery vs. resection for single brain metastases. Int J Radiat Oncol Biol Phys 1997; 39: 445–454.

CHAPTER 10

Stereotactic radiation of intracranial metastases Grifﬁth R Harsh IV

Introduction Focal treatment of metastatic tumors of the brain parenchyma falls within the purview of neurosurgery. Although intracranial extension of systemic tumors is common and increasing in incidence, fewer than one in ﬁve cases will exclusively involve the brain parenchyma1. Approximately half of the patients with parenchymal, rather than leptomeningeal, disease will have a single tumor, and half will have multiple brain metastases, but only about 10% will have more than ﬁve lesions. In patients with a limited number of parenchymal tumors, local control of tumor growth can often achieve freedom from neurological progression and increase the duration of survival. Local control of a parenchymal metastasis of most tumor histologies is unlikely to be achieved by chemotherapy (Chapter 10) or by external beam radiation (Chapter 8) alone2. In the absence of rapidly progressive, untreatable systemic or diffuse intracranial disease, focal treatment of parenchymal metastases is often critical. Fortunately, the tendency of parenchymal metastases to be superﬁcial, spherical, exclusive of normal brain, and relatively well circumscribed facilitates many focal therapies. Focal treatments designed to achieve local tumor control include surgical resection (Chapter 7), stereotactic radiosurgery (Chapter 9), interstitial radiation, stereotactic radiotherapy, and fractionated stereotactic radiosurgery. Interstitial radiation is achieved by stereotactic placement of radioactive source(s) within the tumor. The sources may be either radioactive seeds, placed temporarily or permanently (brachytherapy), or a radiation generating probe (interstitial radiosurgery). Stereotactic radiotherapy and fractionated radiosurgery combine stereotactic principles of targeting and radiation delivery with a noninvasive, relocatable apparatus for head immobilization that permits multiple treatment sessions. The ability to deliver stereotactically targeted radiation in multiple fractions has blurred the distinction between radiosurgery (typically a single fraction delivered focally) and radiotherapy (traditionally at least 10 fractions delivered to the whole brain). Currently, they are best distinguished by intent: radiosurgery is ablative of all tissue within the targeted volume whereas radiotherapy attempts to achieve a differential effect 165

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on tumor and normal cells within the target volume. This chapter will focus on the indications, methods, and outcomes of the use of brachytherapy, interstitial radiosurgery (from the photonic radiosurgery system, PRS), stereotactic radiotherapy (SRT), and fractionated stereotactic radiosurgery (FRS) for brain metastases.

Principles of focal radiation The purpose of focal radiation of a tumor volume is to prevent further local tumor growth without injuring surrounding normal brain. Clinically evident neurotoxicity can occur as a focal deﬁcit from radiation injury to a speciﬁc structure (e.g., the optic nerve, hypothalamus, or brainstem) or as decline in global mental function (e.g., memory loss, inanition) from diffuse exposure. The clinical utility of various techniques of focal radiation accrues from conformal delivery of high doses of radiation to targeted volumes. The more highly conformal the radiation ﬁeld (the more closely its marginally effective dose matches the contours of the targeted lesion and the steeper the dose gradient peripheral to these contours) the higher the dose that can be delivered to the target without exposing surrounding, nontargeted tissue. The higher the dose delivered to the target, the greater the probability of lesion control and the lower the exposure of surrounding tissue, the less the risk of undesirable radiation-induced side effects. Fractionation of dose delivery further decreases the risk of injury to normal cells relative to that suffered by tumor cells because of the greater capacity of normal cells to repair sublethal radiation damage to DNA between treatment fractions3. Different radiation modalities employ different strategies to limit the volume irradiated to that targeted. Placing the radiation source, whether seed or probe, within the target ensures that the immediately surrounding tumor tissue will receive a higher dose than more peripherally located normal tissue. The radiation dose from the photons released from 125I declines from immense adjacent to the source to negligible a decimeter away, according to the inverse square law. Interstitial therapies must create a favorable dose proﬁle by the choice of location, energy, intensity, and duration of activation of the implanted sources. Interstitial radiation using a high number of seeds (usually 10 to 30) has greater ﬂexibility in targeting than does the PRS system, in which a nearly spherical radiation dose is delivered by a probe to one or at most, several positions. External radiation has the disadvantage of depositing an entry dose within tissue overlying the lesion and, with the exception of charged particle radiation manifesting the Bragg peak effect, an exit dose distal to the target4. The strategy for limiting the magnitude of entrance and exit doses of external photon beams to the margin of a target is to distribute this undesired dose over the surface of the lesion. The Gamma Knife does this by targeting multiple isocenters (usually 1 to 12) dispersed throughout a target volume with a large number (up to 201) of multidirectional beams5. Linear accelerator devices respond by rotating the beam relative to a few isocenters (usually 1 to 4) through three

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or four arcs6. The Cyberknife targets a large number of points (100 to 200) within a target from many different directions7. Large beam modalities, such as the Linac and proton beam, can also limit the dose at the periphery of a lesion by shaping the beam, in the plane orthogonal to its path, through collimation8. Collimation, achieved by aiming the beam through the central hole in a cylindrical annulus of highly photon-absorbent metal, is used to limit the dose to the union of cross-sections of the target in the beam’s direction of travel. A target shape that diverges from the tapered spherical dose distribution most readily achieved, however, presents a changing proﬁle to the beam path as the angle of beam path to the target varies. This increases the likelihood of irradiating normal brain tissue. Dynamic multileaf collimation, which varies beam blocking patterns to match the target’s changing proﬁle in the beam path as the beam is rotated about the patient’s target, is one strategy for limiting this problem.

Indications for focal radiation Focal treatment of brain metastases is usually limited to patients who have one to four lesions, who are younger than 70 years old, and capable of self care (Karnofsky Performance Scale [KPS] score of at least 70) or in whom treatment is likely to raise performance to this level, and whose systemic disease is not progressing. Patients in whom surgical resection is precluded by having tumors that are located in deep or eloquent brain regions or by poor general medical condition are particularly suitable candidates for focal radiation treatment. Because traditional frame-based stereotactic radiosurgery (SRS) achieves local control of over 80% of treated tumors for at least one year in a relatively noninvasive fashion, it is the preferred method of focal treatment of surgically inaccessible metastases and an acceptable alternative to surgical resection for many that could be removed. Pretreatment magnetic resonance imaging with gadolinium enhancement is indicated both to exclude leptomeningeal disease and the possibility that numerous intraparenchymal metastases are present and to deﬁne clearly the location, size, and shape of the lesions to be targeted. The need for the biopsy of a single lesion in a patient known to have cancer is disputed9–11. Approximately 10% of patients suspected of having a metastasis based on a computed tomography (CT) scan in Patchell’s study12 had another type of pathology identiﬁed by biopsy, and Alesch et al.9 identiﬁed three patients referred for suspected brain metastasis each of whom had a different disease: lymphoma, infarction, or inﬂammation9, 12. Frequent communication with the patient’s referring oncologist is essential to appropriate coordination of care.

Interstitial radiation of brain metastases Interstitial radiation emanates from sources placed within the target. Multiple techniques have been used:

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1 intracavitary irradiation from radioactive sources suspended in a liquid or gel that is instilled into a tumor cavity or cyst 2 radioactive seeds, temporarily or permanently implanted into a tumor stereotactically or by hand in an open operation 3 transient insertion of a radiation-generating probe within a tumor. Intracavitary irradiation has been most productively used in controlling the size of cysts associated with craniopharyngiomas or gliomas. It has rarely been used to treat a recurrent cystic metastasis. Implantation of radioactive seeds, often called brachytherapy (irradiation at short distances), achieved prominence in the treatment of gliomas in the 1980s13 and has been used for treating metastases both initially and at recurrence14 –16. Interstitial irradiation with the PRS probe has been used for both gliomas and metastases.

Brachytherapy Introduction and indications Although numerous isotopes have been used as seed implants, 192Ir and, especially, 125I have found the most favor. 125I emits photons with average energies of 0.028 MeV over a half life of 60 days13, 17. Activity ranges of 125I seeds used vary from 3–15 mCi9 to 20 to 40 mCi14. In brachytherapy, the aggregated dose rate at the periphery of a targeted lesion varies from 7 cGy/hr11 to 60 cGy/hr13, 14. The dose from the relatively low energy gamma emissions of 125I falls off rapidly, resulting in low risk to brain tissue peripheral to the target and to patient care personnel. Currently, both temporary insertion of high activity seeds and permanent implantation of low activity seeds are used. Advantages of the former include the ability to determine the completion of the irradiation, more precise dosimetry, a shorter period of risk of exposure to others, and the ability to remove the seeds if incorrect positioning or side effects occur9. With the latter, the low dose rate of permanent seeds may be associated with a lower risk of radiation necrosis18. Indications for brachytherapy vary among institutions: Bernstein used brachytherapy for tumors that had regrown after surgery and radiotherapy14; Gutin treated metastases that were solitary, subcortical, supratentorial, and smaller than 5 cm in maximum diameter with a brachytherapy boost to surgery or radiotherapy or at tumor recurrence13; and Alexander reserved brachytherapy for large recurrent tumors following resection19.

Brachytherapy methods The simplest form of brachytherapy is percutaneous stereotactic implantation of a single seed within a tumor. Less spherical tumors are more conformally treated by multiple seeds. The seeds may be implanted into the tumor either percutaneously (using stereotaxy) or at craniotomy, into the tumor bed or residual tumor, using either freehand or stereotactic guidance. Seeds that deliver a lower dose rate do not require removal and may be less prone to induce radiation necrosis18. Alternatively, implanting seeds within a removable catheter permits temporary treatment with high activity seeds.

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Figure 10.1 Brachytherapy. This coronal contrast-enhanced CT image shows a tumor being treated with brachytherapy using after-loaded catheters ﬁlled with 125I seeds. (Courtesy of Dr. Philip Gutin)

Small, spherical tumors can be treated by a single seed within one catheter11. More sophisticated dosimetry can be achieved with multiple seeds placed in multiple afterloaded catheters13, 14. Plastic outer catheters are implanted stereotactically and an inner catheter containing the radioactive seeds is inserted into it. Seeds of varying activity are spaced along the inner catheter at intervals dictated by the desired dose distribution. The use of multiple catheters, often placed in parallel array and containing seeds of varying activity and separation, facilitates the design of a dose distribution that conforms closely to the targeted tumor volume16 (Figure 10.1). In the technique developed by Gutin, a frame-based stereotactic, contrast-enhanced CT image is obtained, and the imaging data are transferred to the BRAIN treatment planning program15. The tumor target is outlined, and a set of catheter trajectories, seed activities, and seed spacings is composed and modiﬁed to create a conformal dose distribution. With the patient under monitored awake anesthesia, twist-drill trephinations are performed at entry points determined by the target coordinates for the catheter tips and the azimuth and declination angles speciﬁed by the treatment plan. The outer silastic catheter is passed to the tumor target through a small plastic collar sewn to the scalp and is then glued to the collar. After all outer catheters have been placed, shielding is acquired. The inner catheters are placed within the outer catheters and clipped to the outer catheter at the collar. Anteroposterior and lateral skull x-rays are then taken to conﬁrm appropriate placement of the seeds. Precautions taken to limit radiation exposure include the surgeon’s use of lead glasses, neck shield, body vest, apron, and gloves; covering the patient’s head with a lead helmet; providing lead vests and aprons for patient care

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personnel and visitors; and monitoring radiation levels in the operating room and the patient’s hospital room. After the prescribed treatment time, all catheters and the contained seeds are removed and the trephination incision is sutured.

Brachytherapy as initial treatment Ostertag and Kreth treated 72 patients with new cerebral metastases (spherical, circumscribed, and less than 4 cm in greatest diameter) with brachytherapy from 1982 to 199211. They temporarily implanted a catheter-ensheathed 125I seed in the center of each tumor so as to deliver 60 Gy to the tumor margin over 40 days (mean dose rate of 7.0 +/− 1.5 cGy/hr). Sixty-ﬁve patients had a single metastasis and seven had two metastases. Thirty-eight patients received brachytherapy (60 Gy) alone, and 34 received brachytherapy (60 Gy) followed by fractionated, external beam radiotherapy (40 Gy) to the entire brain. Seven tumors (three in patients after brachytherapy and four in patients after combined treatment) required a second brachytherapy implant. Approximately 80% of implanted tumors decreased at least 25% in volume, peritumoral edema declined in over 90% of cases, and about 80% of patients had stability or improvement in functional status at three months after treatment. Only two patients suffered a neurological complication; both had a transient hemiparesis. No patient in either group died from progression of a locally treated tumor or developed radionecrosis that required resection. The median durations of survival after treatment in the two groups were 17 months and 15 months, respectively, a difference that did not reach statistical signiﬁcance (p > 0.05). There was no statistically signiﬁcant difference in risk of death from central nervous system disease in the two groups. Multivariate analysis identiﬁed a KPS score of at least 70 (p < 0.05), an interval of at least one year between diagnosis of the primary tumor and presentation of the brain metastasis (p < 0.0001), the presence of a solitary brain metastasis (p < 0.001), and the absence of disseminated systemic disease (p < 0.05), but not the addition of whole-brain radiotherapy (WBRT), as favorable prognostic factors. They concluded that brachytherapy is safe and effective for local control of brain metastases and that the addition of external beam WBRT was not indicated for patients with a single brain metastasis. Their patients’ outcomes strongly support the ﬁrst part of this conclusion. The cogency of the second part is diminished by selection bias: 1 the group treated with both brachytherapy and external beam radiotherapy had a larger mean tumor size 2 it had more patients with systemic metastases 3 it contained 10 patients who received WBRT for disseminated brain disease at least 6 months after brachytherapy. Alesch and colleagues in Vienna9 had a similar experience. They treated 20 previously unresected tumors with 125I brachytherapy to a dose of 60 Gy. Tumors recurred in only one patient, and only one patient suffered a complication, which was temporary worsening of a hemiparesis9. In addition, Bogart

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and colleagues from Syracuse20 treated 15 patients with solitary metastases from non-small cell lung carcinoma with resection and permanent placement of low dose-rate 125I seeds but without WBRT. The median duration of survival after surgery and brachytherapy was 14 months for all 15 patients and 26 months for patients with controlled systemic disease. Intracranial disease progressed in ﬁve of 15 patients: locally in two, distantly in one, and both locally and distantly in one. No patient with a tumor of less than 2.5 cm in maximum diameter experienced local tumor recurrence20. The authors concluded that rates of failure of intracranial tumor control are similar to those seen with WBRT and recommended that patients be spared the acute and potential late toxicity of WBRT20.

Brachytherapy for recurrent metastases Brachytherapy has appeal for treating metastases that have grown despite prior irradiation, particularly in larger tumors after radiosurgery when the chance of local control by external beam treatment is low and the risk of inducing radiation necrosis is high. Implantation of a radiation source within such tumors permits delivery of a very high dose to the center of the tumor without an entrance dose and often with a minimal exiting dose to the surrounding tissues. Gutin and colleagues13 treated 30 patients with brain metastases; 25 were recurrent after WBRT, and ﬁve received it as a complement to radiotherapy (n = 4) or surgery (n = 1) in initial treatment. Targeted tumor volumes ranged from 2.65 to 80.2 cm3 (mean = 20.6 cm3), the numbers of catheters and seeds varied from 1 to 5 (mean = 2) and 1 to 18 (mean = 6), respectively; the dose rate ranged from 20 to 70 cGy per hour (mean = 45 cGy per hour), and the total dose varied from 3,276 to 5,966 cGy (mean = 4,901 cGy). Patients treated for recurrent tumors survived for a median of 13.9 months after treatment compared with 68.2 months for those treated initially. In general, the rates of complication from brachytherapy for metastases were lower than those for treating gliomas13. Radiation necrosis required surgical resection in only three cases. Among those treated for recurrence, KPS score was the most signiﬁcant prognostic factor15. These results are similar to those in the earlier, smaller series of metastases treated with 125I brachytherapy at the University of California at San Francisco (n = 9, median survival time of at least 14 months) and Toronto (n = 10, median survival time = 10.5 months)14, 21. Ostertag and Kreth11 reported a median duration of survival of six months in 21 patients treated with a dose of 60 Gy of 125I brachytherapy to metastases recurring after surgery and WBRT. In another series of 13 patients with surgically accessible recurrent metastases judged too large for stereotactic radiosurgery, Schulder and colleagues22 used surgical resection and permanent implantation of low dose-rate 125I seeds. Tumors received between 43 and 132 Gy (mean = 83 Gy). The patients’ duration of survival after seed implantation ranged from two weeks to nine years (median = 9 months), but operative complications were frequent22.

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In summary, brachytherapy of a spherical tumor with a single, stereotactically placed source is a simple, quickly performed procedure. A high rate of local tumor control can be achieved with a low risk of radiation-induced morbidity. Because of the need for a surgical procedure, the requirement to handle radioactive sources, and the challenge of achieving a conformal dose distribution about a nonspherical target, brachytherapy has been superceded by stereotactic radiosurgery for the initial treatment of a single brain metastasis. Currently, use of brachytherapy is generally limited to tumors that have recurred despite prior focal irradiation and that are too large (between 2 and 5 cm in greatest diameter) for safe retreatment with stereotactic radiosurgery. Such tumors, when surgically accessible, can be treated by a combination of surgical resection and brachytherapy to the tumor. Surgically inaccessible tumors can be treated stereotactically. In both scenarios, permanent implantation of 125I seeds that emit photons at low dose rates is currently preferred by most practitioners.

Interstitial radiation with the Photonic Radiosurgery Source The Photonic Radiosurgery Source (PRS) is a small, battery-powered unit that generates photons from the tip of a probe. Stereotactic implantation of the probe within a tumor permits interstitial irradiation of the tumor mass. Because tumor-necrotizing doses are emitted and a single treatment sufﬁces, this is considered a form of interstitial radiosurgery. The PRS system, developed at Massachusetts General Hospital, has been used in single and multiple institutional trials for the treatment of intracranial metastases for approximately 10 years. The PRS system consists of a control box, the x-ray source, and a Geiger counter23 (Figure 10.2). The control box contains mechanisms for adjusting accelerating voltage, beam current (determinant of dose rate), and activation time, plus a 9.6 volt nickel-cadmium battery pack that powers the entire unit. The 1.6 kg x-ray source is a miniature high voltage generator of low energy photons (a maximum of 40 KeV versus the 1 MeV energy of photons from a cobalt-60 source)24. It consists of a small high voltage power supply, an electron gun, an electron accelerator, and beam deﬂectors. These components are all contained within a housing, 30 cm long and 8 cm in diameter, designed for attachment to a stereotactic arc. Extending from the source is a rigid probe, 3.2 mm in diameter and 10 cm long (coated with nickel and titanium for biocompatibility), containing an evacuated and magnetically shielded tube with thin gold foil at its tip. The beam (0.3 mm in diameter) of electrons (40 KeV in energy) generated in response to activation of the power supply by the control box, passes down the target tube to strike the gold foil at the hemispherical distal tip of the probe. This generates low energy x-rays that pass through a coating of beryllium into tissue about the probe tip. Radiation output is monitored by scintillation detectors in the source housing and in an attachment for the stereotactic head frame.

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(A)

(B)

(C) Figure 10.2 Interstitial stereotactic radiosurgery. (A) The Photonic Radiosurgery Source (PRS) system consists of a control box, the x-ray source, and a Geiger counter. (B) Attaching the PRS source to the carrier arc of a Cosman-Roberts-Wells frame permits stereotactic positioning of the probe tip. (C) The probe is advanced through a simple trephination until its tip lies at the tumor’s center. (Courtesy of Dr. Rees Cosgrove and Photoelectron Corp, Inc.)

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The PRS system produces a spherical dose distribution centered on the distal tip of the probe similar in shape to that generated by a low energy, high dose-rate brachytherapy point source25. Because of the low energy of the photons, the dose rate to surrounding tissue declines in proportion to the cube of the distance of tissue from the probe tip rather than to its square, as is the case with high energy photons. This results in a 30% decline in dose per mm of tissue traversed. The dose rate decreases from approximately 500 Gy per minute at the probe tip, to 0.5 Gy per minute at a distance of 15 mm, to negligible at 50 mm. Typically, a dose of 15 Gy is delivered to the margin of a tumor 3 cm in diameter at a dose rate of 0.5 Gy per minute during a 30 minute treatment26. Although over 99.9% of the energy emitted is in the form of heat rather than x-rays, the temperature of tissue 1 cm from the probe tip does not rise more than 0.5 degree Celsius during a typical treatment24. Radiation exposure of others near the patient falls to background levels (less than 10 mrem per hour) at a distance of 6 meters. For treating brain tumors, the PRS x-ray source is attached to a stereotactic frame. Performing PRS interstitial irradiation immediately after biopsy allows both procedures to be completed during a single frame placement27. Biopsy and irradiation are most efﬁciently accomplished using an intraoperative CT scanner. Intravenous access is obtained and the patient is sedated. After the head frame is attached to the patient, a stereotactic, contrast-enhanced scan is obtained. Reconstructions in the coronal plane are performed. The tumor is outlined, and its maximal diameters in all three planes are measured. The coordinates of the center of the tumor mass are calculated. A trephination is drilled, and a stereotactic biopsy is taken from the tumor center or from some other point on a ray of approach10. After considering the size and location of the tumor and the dose distribution proﬁle of the PRS device, a treatment plan specifying probe tip placement (usually the tumor’s center), treatment time, beam voltage, and beam intensity is devised. After pathological analysis conﬁrms that a treatable tumor is present, the biopsy needle track is enlarged by passing a series of progressively larger probes to the target point. Optional repetition of the CT scan permits conﬁrmation of the desired placement of the probe tip and exclusion of intracerebral hematoma. The x-ray source is then ﬁxed to the stereotactic arc, and its probe is advanced along the enlarged track until it lies at the target point. The external scintillation detector is also afﬁxed to the frame. Treatment time, current, and voltage are set on the control box, and with all personnel at least 6 meters away, the automatic timer is activated. After the prescribed treatment time has elapsed, the probe is removed. The CT scan is repeated if there is any suggestion of hemorrhage. The incision is then repaired and the stereotactic frame removed. The PRS system has been the subject of both single institutional and multinational clinical trials. At Massachusetts General Hospital (MGH), 40 patients whose tumors were deemed inappropriate for resection were selected for treatment of brain metastases with PRS interstitial radiosurgery (R. Cosgrove,

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personal communication). Almost all patients had either non-small cell lung carcinoma (n = 25) or malignant melanoma (n = 10). Although patients with multiple brain metastases were accepted, only one tumor per patient, usually the one most likely to become symptomatic by virtue of size and location, was treated. If a patient had not previously received it, fractionated WBRT (n = 26; 30 Gy in 10 fractions) was given after the interstitial treatment. Forty tumors, ranging in largest diameter from 4 to 40 mm (mean = 16.8 mm), were treated using treatment volumes (8 to 44 mm in diameter) that encompassed the contrast enhancement observed on the CT image and a 2 mm margin. The radiation dose ranged from 10 to 20 Gy (mean = 15.8 Gy) at the margin of the treatment volume over a treatment time that varied from four to 75 minutes (mean = 19.5 minutes). Although there were no intraoperative complications, two patients developed focal motor deﬁcits that resolved after treatment with corticosteroids and dehydrating agents, and two experienced focal motor seizures that were treated successfully with anticonvulsant medication. Almost all patients were discharged the day after surgery. One patient developed a chronic subdural hematoma contralateral to the treated lesion three months after treatment. No patient developed an infection or permanent neurological deﬁcit. During clinical and radiographic follow up ranging from one to 30 months (mean = 7 months), the treated tumor remained stable or decreased in size in 36 of 40 patients (local tumor control rate = 90%). Treated lesions grew in four patients, at 3, 3, 6, and 10 months, respectively; all four were resected. Two of these lesions proved to be radiation necrosis alone, and two contained radiation necrosis rimmed by viable tumor cells. In this study, the median duration of survival after treatment was 13 months. At the last follow-up visit, thirty-four of the 40 patients had died: 27 from systemic disease, seven from distant CNS disease, and none from progression of treated tumor. Subsequent follow up of a total of 65 patients treated at MGH has shown a local tumor control rate of 85%, a result comparable to that achieved in a multi-institutional international trial (R. Cosgrove, personal communication). In summary, the PRS system offers the ability to treat a brain metastasis at the time of diagnostic biopsy. Advantages relative to seed brachytherapy include avoidance of handling of radioactive sources and thus no requirement for shielding, a shorter treatment time, an adjustable dose rate, and a steeper dose gradient. The very steep dose gradient both limits any radiotherapeutic potential (the rim of tissue around the target’s periphery receives little dose that might have the beneﬁcial speciﬁc antitumor effect of a brachytherapy seed) and permits irradiation of tumors larger than the size safely treated with external beam stereotactic radiosurgery. Disadvantages relative to external beam stereotactic radiosurgery include highly inhomogeneous exposure within the tumor (from 15,000 Gy at the tumor’s center to 15 Gy at its periphery), limited ability to shape the dose distribution beyond the spherical, and the need for percutaneous insertion. When performed after a stereotactic biopsy, however, insertion of the PRS probe should minimally increase the risk of

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infection, hemorrhage, and provocation of edema incident to the biopsy. The PRS system is most likely to be useful when biopsy is needed and external beam stereotactic radiosurgery is not available.

Fractionated stereotactic radiation Fractionation of the radiation dose to a tumor may afford an increase in the therapeutic ratio of the radiation’s effect and thus allow effective irradiation of targets whose size or location might otherwise preclude it. The concept of fractionated stereotactic radiation of brain tumors has evolved from two directions: the use of stereotactic targeting and delivery of traditionally fractionated treatments (stereotactic radiotherapy, SRT28) and the fractionation of standard stereotactic radiosurgery (fractionated radiosurgery, FRS), such as that from the Cyberknife7. Both have been made possible by the development of noninvasive, precisely relocatable head ﬁxation systems.

Stereotactic radiotherapy Stereotactic radiotherapy (SRT), advocated by Loefﬂer (among others) for the treatment of primary malignant brain tumors, uses daily reapplication of a modiﬁed Gill-Thomas frame in delivery of a conventionally fractionated 60 Gy over 6 weeks29, 30. The frame immobilizes the patient’s head by frontal and occipital supports and a bite block. This ﬁxation permits reproducibly accurate positioning and thus precise targeting and delivery. Increased accuracy allows treatment that is more conformal and thus safer administration of an optimally effective dose. Although used extensively to treat both acoustic neuromas and gliomas, SRT has not been used frequently to treat brain metastases. Tokuuye et al. at the National Cancer Center in Japan31 treated 64 patients who had intracranial metastases with 42 Gy in seven fractions over 2.3 weeks (or used a smaller fraction size for tumors larger than 3 cm in greatest diameter or close to radiation-sensitive structures). The median duration of survival was 8.3 months, and the actuarial rate of survival at 1 year was 33%. Characteristics of patients having adverse prognostic signiﬁcance included having the lung as the primary cancer site, the presence of extracranial metastases, and a low pretreatment neurological performance status. Patients without extracranial metastases prior to SRT had a median duration of survival of 21.2 months. These authors reported high rates of local tumor control and low morbidity, except in patients who had previously received intensive radiation31. In another study32, thirty-two patients with a total of 57 metastases received three fractions of 9 Gy each of Linac stereotactic radiotherapy as a boost to 30 Gy of WBRT (using a relocatable frame) at Virginia Commonwealth University. This was the initial treatment in 23 patients and was used for recurrent disease in nine patients. The median duration of survival after treatment was 12 months. The RTOG-RPA class and KPS scores of these patients carried prognostic signiﬁcance for duration of survival. Although no acute toxicity

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(A)

(B) Figure 10.3 Cyberknife fractionated stereotactic radiosurgery. (A) The ﬂexibility of the Cyberknife’s robotic arm, guided by almost instantaneous feedback from the imaging system, permits stereotactic delivery of radiation without frame ﬁxation. (B) The isodose distribution (20, 30, 40, 50, 60, 70, 79–81, and 90 percentile isodose lines) of a three-fraction, 18 Gy (80 percentile isodose line) Cybernife treatment of a 3.5 cm3 dorsal pontomesencephalic tumor (dotted line). (Courtesy of Dr. John Adler and Accuray, Inc.)

was observed, four patients suffered delayed seizures, and two developed radiation necrosis. This hypofractionated stereotactic radiotherapy was found to be less costly than SRS32.

Fractionated stereotactic radiosurgery The Cyberknife, developed by Adler et al. at Stanford7, achieves stereotactic accuracy without invasive head ﬁxation. It consists of a small, lightweight, high-energy linear accelerator attached to a highly maneuverable robotic arm and guided by rapidly acquired orthogonal plain x-ray ﬁlms (Figure 10.3). The high (7.5 G/Hz) radio frequency of operation of the linear accelerator permits its smaller size (130 kg), limited shielding, and ﬁner collimation. The Fanuc robotic arm can direct the linear accelerator with submillimeter pointing precision through six degrees of freedom. Advanced image registration techniques relate information regarding patient position during treatment to reconstructions from treatment planning CT scans. Guidance software translates discrepancies in patient positioning into corrective adjustments of the beam pointing. In this way, minor changes in the patient’s head position, and thus of the target during treatment, are compensated for automatically and

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almost immediately33. This novel system provides readily reproducible stereotactic accuracy without rigid, invasive frame ﬁxation and thus facilitates highly conformal fractionated therapy. The imaging system contains two sources of diagnostic x-rays that pass orthogonally through the patient’s head, held in place by a pliable mask of webbed plastic, and are directed at ﬂuoroscopes on either side of the patient34. The stationary position of the two sources provides a ﬁxed frame of reference for locating the contours of the patient’s skull in the stereotactic space of the imaging system. Within this imaging space, the robotic manipulator, the linear accelerator, and its beam also occupy known positions. The target’s position within the imaging space is identiﬁed by reconstructing data from the treatment planning CT images into digitally reconstructed radiographs (DRRs) that can be virtually superimposed upon the radiographs acquired during treatment. In this manner, the coordinates of the targeted lesion on the pretreatment CT scan are related to the skull’s contour on DRRs, which relate to the skull’s outline on the treatment ﬁlms, which relate the position of the patient’s head to that of the treatment beam. The robotic manipulator can thus be directed to aim the beam at any point within the target. This process is performed with such speed that changes in head position can be detected and compensated for in less than one second. To plan a treatment, the physician deﬁnes the shape, size, and location of the tumor and identiﬁes critical normal structures from which the radiation dose should be constrained by outlining their perimeters on thin sections of the contrast-enhanced planning CT images. Thereafter, treatment planning is automatically performed. From these outlines, the treatment planning software creates a three-dimensional representation of the tumor in the treatment planning stereotactic space. A treatment sphere, 80 cm in diameter, is deﬁned about the target, and 300 equally spaced points are identiﬁed on its surface. These points are nodes of possible positioning of the x-ray source by the robotic manipulator about the patient’s head. The beam’s direction and the duration of exposure from each node can be varied. Various combinations of nodes, beam directions, and beam weightings (treatment times) are used to generate dose distributions that are assessed in terms of the desired dose and targeting constraints. The software initially selects a set of beams aimed at points evenly spaced over the tumor’s surface (usually approximately 100 per lesion), beam directions, and exposure durations. The resulting dose distribution is compared with the constraints set by the treatment planner, and the initial selections are modiﬁed automatically to generate a superior plan. Automatic parameter modiﬁcation and evaluation of the resulting dose distributions is continued in iterative fashion under an optimization scheme in which information gained during one iteration is used to improve the next. This process continues until a satisfactory solution is reached. The Cyberknife has signiﬁcant advantages beyond conventional radiosurgical systems, which have restricted movement of the radiation source relative to the target and isocentric treatment planning and delivery. The positional

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ﬂexibility of the Cyberknife’s robotic arm and its nonisocentric method of treatment planning and delivery permit delivery of highly conformal, homogeneous doses of radiation to even irregularly shaped tumor volumes. Both single session and fractionated treatments can be delivered with stereotactic accuracy without the pain, invasiveness, and inconvenience of frame placement. Early clinical experience with the Cyberknife has been accumulated at Stanford University (J. Adler, S. Chang, personal communication). Between June 1994 and February 2001, 46 brain metastases were treated in 31 patients, including eight men and 23 women. Patients ranged in age from 19 to 80 years (mean = 54 years). Eighteen patients had single lesions, 11 had two lesions (three of these had metachronous tumors), and two had three. Lung cancer10, breast cancer7, melanoma4, ovarian cancer3 and renal cancer3 were the most common primary pathologies. Thirty-three of the tumors were supratentorial, six were cerebellar, three were in the brainstem, three were in the spinal cord, and one was in the cavernous sinus. Eleven of the patients had received WBRT (25 to 54 Gy) prior to radiosurgery, and one patient had undergone resection of a metastasis at a different site. The pretreatment volume of the tumors ranged from 0.006 to 19.7 cc (mean = 3.18 cc). The dose prescribed to the tumor’s margin ranged from 10 to 25 Gy (mean = 18.8 Gy), and the maximal dose delivered to the interior of the tumor ranged from 16 to 30 Gy. For the 46 brain metastasis treatments, the following collimator sizes were used: 7.5 mm6, 10 mm16, 12.5 mm10, 15 mm4, 17.5 mm4, 20 mm1, 25 mm3, 30 mm1, and 40 mm1. All but seven patients received radiation as a single fraction dose. Tumors receiving fractionated treatment because of a combination of their respective sizes and locations were as follows: two large supratentorial tumors (13.29 cc and 19.70 cc in volume) received two and ﬁve fractions, respectively; a large cerebellar tumor (15.36 cc in volume) received three fractions; two brainstem tumors (3.59 cc and 3.50 cc in volume) received two and three fractions, respectively; and two tumors in the cervical spine (0.17 cc and 6.37 cc in volume) received two and four fractions, respectively. At follow-up intervals ranging from 1 to 26 months (mean = 9.2 months) in 22 patients, 12 had died at intervals of 1 to 26 months after treatment (mean = 10 months), and 10 were alive and normal neurologically at intervals ranging from 1 to 26 months after treatment (mean = 8.6 months). Follow-up imaging data were available for 11 tumors in nine patients. Five tumors had disappeared, six were signiﬁcantly smaller, and two had enlargedaone (a small metastasis of renal cell carcinoma treated with 21 Gy to its margin) to the point that it required retreatment. No patient suffered a neurological deﬁcit or died from either progression of a treated tumor or from complications of treatment. In summary, stereotactic radiotherapy (SRT) and fractionated radiosurgery (FRS) offer high rates of local control of tumors whose size, location, or prior treatment might increase the risk of single fraction radiosurgery. The Cyberknife, speciﬁcally engineered for the purpose of frameless delivery of

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highly conformal fractionated radiation, will probably see increased use in this scenario.

Conclusion The value of focal treatment of brain metastases in combination with WBRT has been established in prospective, randomized, controlled clinical trials. The combination of surgery and radiotherapy yields longer survival, greater freedom from local recurrence, and higher quality of life than does radiotherapy alone2, 12, 35. In the randomized study from the University of Kentucky2, patients with a single brain metastasis treated with surgical resection and WBRT had a median duration of survival after treatment of nine months versus three months for those treated with WBRT alone. In a similar randomized study, Noordijk and colleagues35 showed longer survival (10 months versus 6 months, respectively; p = 0.04) for patients receiving surgery and WBRT than for those receiving WBRT alone. The addition of surgery was less beneﬁcial among patients more than 60 years old and those with active systemic disease. These studies suggest that aggressive local therapy is warranted in some patients with brain metastases. It should probably be reserved for patients in whom progression of local CNS disease represents the predominant threat to survival, i.e., patients less than 70 years old and capable of self-care (KPS score of at least 70), with a maximum of four metastases and with no active systemic disease. Several stereotactic radiation techniques purport to achieve the same beneﬁt of local tumor control as surgery but in a less invasive manner. These include stereotactic radiosurgery (SRS), brachytherapy, interstitial radiosurgery, stereotactic radiotherapy (SRT), and fractionated radiosurgery (FRS). These techniques can be performed much less invasively than can surgery. Cranial opening is either nonexistent or is limited to a small trephination. They can also be used in patients with lesions inaccessible to surgery because of either their depth or proximity to critical structures, or in patients with contraindications to open surgery. Single fraction SRS is generally considered the preferred alternative to surgery for the initial focal treatment of a single metastasis smaller than 3 cm in greatest diameter6, 36. Indications for using the four techniques discussed in this chapter vary by technique and by surgeon. Although a few surgeons use brachytherapy as the primary radiation modality for solitary metastases at the time of stereotactic biopsy37, most of its practitioners reserve it for larger metastases (maximum diameter of 3 to 5 cm and thus too large for SRS) that recur after prior irradiation (either WBRT or focal radiation)14, 15. This may involve either implantation of radiation sources at the time of resection of the tumor or their stereotactically guided percutaneous implantation in a surgically inaccessible tumor. The PRS interstitial probe, too, has been used predominantly as an alternative to single fraction SRS, usually at the time of diagnostic biopsy of tumors up to 4 cm in maximum diameter27.

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Finally, SRT and FRS are noninvasive options for tumors whose combination of size, location, and prior treatment make them risky targets for single fraction treatment. Examples include tumors at the limit of the radiosurgical range (2 to 4 cm in maximum diameter), tumors adjacent to the optic apparatus or within the brainstem, and tumors recurrent within the ﬁeld of prior radiation. The ability of these two techniques to deliver highly conformal fractionated radiation noninvasively makes them the most attractive option for focal treatment of metastases not requiring resection yet inappropriate for standard single fraction radiosurgery.

References 1 DeAngelis LM: Management of brain metastases. Cancer Invest 1994; 12: 156 –165. 2 Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 3 Larson DA, Flickinger JC, Loefﬂer JS: The radiobiology of radiosurgery. Int J Radiat Oncol Biol Phys 1993; 25: 557–561. 4 Harsh G, Loefﬂer JS, Thornton A, et al.: Stereotactic proton radiosurgery. Neurosurg Clin N Am 1999; 10: 243 –256. 5 Coffey RJ, Flickinger JC, Bissonette DJ, et al.: Radiosurgery for solitary brain metastases using the cobalt-60 gamma unit: methods and results in 24 patients. Int J Radiat Oncol Biol Phys 1991; 20: 1287–1295. 6 Alexander E, Moriarty TM, Davis RB, et al.: Stereotactic radiosurgery for the deﬁnitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995; 87: 34 – 40. 7 Adler JR, Chang SD, Murphy MJ, et al.: The Cyberknife: a frameless robotic system for radiosurgery. Stereotact Funct Neurosurg 1997; 69: 124 –128. 8 Hacker FL, Kooy HM, Bellerive MR, et al.: Beam shaping for conformal fractionated stereotactic radiotherapy: a modeling study. Int J Radiat Oncol Biol Phys 1997; 38: 1113 – 1121. 9 Alesch F, Hawliczek R, Koos WT: Interstitial irradiation of brain metastases. Acta Neurochir (Suppl) (Wien) 1995; 63: 29 –34. 10 Carter BS, Harsh GR 4th: Diagnosis of suspected intracranial metastases. Role of direct tissue examination. Neurosurg Clin N Am 1996; 7: 425 – 433. 11 Ostertag CB, Kreth FW: Interstitial I-125 radiosurgery for cerebral metastases. Br J Neurosurg 1995; 9: 593 – 603. 12 Patchell RA: The treatment of brain metastases. Cancer Invest 1996; 14: 169–177. 13 Gutin PH, Phillips TL, Wara WM, et al.: Brachytherapy of recurrent malignant brain tumors with removable high-activity iodine-125 sources. J Neurosurg 1984; 60: 61– 68. 14 Bernstein M, Cabantog A, Laperriere N, et al.: Brachytherapy for recurrent single brain metastasis. Can J Neurol Sci 1995; 22: 13 –16. 15 McDermott MW, Cosgrove GR, Larson DA, et al.: Interstitial brachytherapy for intracranial metastases. Neurosurg Clin N Am 1996; 7: 485 – 495. 16 Ten H, Diaz RF, McShan DL, et al.: From manual to 3-D computerized treatment planning for 125-I stereotactic brain implants. Int J Radiat Oncol Biol Phys 1988; 15: 467– 480. 17 Heros DO, Kasdon DL, Chun M: Brachytherapy in the treatment of recurrent solitary brain metastases. Neurosurgery 1988; 23: 733 –737. 18 McDermott MW, Sneed PK, Gutin PH: Interstitial brachytherapy for malignant brain tumors. Semin Surg Oncol 1998; 14: 79 – 87.

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19 Alexander E 3rd, Loefﬂer JS: Recurrent brain metastases. Neurosurg Clin N Am 1996; 7: 517–526. 20 Bogart JA, Ungureanu C, Shihadeh E, et al.: Resection and permanent I-125 brachytherapy without whole brain irradiation for solitary brain metastasis from non-small cell lung carcinoma. J Neurooncol 1999; 44: 53 –57. 21 Prados M, Leibel S, Barnett CM, et al.: Interstitial brachytherapy for metastatic brain tumors. Cancer 1989; 63: 657– 660. 22 Schulder M, Black PM, Shrieve DC, et al.: Permanent low-activity iodine-125 implants for cerebral metastases. J Neurooncol 1997; 33: 213 –221. 23 Dinsmore M, Harte KJ, Sliski AP, et al.: A new miniature x-ray source for interstitial radiosurgery: device description. Med Phys 1996; 23: 45 –52. 24 Hakim R, Zervas NT, Hakim F, et al.: Initial characterization of the dosimetry and radiology of a device for administering interstitial stereotactic radiosurgery. Neurosurgery 1997; 40: 510–516. 25 Beatty J, Biggs PJ, Gall K, et al.: A new miniature x-ray device for interstitial radiosurgery: dosimetry. Med Phys 1996; 23: 53 – 62. 26 Douglas RM, Beatty J, Gall K, et al.: Dosimetric results from a feasibility study of a novel radiosurgical source for irradiation of intracranial metastases. Int J Radiat Oncol Biol Phys 1996; 36: 443–450. 27 Cosgrove GR, Hochberg FH, Zervas NT, et al.: Interstitial irradiation of brain tumors using a miniature radiosurgery device: Initial experience. Neurosurgery 1997; 40: 5518 –5525. 28 Shrieve DC, Kooy HM, Tarbell NJ, et al.: Fractionated stereotactic radiotherapy. Important Adv Oncol 1996; 1966; 205 –224. 29 Kooy HM, Dunbar SF, Tarbell NJ, et al.: Adaptation and veriﬁcation of the relocatable GillThomas-Cosman frame in stereotactic radiotherapy. Int J Radiat Oncol Biol Phys 1994; 30: 685–691. 30 Tome WA, Meeks SL, Buatti JM, et al.: A high-precision system for conformal intracranial radiotherapy. Int J Radiat Oncol Biol Phys 2000; 47: 1137–1143. 31 Tokuuye K, Akine Y, Sumi M, et al.: Fractionated stereotactic radiotherapy of small intracranial malignancies. Int J Radiat Oncol Biol Phys 1998; 42: 989–994. 32 Manning MA, Cardinale RM, Benedict SH, et al.: Hypofractionated stereotactic radiotherapy as an alternative to radiosurgery for the treatment of patients with brain metastases. Int J Radiat Oncol Biol Phys 2000; 47: 603 – 608. 33 Chang SD, Murphy MJ, Tombropolous R, et al.: Robotic radiosurgery. In Maciunas RJ (ed): Advanced Neurosurgical Navigation. 1999; New York: Thieme. 34 Murphy MJ, Cox RS: Frameless radiosurgery using real time image correlation for beam targeting. Med Phys 1996; 25: 1052–1058. 35 Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al.: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994; 29: 711–717. 36 Kim YS, Kondziolka D, Flickinger JC, et al.: Stereotactic radiosurgery for patients with non-small cell lung carcinoma metastatic to the brain. Cancer 1997; 80: 2075 –2083. 37 Kreth FW, Muacevic A, Siefert A: In regard to Dr. Kondziolka et al.: stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 2000; 47: 850 – 851.

CHAPTER 11

Chemotherapy for brain metastases Sigmund H Hsu, WK Alfred Yung

The incidence of brain metastases is estimated at greater than 100,000 cases per year in the United States. The diagnosis is associated with a poor prognosis, with a median survival from four to six months. Brain metastases occur nearly 10 times more frequently than primary brain tumors, with the most common tumors arising from lung cancer, breast cancer, malignant melanoma, renal cell carcinoma, and colorectal cancer1, 2. Autopsy studies have documented brain metastases in 24% of all cancer patients, ranging from a prevalence of 7% for pancreatic and colorectal cancer to 72% for melanoma patients3, 4. Advances in the treatment of cancer have led to better local control and improved survival, but they unfortunately also increase the possibility that brain metastases will become a more pressing impediment to long-term survival5. Patients may successfully respond to systemic chemotherapy but then relapse with brain metastases or leptomeningeal disease. Nevertheless, most patients with brain metastases die from progression caused by uncontrolled systemic tumor growth3. Chemotherapy has historically been considered ineffective for the treatment of brain metastases, compared with surgery and radiotherapy6. The failure of chemotherapy has been attributed to several factors, particularly, inadequate penetration of the central nervous system (CNS) by therapeutic drugs due to the blood-brain barrier (BBB). Other stumbling blocks include the inherent chemoresistance of tumor cells that have already survived systemic chemotherapy and have further metastasized to the brain, and brain metastases occurring in the setting of relapsing progression of systemic disease5. Despite a historic lack of proven success, chemotherapy may have a selected role in the treatment of patients with brain metastases. A retrospective study of “long-term” (greater than 2 years) survivors with brain metastasis has identiﬁed young age, having single metastases, and undergoing surgical resection, whole-brain radiotherapy, or chemotherapy as favorable prognostic factors7. The primary tumor pathology is an important consideration, as some tumors are more responsive to chemotherapy, such as breast cancer, whereas others, such as melanoma and renal cell carcinoma, are relatively chemoresistant8. The development of brain metastases is a sequential process that requires speciﬁc steps. Tumor cells must migrate and enter the systemic circulation, survive and be transported through the blood to the brain, adhere and extravasate through the endothelium, invade the brain parenchyma and proliferate, which requires recruitment of a secondary blood supply. Failure at any of 183

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these steps will halt the process9–11. These stages each require complex interactions between the tumor cell and its changing microenvironment. The location of tumor metastases is not random and requires interaction between the tumor cell and tissue in a process that has been characterized as the “seed and soil” hypothesis12–14. The primary tumor is regarded as biologically and molecularly heterogeneous and is subject to a biological imperative that favors the selection of tumor cells that can survive the arduous process required for metastasis, i.e., the “seed.” Experimentally, metastases arising from the same primary tumor can have different clonal origins and be traced back to different single cells15. The local environment of the tumor cell, i.e., the “soil,” greatly affects its success in proliferating and recruiting an adequate blood supply through angiogenesis. The properties that allow success in producing tumor metastases are unrelated to the proliferative capacity of the cells at the primary site, and in clinical practice this is seen when distant metastases develop in the context of good local response of the tumor to treatment16. Understanding the biological processes of metastases and the role of the BBB provides potential targets for intervention to improve treatment of brain metastases. The multiple regulators of cell adhesion are complex and include molecules such as integrins, cadherins, selectins, and heparin sulfate proteoglycans16. These molecules mediate cell adhesion. Additionally, the integrins can recruit intracellular signaling molecules such as focal adhesion kinase and src, which can lead to a cascade of cellular signaling that affects cell cycle control and proliferation17, 18. The molecules that mediate invasion include the family of matrix metalloproteinases (MMPs), serine proteases, and heparinase. The MMPs are proenzymes that degrade the extracellular matrix and basement membrane, promoting tumor invasion. The gelatinases (MMP-2 and MMP-9) are thought to have especially important roles in brain tumor invasion19. Heparinase is an enzyme that degrades the heparin sulfate chains, which are important components of the basement membrane20. Heparinase activity has been detected in melanoma cells derived from brain metastases21. Tumor cells must generate a blood supply if they are to grow successfully and remain viable. The regulation of this process, known as angiogenesis, is inﬂuenced both by activators and inhibitors. These are expressed either by tumor cells or other cells in the tumor’s microenvironment. Important activators of angiogenesis include vascular endothelial growth factor (VEGF), angiopoietin, hypoxia-inducible transcription factor (HIF), cyclo-oxygenase 2 (COX 2), platelet-derived growth factor (PDGF), integrins, MMPs, and others. Important inhibitors of angiogenesis include angiostatin, endostatin, tissue inhibitors of matrix metalloproteinases (TIMPs), interferons, and platelet factor 422. Upregulation of activators or downregulation of inhibitors would favor angiogenesis. The existence of a multitude of pathways involved in tumor growth and invasion suggests that if one pathway is inhibited, cells may escape through alternate pathways, because as tumors grow, they begin to produce increasing numbers of angiogenic molecules that can participate in metastasis22.

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The BBB is formed by tight junctions and continuous, nonfenestrated endothelial cells. The brain lacks lymphatic drainage and depends on the BBB to ﬁlter and block the entrance of macromolecules and invasion by microorganisms23. The barrier to hydrophilic drugs created by the BBB is passive and is also augmented by active transport from P-glycoprotein, which is expressed at high levels in the brain’s endothelium24. The P-glycoprotein family of transporters actively exports drugs such as anthracyclines (doxorubicin), vinca alkaloids (vincristine), and taxanes (paclitaxel), and etoposide25. The integrity of the BBB is also dependent on interactions between the endothelial cells and astrocytes and oligodendrocytes13, 26. Unfortunately, the BBB can be breached by circulating metastatic cells, a process that has been duplicated experimentally by direct carotid artery injection of tumor cell lines into nude mice27. These tumor cells can migrate across the BBB without degrading its permeability and then proliferate. Once the tumor reaches a size that requires recruitment of new vessels, the BBB is disrupted, which allows imaging of brain tumors with contrast agents. In experimental models, brain metastases smaller than 0.25 mm in greatest diameter are associated with an intact BBB, whereas larger tumors show permeability of the BBB13. Despite the presence of the BBB, studies of drug levels in brain tumors from systemic administration before surgery demonstrate pharmacologically relevant concentrations of drugs28 –30. As decreasing amounts of drug reach the tumor periphery and adjacent brain in rats, comparatively lower drug levels are achieved in brain tumors compared with levels in subcutaneously implanted tumors31. Measurements of drug levels in cerebrospinal ﬂuid are not accurate indicators of tissue drug levels in brain tumor metastases and should not be assumed to predict activity32. Several small clinical trials and case reports in the literature support the concept of activity of systemic chemotherapy for treating brain metastases. Chemosensitive tumor types include breast cancer, small cell lung cancer, and germ cell tumors. One problem in brain tumor chemotherapy is the use of corticosteroids, which is often necessary to control cerebral edema but can reestablish disrupted BBB function, which may impair delivery of chemotherapy33. A review of treatment with systemic chemotherapy for brain metastases from small cell lung cancer pooled data from ﬁve clinical trials. A 66% response rate was demonstrated34. Unfortunately, this response is not durable when chemotherapy is used by itself, even in cases of complete response. Prophylactic cranial irradiation of small cell lung cancer patients who have a complete response to systemic chemotherapy can signiﬁcantly reduce the incidence of brain metastases35. A trial using combination chemotherapy of cyclophosphamide, 5-ﬂuorouracil, methotrexate, vincristine, and prednisone for treatment of breast cancer in patients who had not received prior chemotherapy demonstrated a greater than 50% response rate, although the median duration of response was only seven months36. In these trials, the response rate of brain metastases was comparable to the response rates of the systemic disease. Patients who received prior chemotherapy responded at lower rates.

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A recent small trial of ﬁrst line chemotherapy for brain metastases from non-small cell lung cancer demonstrated a response rate of 45%, with an equal number of patients showing minor responses and stable disease. The median time to response was 10 weeks, and the median duration of response was 25 weeks. However, the median survival time for the entire group was 33 weeks and only 48 weeks in the responders37. A trial of patients who had failed to respond to radiotherapy utilized the multidrug regimen of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, 5-ﬂuorouracil, and hydroxyurea to demonstrate overall (responders plus those with stable disease) response rates of 60% for breast cancer, 52% for non-small cell lung cancer, and 66% for small cell lung cancer. The disease-free period of survival in these patients was 27 weeks for those with breast cancer, 21 weeks for those with non-small cell lung cancer, and 133 weeks for those having small cell lung cancer38. A study of fotemustine, a chloroethylnitrosourea, in patients with brain metastases from malignant melanoma demonstrated a median response rate of 24%39. Chemotherapy produces a high response rate in patients with brain metastases arising from germ cell tumors. A regimen of etoposide, methotrexate, dactinomycin, vincristine, cyclophosphamide, and cisplatin for treatment of gestational choriocarcinoma induced a 72% durable response rate40. In a study of brain metastases from germinoma, eight of 10 patients had a complete response to a combination regimen of cisplatin, vincristine, methotrexate, bleomycin, etoposide, dactinomycin, and cyclophosphamide41. Considering the widespread prevalence of brain metastases, relatively few clinical trials have addressed them speciﬁcally. Most clinical trials of investigational chemotherapeutic agents for solid tumors explicitly exclude patients with brain metastases. Compounding this omission is the common inclusion in studies of a heterogeneous group of patients with mixed tumor types and differing in prior exposure to chemotherapy. Patients might also be expected to be more resistant to treatment with chemotherapeutic agents if they have failed to respond to radiotherapy. If chemotherapy is given during and after radiotherapy, it may be difﬁcult to separate the efﬁcacy of the radiotherapy from the efﬁcacy of the chemotherapy. These factors combined make it difﬁcult to compare treatment regimens and interpret studies42. One approach to this problem is to stratify patients according to pretreatment factors. These can be analyzed to identify factors that have prognostic value. The radiation therapy oncology group (RTOG) analyzed a database of 1,200 patients using differing radiation fractionation schemes or radiosenzitizers for brain metastasis treatment. First, a univariate analysis was performed that considered 18 pretreatment factors, including age, tumor histology, control of the systemic cancer, neurological status, Karnofsky Performance Scale (KPS) score, location of brain lesions, and three treatment-related variables, such as radiation dose. A recursive partitioning analysis (RPA) was performed to rank the signiﬁcance of these factors. The study grouped patients into three classes. Class 1 patients had a KPS score ≥ 70, age < 65, a controlled primary tumor site, and no extracranial metastases. Class 3 patients had a KPS score

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< 70 and Class 2 patients included all others. The median survival time was 7.1 months for patients in Class 1, 4.2 months for Class 2, and only 2.3 months for Class 3 patients43. The validity of this database was veriﬁed by a second RPA on a trial of 445 patients randomized to an accelerated hyperfractionation group or to an accelerated fractionation group. Class 1 patients had a median survival time of 6.2 months compared with 7.1 months for the database as a whole and a one-year survival rate of 29% compared with 32% for the database44. The use of RPA allows the most important pretreatment prognostic factors to be identiﬁed and provides an historic database from which to compare future studies. Recent strategies for improving chemotherapy response rates for brain metastases have focused on developing novel agents and combinations of agents to overcome the intrinsic chemotherapeutic resistance of the tumors as well as on improving systems for delivering adequate drug concentrations to the tumor bed. The primary consideration in choosing a given regimen of chemotherapy is to use agents known to be active in a given tumor type8. In this respect, developing new chemotherapy options for brain metastases is no different than the development of established salvage chemotherapeutic regimens, except for including the stratiﬁcation of prognostic factors in the clinical trial design. Temozolomide is an imidazotetrazine derivative of dacarbazine that has reasonable CNS penetration and is approved for use in malignant gliomas. This drug has been used as a single agent for recurrent brain metastases for a variety of tumor types, predominantly non-small cell lung cancer. It demonstrated a modest tumor response and ability to control this cancer (partial response plus disease stabilization) in 41% of a small group of patients in one study; their overall median survival time was 6.6 months45. Capecitabine is an oral 5-ﬂuorouracil prodrug that is approved for treatment of metastatic breast cancer. A case report demonstrated a response of brain metastases to capecitabine following failure to respond to whole-brain irradiation, hormonal therapy, and systemic chemotherapy that included 5-ﬂuorouracil46. After demonstrating single agent activity, the next step is to investigate combination therapy. A study for recurrent non-small cell lung disease investigated the combination of cisplatin, ifosfamide, and irinotecan in 121 patients. Thirty of these patients had brain metastases, which showed a 50% response rate without the use of radiotherapy47. Other strategies for devising combination therapy have used novel biological agents combined with traditional cytotoxic agents. In a small phase I trial, temozolomide on a daily low-dose schedule combined with thalidomide was given to melanoma patients who had systemic metastases. When a temozolomide daily dosing schedule of 75 mg/m2/d was administered, ﬁve of these patients showed major responses, with a median duration of 6 months, and there was a median survival interval of 12.3 months48. Patients with brain metastases were excluded from this trial because of concerns about overlapping neurotoxicity from thalidomide; however, a case report from the same institution demonstrated a complete response of melanoma metastatic to the

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brain and leptomeninges when treatment included temozolomide combined with thalidomide49. Thalidomide is an inhibitor of angiogenesis. Many other angiogenesis inhibitors are being studied in clinical trials for cancer treatment. Angiogenesis can be blocked by interfering with angiogenic ligands and receptors or downstream signaling, including upregulating or delivering endogenous inhibitors, or by directly targeting tumor endothelium22. Agents used include PTK 787, which blocks VEGF receptor signalling; endostatin, which induces endothelial cell apoptosis; TNP-470, which inhibits endothelial cell proliferation; marimastat, a metalloproteinase inhibitor; and interferon alpha, which inhibits production of VEGF and basic ﬁbroblast growth factor (bFGF). Because brain metastases must induce angiogenesis to proliferate, these agents may also improve brain tumor therapy, most likely when used in combination with a cytotoxic drug. Although inhibition of angiogenesis would halt tumor growth but not necessarily cause tumor regression, the assessment of a “response” to angiogenesis-inhibiting strategies will need to be carefully considered. Another area of intense chemotherapy development is aimed at intracellular signaling. The best known example of this type of drug is Gleevec™ (imatinib mesylate; Novartis Pharmaceuticals, East Hanover, NJ), which targets the bcr-abl kinase as well as the c-kit proto-oncogene protein and PDGF and has good activity against chronic myelogenous leukemia and gastrointestinal stromal tumors50. This drug targets a speciﬁc genetic abnormality present in the tumor cells and avoids the toxicities expected when cytotoxic agents are used that target DNA replication. Small molecule signal transduction inhibitors are being developed to block multiple pathways important for cancer, such as the phosphatidylinositol-3-kinase/AKT gene pathway, which is blocked downstream at the mTOR kinase by the rapamycin derivative CCI-77951–53, and the ras gene pathway, which can be blocked by inhibition of farnesyl transferase that is required for ras gene activation54. Research efforts have also been directed toward the cell survival genes that are often upregulated in chemotherapy-resistant tumors, such as bcl-255. Cancer is fundamentally characterized by unregulated cellular proliferation, and the cell cycle is central to this process. The cyclins and cyclin-dependant kinases are crucial regulators of the cell cycle, and much effort is being focused on developing agents that can restore normal cell cycle control and retain selectivity for cancer cells over normal cells56–59. The contemporary focus on developing molecular targeting and therapy for cancer has in part been driven by the explosion of information being provided to investigators by high-volume DNA sequencing and immunohistochemistry techniques, such as gene and tissue arrays60, 61. Ideally, in the future, the exact molecular proﬁle of a tumor could be determined by analysis of tumor tissue at primary resection or biopsy, and then an individualized therapy could be designed for the patient. Such therapy would be based on the identiﬁcation of speciﬁc upregulated or downregulated cellular pathways that control cell proliferation, survival, and angiogenesis, which are among the multiple aberrant

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pathways in cancer. Interventions for achieving this goal include agents that block signals at the receptor level and those that target intracellular signaling, direct cell cycle control, or interfere at the gene transcription level via gene therapy or antisense oligonucleotides. These strategies are all being pursued as novel therapeutic approaches62–64. Chemotherapy is being studied in combination with radiotherapy to improve response rates. A phase III study of teniposide with and without whole-brain radiotherapy for brain metastases from small cell lung cancer demonstrated a response rate of 58% of patients for chemotherapy/radiotherapy and a 22% response rate for chemotherapy alone. There was no difference in patient survival between the two arms of the study due to progression of systemic disease65. A small phase I/II study of topotecan in combination with a 40 Gy dose of whole-brain irradiation demonstrated four complete responses, two partial responders, and six with stable disease among 20 patients. The complete responders had brain metastases from small cell lung cancer, non-small cell lung cancer, or breast cancer. The median survival time was ﬁve months, with systemic progression of disease in greater than 50% of patients66. Bioimmunotherapy is being assessed for treating patients with malignant melanoma, and a few responses have been demonstrated in patients with brain metastases. At the National Cancer Institute, a retrospective review of high dose IL-2 found that of 36 patients with evaluable brain metastases, two patients had a regression of their brain lesions, a response that reﬂected the systemic response to IL-2. The overall response rate for patients with previously untreated brain metastases was only 5.6% compared with 19.8% for patients without brain metastases. The patients with brain metastases did not experience excess toxicity relative to the overall group67. A study of interferon alfa with IL-2 after chemotherapy with cisplatin, dacarbazine, and carmustine included 15 patients with brain metastases. Tumors in seven (47%) of these patients showed a partial response, with a median time to disease progression of 6 months and a median survival time of 6.5 months68. Because the BBB was identiﬁed as limiting the effectiveness of chemotherapy for brain tumors, experimental techniques have been developed to combine BBB disruption with chemotherapy69, 70. Agents to disrupt the BBB have included dimethyl sulfoxide, bradykinin, histamine, and hypertonic or hyperosmolar solutions. If the BBB is permanently damaged, vasogenic edema will cause neurological toxicity. Mannitol is thought to disrupt the BBB by causing separation of tight junctions of the endothelial cells. Clinically, intra-arterial mannitol has been used in conjunction with intra-arterial carboplatin in combination with intravenous etoposide to treat various brain tumors, notably primary CNS lymphoma71, 72. A major toxicity seen with this approach has been high-frequency hearing loss, and seizure and stroke have been reported73. A study of the effects of mannitol in gliomas and normal brain unfortunately demonstrated greater perfusion in normal brain than in tumors, with a more rapid recovery of perfusion rates in the tumor than in normal brain74. This approach (mannitol, carboplatin, and etoposide), has been used to treat brain

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metastases. A report of 24 patients demonstrated six complete responses, with a time to progression of 14.6 months (66 weeks) and 11 partial responses with a time to progression of 8.6 months (39 weeks)75. Delayed sodium thiosulfate administration has been administered along with intra-arterial carboplatin to reduce ototoxicity76. The use of this technique remains experimental and appears to be limited to single institution studies77. A randomized phase III trial of intra-arterial versus intravenous chemotherapy with carmustine (BCNU) for patients with malignant glioma showed a decreased survival time for patients receiving intra-arterial chemotherapy78. Another strategy for improved treatment of brain tumors involves directly delivering the drug into the tumor bed. This approach has been pioneered for treatment of malignant gliomas79, 80. The aim of this strategy is to deliver locally high concentrations of therapeutic agent while avoiding systemic toxicity. In the case of malignant brain tumors, this has been done by direct infusion of chemotherapy into tumor resection beds using Ommaya reservoirs and catheters81– 84. This technique was advanced further by incorporating BCNU in polymer wafers for local drug delivery85, 86. This technique requires adequate surgical debulking of the tumor to limit further brain edema that might result from the local concentration of BCNU. In a prospective, randomized, placebo-controlled, phase III trial of 222 patients with recurrent glioblastoma, the application of BCNUloaded wafers after tumor resection improved the 6-month survival rate and was safe87. This technique has been tested in preclinical model systems of metastatic brain tumors in mice88, 89. Multi-institutional trials of BCNU-loaded polymer have been launched for treatment of metastatic brain cancer at the time of tumor resection. This strategy is being investigated in animals, employing local delivery of different drugs, such as camptothecins, taxanes, and platinum compounds90 –92. The strategy of local delivery is not limited to standard cytotoxic chemotherapy agents. Clinical trials for malignant primary brain tumors have used local delivery techniques to administer gene therapy (p53) and immunotoxins (IL13-linked Pseudomonas exotoxin)93 –97. These developments may improve local control if applied to brain metastases, but they will not be expected to prevent development of new metastases or to overcome resistance to chemotherapy in patients with progressive systemic disease.

Summary The use of chemotherapy for brain metastases faces great challenges. The most important imperative is to discover new agents that can overcome the resistance of tumor cells to standard chemotherapy agents, whether the resistance originates through selection by prior pretreatment or is inherent chemoresistance of tumor cell clones that metastasize from a primary site. Because most patients with brain metastases succumb to progressive systemic disease, improvement of local tumor control in the brain will probably have a limited impact on survival. Conversely, development of agents that are effective in establishing durable tumor control, both systemically and in the brain, will

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improve survival in a manner similar to what is seen in the unique case of germ cell tumors. If cancer patients with a good performance status who have brain metastases are excluded from clinical trials of novel agents, it will be difﬁcult to accurately determine the possible effectiveness of these agents against CNS disease. The use of recursive partitioning analysis may help to identify patients who might beneﬁt from chemotherapy, as well as to design clinical trials that take into account speciﬁc tumor histology and prior exposure to chemotherapy. Improvement in patient survival will result from improved local control of CNS disease if the primary disease site remains dormant, illustrating the need for a multimodality approach to the treatment of the patient with brain metastases.

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PART III

Speciﬁc tumor sites

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Metastatic lung cancer James L Frazier, Ira M Garonzik, Laurence D Rhines

Introduction Lung cancer is the most frequently diagnosed cancer in the world and the leading cause of death from cancer. In the United States, it is the second leading cause of cancer and the leading cause of cancer death in both men and women1. Based on a statistical compilation conducted in 1990, the incidence of lung cancer in U.S. men and women was 70/100,000 and 33.4/100,000, respectively. In the same year, the cancer mortality rates for men and women were 58.3/100,000 and 25.2/100,000, respectively. The American Cancer Society estimated that, in 1999, 171,600 new cases of lung cancer would be diagnosed and more than 158,900 would die from this disease2. Moreover, the patterns of lung cancer incidence and mortality vary between men and women, in that the rates are declining dramatically in men while they are increasing in women. In men, incidence rates peaked in 1984 and are declining at a rate of 1.4% per year, with the largest declines in small cell and squamous cell lung cancers3. Since 1987, lung cancer death rates in women have exceeded breast cancer death rates4. Worldwide, it continues to be the most common form of cancer among men (37.5/100,000) compared with women (10.8/100,000), with the highest rates observed in North America and Europe, especially eastern Europe. In 1990, approximately 1.04 million new cases of lung cancer were diagnosed (12.8% of the world’s total cancer incidence), and an estimated 921,000 lung cancer deaths occurred (17.8% of the world’s total cancer mortality)5. More than half of the world’s incidence occurred in developed nations. The Surveillance, Epidemiology, and End Results (SEER) Program estimates the 5-year relative survival rate for lung cancer to be 14% in the United States, 8% in Europe, and approximately 7% in developing countries3. Tobacco smoke continues to be the greatest known risk factor associated with the development of lung cancer. Approximately 10% of smokers develop cancer, but of all patients diagnosed with lung cancer, 80 to 85% are long-term cigarette or tobacco users6. The lifetime risk for lung cancer among male smokers is 14.6%, and 8.3% in female smokers2. In contrast, the lifetime risk of lung cancer in nonsmokers is less than 1%. Asbestos, radon, and dietary factors are other important occupational and environmental risk factors for this disease. Arsenic, nickel, ionizing radiation, chromium, chloromethyl ether, vinyl chloride, and polycyclic aromatic hydrocarbons are less common carcinogens 199

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contributing to lung cancer. Pulmonary ﬁbrosis and chronic obstructive pulmonary disease are associated with an increased risk for the development of lung cancer. It has been estimated that 18 to 65% of lung cancer patients develop brain metastases7–9. Primary lung cancers account for approximately 30 to 60% of all brain metastases10 –20. Lung cancer is the most common source of brain metastasis in men whereas breast cancer is the most common source in women21. This difference is most likely a result of the varying incidences of lung and breast cancers in men and women. Lung cancer has a large tendency to produce multiple brain metastases, and it should be emphasized that the various histological types of lung cancer, which encompasses both small cell lung cancer (SCLC) and non-small cell lung cancers (NSCLC), have different rates of metastasis to the brain. NSCLC includes adenocarcinoma, large cell carcinoma, and squamous cell carcinoma. Adenocarcinoma and SCLC metastasize to the brain commonly, whereas squamous cell carcinoma does so rarely22. In clinical studies, CT scans have demonstrated cerebral metastases in 6 to 21% of neurologically asymptomatic patients undergoing staging for resection of primary lung cancers23 –25. Moreover, several autopsy studies have been performed to assess the frequency of brain metastases in patients dying of lung cancer: 44 to 54% in patients with adenocarcinoma, 52% in patients with largecell carcinoma, 40 to 50% in patients with small cell lung carcinoma, and 13% in patients with squamous cell carcinoma21, 22, 26 –28. This chapter will discuss the pathological classiﬁcation, presentation, diagnostic work-up, staging, and management of the most common lung cancers and the neurosurgical management of brain metastases from the respective primary lung cancers.

Histological subtypes of lung cancer Small cell lung cancer According to epidemiological studies, SCLC represents approximately 18 to 30% of all lung cancer cases29–31. Ten to 20% of men and 10 to 30% of women with lung cancer have the SCLC histological subtype32. Patients with SCLC have a dismal prognosis, and there is very little hope of a cure with current therapy. It is characterized by early and rapid dissemination to hilar lymph nodes, mediastinal lymph nodes, and distant sites including brain, liver, bone, bone marrow, other lobes of the ipsilateral lung, contralateral lung, retroperitoneal lymph nodes, supraclavicular lymph nodes, and adrenal glands33. An autopsy study of 174 SCLC patients by Jereczek et al. found distant metastases to be distributed in 143 patients (82%), most frequently in the liver (49%), adrenal glands (25%), peripheral lymph nodes (21%), kidneys (18%), brain (17%), and pancreas (12%)34. SCLC is highly associated with the extent of tobacco use by patients. SCLC presumably arises from the basal neuroendocrine Kulchitsky cells and develops in the central airways, particularly the main-stem or lobular

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bronchi. It is composed of neoplastic cells, with scant cytoplasm and ﬁne granular chromatin. These cells are usually arranged in clusters, sheets, or trabeculae separated by a delicate ﬁbrovascular stroma. In 1981, the World Health Organization (WHO) developed a classiﬁcation system that recognizes three subtypes of SCLC: oat cell carcinoma, intermediate cell type, and combined oat cell carcinoma, which is oat cell carcinoma combined with squamous cell carcinoma or adenocarcinoma31. This classiﬁcation system has been viewed as imprecise by many pathologists, and in 1988 the International Association for the Study of Lung Cancer (IASLC) proposed a revised classiﬁcation that recognizes pure SCLC and two less common variants: mixed small cell and large cell carcinoma and combined small cell carcinoma.

Squamous cell carcinoma Squamous cell carcinoma represents 30 to 40% of all lung cancer cases. In the 1970s, this cancer represented approximately 50% of all lung cancer cases, but there has been a steady decline in its prevalence for unknown reasons. It frequently arises centrally in the subsegmental or large bronchi. It is usually endobronchial and has a tendency to spread towards the main stem bronchus. Squamous cell carcinomas are slow growing, and they progress from the in situ stage to a clinically evident tumor over a period of three to four years. Microscopically, a hallmark feature of these tumors is keratinization with pearl formation. They are composed of sheets of epithelial cells that range from well-differentiated to poorly differentiated.

Adenocarcinoma The most common subtype of all lung cancers occurring in the United States is adenocarcinoma, representing 40 to 50% of all cases31. In comparison with squamous cell carcinoma, adenocarcinoma has a worse prognosis for each respective stage. Adenocarcinoma has the greatest likelihood of being localized at the time of diagnosis. It is most commonly found in women and tends to arise in the periphery of the lung. In addition, adenocarcinomas can develop in scarred or ﬁbrotic areas of lung. This form of lung cancer has been found in nonsmokers. Adenocarcinomas can exhibit glandular formation, development of papillary structure, production of mucin, and acinar formation31. A classiﬁcation scheme developed by the WHO divides adenocarcinomas into four subtypes: papillary, acinar, bronchioloalveolar, and solid with mucin production. Bronchioloalveolar carcinoma deserves special mention because it behaves as a distinct clinicopathological entity35. This neoplasm develops from cells along the alveolar septa and can present as a single peripheral nodule, as a multifocal disease, or as a rapidly diffuse pneumonic form that can involve both lungs.

Large cell cancer In comparison with squamous cell carcinoma and adenocarcinoma, large cell carcinoma is less differentiated and less prevalent, representing 10 to 15% of all

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lung cancer cases. It usually arises in the lung’s periphery, with subsequent spreading to subsegmental bronchi or larger airways. Large cell carcinoma has a propensity to metastasize at an earlier stage than other forms of NSCLC. Microscopically, large cell carcinoma is seen as epithelial cells with large nuclei and prominent nucleoli. The WHO has classiﬁed this cancer into two variants: giant cell and clear cell.

Carcinoid tumor Carcinoid tumors are neoplasms of low malignant potential and constitute 1 to 2% of lung cancers. They are considered neuroendocrine lung tumors, with approximately 80% of them located centrally. Microscopically, these tumors display neuroendocrine differentiation. Although carcinoid tumors can occur at any age, they most commonly present in the ﬁfth and sixth decades of life with cough, hemoptysis, or obstructive pneumonia, but they can also be asymptomatic. In rare cases, patients present with the carcinoid syndrome. The carcinoid tumors frequently follow a benign course without metastasis, although rare cases of brain metastases have been reported36. Because they are resistant to radiation and chemotherapy, surgery is the preferred treatment, with a 5-year patient survival rate of 95%. A minority of carcinoids are classiﬁed as atypical. They exhibit a more aggressive behavior, cytologic atypia, and necrosis. In their most malignant form, atypical carcinoids resemble small cell lung cancers in appearance and behavior.

Clinical presentation The clinical manifestations of lung cancer are variable and depend on several factors, including local effects from the cancer, the presence of associated paraneoplastic syndromes, or any distant metastases. Patients are rarely asymptomatic at presentation. The most common presenting symptom is cough, and the recent acceleration of cough or accompanying hemoptysis increases the likelihood that an underlying cancer is present. Additionally, dyspnea and weight loss are frequent presenting signs and symptoms. Chest pain, bone pain, hypertrophic osteoarthropathy, clubbing, wheezing, dysphagia, and hoarseness are other possible ﬁndings. Superior vena cava syndrome is most commonly caused by lung cancer. Superior sulcus tumors at the lung apex usually cause Pancoast syndrome, which includes Horner’s syndrome along with shoulder pain and radicular pain along the ulnar nerve distribution31. The causes of Pancoast syndrome according to frequency and histological subtype are as follows: squamous cell carcinoma (52%), adenocarcinoma (23%), large cell carcinoma (23%), and small cell carcinoma (1%). Lung cancers metastasize via hematogenous, lymphangitic, or interalveolar routes. The brain, bones, lymph nodes, liver, and adrenal glands are common sites for metastatic colonization of these tumors. A patient may initially present because of problems arising from distant metastases from a primary lung

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tumor37. Although bone, hepatic, and adrenal lesions are often asymptomatic, radiographically conﬁrmed brain metastases are symptomatic in a majority of cases. Symptoms of cerebral metastases include headache, vomiting, motor deﬁcits, sensory deﬁcits, seizures, behavioral and mental status changes, or aphasia. According to one study, the majority of patients with cerebellar metastases have at least three of the following symptoms: headache, gait difﬁculty, nausea and/or vomiting, or dizziness38. A variety of paraneoplastic syndromes have been found to be associated with lung cancer. Their incidence ranges from 1 to 10% of all lung cancer patients. Cushing’s syndrome, syndrome of inappropriate antidiuretic hormone (SIADH), clubbing, hypercalcemia, anorexia, cachexia, peripheral neuropathy, and Eaton-Lambert myasthenic syndrome are some of the more common associated paraneoplastic syndromes. Tumors producing ACTH and ADH are predominantly SCLCs, with SCLC accounting for approximately 75% of lung cancer associated with SIADH. Squamous cell carcinoma is primarily responsible for hypercalcemia in lung cancer patients. In general, paraneoplastic syndromes can be manifested as renal, neurological, systemic, endocrine, hematologic, or cutaneous abnormalities.

Diagnosing lung cancer Chest x-rays detect a majority of lung lesions as part of routine physical examinations or during the examination of patients with acute or chronic respiratory problems. Whenever possible, old radiographs should be used for comparison to determine the likelihood of a malignant or benign lesion. Computed tomography (CT), magnetic resonance (MR) imaging, and positronemission tomography (PET) are additional radiologic modalities used in the workup of lung cancer. CT scanning is a noninvasive method used both in the preoperative staging of lung cancer and in the clariﬁcation of the relationship of the lung lesion to adjacent structures, including lymph nodes, trachea, esophagus, heart and great vessels, spinal cord, and chest wall39. The compression or invasion of vascular structures, such as the aortic arch or superior vena cava, can be visualized with intravenous contrast agents. In the determination of mediastinal nodal status, CT has a sensitivity and speciﬁcity of 75% and 60%, respectively40. During the procurement of a chest CT scan, imaging of the upper abdomen is usually performed to ascertain if metastases are present in the liver and adrenal glands. MRI has a vital role in the visualization of superior sulcus tumors and their invasion of adjacent structures. The involvement of subclavian vessels, brachial plexus, and vertebral bodies can be assessed with MRI. Invasion of any of these structures would normally preclude a patient from consideration for surgery. Recently, a retrospective study demonstrated that invasion of the thoracic spine by lung cancer can be treated with surgical resection and occipitocervicothoracic ﬁxation as an effective means of attaining

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stabilization that can provide pain relief and neurological preservation or improvement41. PET uses a radioactive ﬂuorine isotope bound to glucose, 18Fﬂuorodeoxyglucose, and detects the consumption of glucose by metabolically active tissue to ascertain the presence of disease42. In addition to the level of metabolic activity of cells, the sensivity of PET is a function of the tumor volume, resolution of the images, and contrast between the tumor and surrounding normal structures. In the detection of cancer, PET has a sensitivity greater than 90% for primary lesions that are not discernible on CT43. Pulmonary lesions of at least 1 cm in maximal diameter can be detected, but smaller nodules are more difﬁcult to detect because of respiratory motion and the limits of resolution. In contrast, cancerous mediastinal nodes of less than 1 cm in maximal diameter can be detected by PET44. The speciﬁcity of PET in the mediastinal staging of lung cancer is inﬂuenced by the presence of inﬂammatory disease, because it has been documented that 18Fﬂuorodeoxyglucose accumulates in benign inﬂammatory disease45. In a study of mediastinal metastases in non-small cell lung cancer, PET had a sensitivity and speciﬁcity of 91% and 86%, respectively, with inﬂammatory disease accounting for the false positive results46. Sputum samples, percutaneous ﬁne-needle aspiration (FNA), bronchoscopy, video-assisted thoracoscopic surgery (VATS), and mediastinoscopy can be utilized for the diagnosis and histological classiﬁcation of lung cancer. Centrally located tumors can be diagnosed through the analysis of sputum, specimens obtained by washings and brushings, and direct biopsy with bronchoscopy. The endobronchial anatomy and distortions by extrinsic compression can be visualized with bronchoscopy. When bronchoscopy is inconclusive or the tumor is peripherally located, FNA can be used to establish a tissue diagnosis. Fluoroscopy or CT guidance is more than 85% accurate in obtaining a diagnosis47. A majority of mediastinal nodes can be assessed with mediastinoscopy for diagnosis and staging, with a sensitivity and speciﬁcity that approach 90% and 100%, respectively31. Potential contraindications for mediastinoscopy include prior radiotherapy, large cervical goiter, tracheostomy, signiﬁcant calciﬁcation or aneurysm of the aortic arch, or prior mediastinoscopy48. In addition, VATS may contribute to diagnosis and staging by allowing the surgeon to visualize the entire lung, pleura, and mediastinum49. Biopsy of suspected distant metastases and analysis of pleural effusions via thoracentesis may aid in diagnosis. Laboratory evaluation should include a complete blood count, prothrombin time, liver function studies, and a determination of electrolyte, serum calcium, creatinine, blood urea nitrogen, albumin, alkaline phosphatase, total bilirubin, and lactate dehydrogenase levels. A total body bone scan is recommended for the detection of bone metastases. Bilateral bone marrow aspiration and unilateral bone marrow biopsy are recommended for patients with SCLC unless there is apparent extensive-stage disease or limited-stage disease with a normal LDH value31.

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Staging of lung cancer SCLC The Veterans Administration Lung Cancer Study Group introduced a twostage system that is widely used for the staging and classiﬁcation of SCLC because of its simplicity and clinical utility50. Patients are staged as having either limited or extensive disease based on the extent of the cancer in the chest. This staging system is used to place patients in the appropriate therapeutic categories and provides valuable prognostic information. Approximately 30% of patients with SCLC have limited-stage disease, which is deﬁned as disease that can be encompassed in a tolerable radiation ﬁeld51. The deﬁnition also includes disease conﬁned to the hemithorax and regional lymph nodes, including the ipsilateral mediastinal, ipsilateral supraclavicular, and contralateral hilar lymph nodes. This deﬁnition is the consequence of the adaptation of a staging system to deﬁne patients likely to beneﬁt from chest irradiation. Past attempts at surgical resection proved inferior to chest irradiation for the then-deﬁned local disease; most patients died of disseminated disease52. Patients with extensive disease have metastases in the contralateral lung, distant metastases, or malignant pleural effusions. Controversy surrounds the two-stage system’s prognostic information. Patients with limited-stage disease survive longer, when it is applied to the staging classiﬁcation of patients with locoregionally advanced disease manifested as the presence of an ipsilateral pleural effusion, contralateral supraclavicular lymphadenopathy, or contralateral mediastinal lymphadenopathy33. Another problem is the demonstration that patients with bronchial obstructions on CT scans had an inferior survival in contrast to those without obstructions53. Also, patients with one extrathoracic organ containing extensive-stage disease had a better outcome than those with multiple organs so affected53 –57. Therefore, the IASLC reviewed these concerns and concluded that the more descriptive tumor-node-metastasis (TNM) staging system is useful for patients with disease limited to the lung, when surgical resection may be feasible, which occurs in less than 10% of cases.

NSCLC The International System for Staging (ISS) lung cancer uses the TNM system that was accepted as the worldwide standard in 1986 for the classiﬁcation of NSCLC58. Based upon new knowledge about lung cancer, new techniques in its detection and treatment, and data derived from the evaluation of outcomes from patients treated with surgery, the ISS for lung cancer was revised in 1997 to more accurately represent prognostic implications59. Eight stages (IA, IB, IIA, IIB, IIIA, IIIB, IV, and occult) are used to categorize NSCLC based upon various combinations of TNM descriptors. Occult carcinomas are not detected by bronchoscopic or radiographic modalities, but malignant cells can be detected in bronchopulmonary secretions. Stage IA (T1 N0 MO) and IB (T2 N0 M0) carcinomas account for 13% and

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23%, respectively, of patients with NSCLC and are completely located within the lung without nodal involvement or distant metastases. Stage IIA (T1 N1 MO) and IIB (T2 N1 M0 or T3 N0 M0) cancers represent 1% and 7%, respectively, of NSCLC patients. Stage II carcinomas may have either nodal involvement or extrapulmonary extension. Stage IIIA (T3 N1 M0 or T1–3 N2 M0) and IIIB (T1–3 N3 M0 or T4 N0–3 M0) cancer patients are differentiated by the surgical resectability of the tumor. Stage IIIA tumors are resectable and are deﬁned by lesions with extrapulmonary extension and limited lymph node involvement. They account for 10% of NSCLC patients. Stage IIIB cancers are not surgically resectable and represent 20% of those diagnosed with NSCLC. In addition to extensive extrapulmonary involvement, patients may have pleural effusions that test positive cytologically for malignant cells. Twentyseven percent of NSCLC patients are classiﬁed as stage IV (any T any N M1) and are deﬁned as having distant metastases.

Treatment options NSCLC Surgical resection remains the best treatment option for most lung cancer patients with stage I and II disease and for some patients with stage IIIA disease. Surgical options include bronchial sleeve resection, lobectomy, bilobectomy, pneumonectomy, segmentectomy, or wedge resection. Wedge resection and segmentectomy are limited resections used for high-risk patients to preserve pulmonary function. Unfortunately, there is an increased risk for local tumor recurrence, decreased patient survival time, prolonged air leaks, and missed nodal disease60. Lobectomy is the preferred treatment modality for tumors of any size limited to one lobe, because the prospects for long-term survival are much better with this option. Bilobectomy is used for tumors that involve more than one lobe. Endobronchial tumors can be extirpated with a bronchial sleeve resection to conserve functioning lung parenchyma, as an alternative to pneumonectomy, which is recommended for large, central lesions involving the main stem bronchus or invading the main pulmonary artery61, 62. When stage IIB and IIIA tumors invade the chest wall, an en bloc resection, with removal of accompanying ribs, may be performed41. Videoassisted thoracoscopic surgery is currently being explored as an alternative to thoracotomies63, 64. The ﬁve-year patient survival rates for stage IA, IB, IIA, IIB, and IIIA lung disease are 67%, 57%, 55%, 39%, and 23%, respectively. Chemotherapy and radiation therapy play an important role in the treatment of lung cancer, which is contigent upon the stage of the disease. In general, radiotherapy has a palliative role for superior vena cava syndrome, hemoptysis, and postobstructive pneumonia, and radiotherapy is used preoperatively for Pancoast syndrome. Chemotherapeutic agents used in the treatment of NSCLC include cisplatin, etoposide, vinblastine, ifosfamide, mitomycin-c, paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan. For stage I disease, radiotherapy prolongs the ﬁve-year survival rate by 20 to 40% in

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medically inoperable patients and those with surgically unresectable tumors65. Although there are relative indications for postoperative radiotherapy, such as tumor-cell positive surgical margins, tumor-cell positive regional lymph nodes, extracapsular lymph node invasion by tumor, or tumor invasion of adjacent or unresectable structures, preoperative or postoperative irradiation has no proven role; indeed, the Patient Outcomes Research Team analysis has suggested that postoperative radiotheraphy has an adverse effect here66. In stage II disease, postoperative radiation does not prolong long-term survival but reduces the risk of relapse, especially in squamous cell carcinoma67. There is a prolongation of disease-free survival and median survival with adjuvant chemotherapy, but there is no effect on long-term survival68, 69. For stage III NSCLC, radiation therapy has a preoperative role in locally advanced resectable disease. The long-term survival is only 3 to 7% for patients with stage III unresectable tumors who are receiving radiotherapy70 –73. Chemotherapy, as part of combined modality therapy, is indicated in locally advanced NSCLC. Six randomized phase III clinical trials have demonstrated the superiority of combined modality chemoradiation to radiation alone74 –79. In addition, two clinical trials have provided data demonstrating increased efﬁcacy of concurrent chemoradiation over sequential therapy. The current ﬁve-year survival rate for stage IIIB NSCLC patients is 5% with multimodal therapy. Jiroutek et al. analyzed the ﬁndings of studies spanning 20 years conﬁrming the signiﬁcance of performance status, appetite/weight loss, and gender as major prognostic determinants in systemic therapy for metastatic NSCLC80. Clinical trials with chemotherapy have proven cisplastin-based combination regimens to be much better than the best palliative care. There is an improvement in quality of life and better symptom control. Although the ﬁve-year survival rate is 1%, chemotherapy improves the median patient survival time by six to 12 weeks and produces a 10 to 15% increase in the one-year survival rate81.

SCLC Without therapy, the average survival time for SCLC patients is 6–17 weeks. Surgical intervention has a limited role in very early stage SCLC that is conﬁned to the chest without involving the lymph nodes, whereas chemotherapy is the standard treatment for both limited-stage and extensive-stage disease. The standard regimens for SCLC include etoposide/cisplatin, etoposide/ carboplatin, irinotecan/cisplatin, topetecan, paclitaxel, and cyclophosphamide/ adriamycin/vincristine (CAV)81. In extensive-stage disease, the current drug response rate is 10 to 20% with a median patient survival interval of less than one year. Jeremic et al. performed a clinical trial demonstrating a signiﬁcantly higher median survival time and ﬁve-year survival rate for a regimen of concurrent chemoradiation than for chemotherapy alone82. A meta-analysis, involving thirteen trials and 1,862 patients, has demonstrated a signiﬁcant improvement in survival of patients with limited-stage SCLC treated with concurrent chemoradiation relative to chemotherapy

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alone83. The current drug response rate is greater than 50 to 85%, with a median patient survival time of 12 to 20 months and two-year disease-free survival rates of 15 to 40%84 –86. Murray et al. conducted a study showing that that early concurrent chemoradiation resulted in a statistically signiﬁcant improvement in survival (20%) when compared with delayed concurrent chemoradiation (10%)87. Another clinical trial demonstrated that concurrent chemoradiation with a more aggressive hyperfractionated regimen resulted in a signiﬁcant improvement in the ﬁve-year patient survival rate (26%) relative to the standard radiation therapy regimen (15%), although more local toxicity, especially esophagitis, was observed86.

Management of intracranial metastases Brain metastases will develop in 18 to 65% of patients with lung cancer8, 9, 19, 88. In patients who develop brain metastases, approximately two-thirds of the metastases are multiple13, 16. In one series of patients with NSCLC, the median interval between diagnosis of a lung primary tumor and the discovery of brain metastases was six months, with 37% of patients having an interval of less than one month89. In patients with resected NSCLC, brain metastases constitute more than 25% of all observed tumor recurrences90. Ten percent of patients with SCLC are diagnosed with brain metastases at the initial diagnosis, with an additional 20% diagnosed during the course of the disease, and 40% prior to death88, 91, 92. Moreover, autopsy studies have discovered brain metastases in 40 to 50% of SCLC patients and 13 to 54% of NSCLC patients, depending on the tumor’s histological subtype. There are some data demonstrating that peripheral lung carcinomas metastasize to the brain more frequently than those occurring centrally93. Screening lung cancer patients for brain metastases continues to be a controversial issue. Several clinical studies have been conducted in an attempt to resolve this issue, but a consensus has yet to be reached. Based on the results of one large study of 245 lung cancer patients, the investigators recommend routine CT screening for brain metastases. They found brain metastases by CT in 94.5% of SCLC patients with speciﬁc neurological ﬁndings, 26.6% of patients with vague neurological ﬁndings, and 11% of patients with a normal neurological examination. Forty percent of patients with lung adenocarcinoma and a normal neurological examination were also found to have brain metastases94. In another large study of 271 lung cancer patients, contrast-enhanced CT imaging was performed for initial staging. Overall, 14% of the patients had brain metastases, although the clinical utility was contigent upon the tumor histological subtypes and clinical stage of the tumor. Brain metastases were found in 10.8% of asymptomatic patients and 33.3% of symptomatic patients. A majority of the lesions in the asymptomatic patients were less than 2 cm in maximal diameter. Brain metastases were discovered in 17.5% of patients with stage III NSCLC, whereas none were found in those with stage I or II disease. A majority of these NSCLC patients had either adenocarcinoma or large cell

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carcinoma. Brain metastases were found in 13.8% of patients with SCLC who had limited disease. The authors of the study concluded that routine cerebral imaging should be performed in patients having resectable stage III thoracic disease without known distant metastases24. Furthermore, a study found brain metastases in 13% of patients with potentially resectable NSCLC. Of patients with metastases, 21% were neurologically asymptomatic. The patients with brain metastases in this study had either large cell carcinoma or adenocarcinoma; thus, the investigators recommended routine screening of patients who had either of these histological subtypes of lung cancer for brain metastases25. Another study95 found no statistically signiﬁcant differences among patients with different NSCLC histological subtypes in the likelihood of discovering brain metastases with CT, but CT detected metastases in 64% of asymptomatic patients. Moreover, the authors found contrast-enhanced CT to be 92% sensitive, 99% speciﬁc, and 98% accurate in detecting brain metastases. They concluded from this study that cerebral metastases should not be excluded from the diagnosis because of an unremarkable neurological exam. A study of 112 patients evaluated the usefulness of MR imaging in the detection of asymptomatic brain metastases at the initial diagnosis in patients with SCLC. Of these 112 patients with a normal neurological examination, MR imaging demonstrated brain metastases in 17 patients (15%). A repeat MR imaging study in 12 of these patients who completed chemotherapy demonstrated one in complete remission, four with partial remission, and seven with progressive metastatic brain disease. The investigators proposed that MR imaging of the brain should be included in the staging of SCLC as well as for prognosis and therapy96. In contrast, another study, using contrast-enhanced, CT, found no brain metastases in neurologically normal patients with SCLC. The authors of this study recommended that routine CT screening does not have any clinical utility in neurologically asymptomatic patients with SCLC97. The different ﬁndings in these two studies result from the fact that MRI has a greater sensitivity than CT for the detection of brain metastases. In general, radiographic screening for brain metastases is indicated in lung cancer patients with any stage of disease or cell type who present with focal neurological symptoms, nonfocal neurological symptoms, or unexplained systemic symptoms98. MR imaging might be useful in asymptomatic patients with SCLC for staging, prognosis, and therapy. In asymptomatic patients with either adenocarcinoma or large cell carcinoma, routine CT or MR image screening appears to be efﬁcacious in those with intrathoracic stage III disease98. Surgically accessible metastatic brain lesions of any histological subtype of lung cancer may be resected to treat mass effect, hemorrhage, acute deterioration subsequent to hydrocephalus, or impending brain herniation. Surgical resection is usually followed by whole-brain radiation therapy (WBRT) with or without stereotactic radiosurgery (SRS), especially in cases in which all lesions are not able to be resected. For asymptomatic solitary lesions, surgically

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inaccessible solitary lesions, or multiple lesions with no mass effect, WBRT with or without SRS is indicated. Patients with uncontrolled primary lung cancer and/or a poor neurological performance status should be given corticosteroids and palliative WBRT99. The optimal treatment for NSCLC is surgical resection followed by radiation therapy. In contrast, SCLC is both chemosensitive and radiosensitive, with a small subset of patients being treated surgically, because approximately 70% of patients have extensive-stage disease with widespread dissemination. A substantial body of clinical data exists describing the chemosensitivity of SCLC brain metastases, whereas relatively little data are available to demonstrate the chemosensitivity of NSCLC brain metastases. A meta-analysis100 has reviewed the chemotherapeutic response rates of patients with brain metastases from SCLC. The analysis involved 12 clinical trials, 116 patients, and treatment with either etoposide or teniposide in combination with either cisplatin or carboplatin in ﬁve of the trials. The response rate was 76% (32% complete responses and 44% partial responses) in newly diagnosed patients with brain metastases and 43% (18% complete responses and 25% partial responses) in those diagnosed with brain metastases at relapse100. Postmus et al.101 conducted a study with high-dose etoposide administered at the time of SCLC relapse in the brain and found the median survival to be eight months in chemoresponsive patients and one month in those not responsive. In NSCLC patients with brain metastases, few clinical trials using chemotherapy have been conducted. In one study, three of eight patients responded to cisplatin treatment102. Another study with high-dose etoposide demonstrated a response in four of 14 patients103. Conte et al.104 found that a combination regimen of doxorubicin, teniposide, and lomustine resulted in a median survival time of 4.8 months in three of 11 NSCLC patients. Moreover, SCLC patients with metastatic brain disease are treated with both chemotherapy and WBRT. The extent of disease dissemination is a large determinant of the efﬁcacy of this dual-modality treatment. Drings et al.91 found a median survival time of 2.7 months for SCLC patients whereas another study105 revealed a median survival of four to seven months, with a 40% complete response rate. Giannone et al.92 determined that the median survival in SCLC patients with brain metastases as the only site of disseminated disease was 11 months, whereas it was ﬁve months for those with additional metastatic sites. The role of prophylactic cranial irradiation (PCI) in the treatment of SCLC patients has endured a great deal of controversy. The results of PCI in children with acute lymphocytic leukemia led to the integration of PCI into the treatment of SCLC more than 20 years ago106. During the 1980s, several clinical trials compared the treatment of SCLC patients in complete remission with and without PCI, and they consistently demonstrated a signiﬁcant decrease in the incidence of brain metastases, but improved survival remained in question107. Studies employing PCI during the early 1990s also revealed a decrease in brain metastases from SCLC, with some demonstrating an improvement in patient survival time108, 109. Design ﬂaws in these early studies led to the

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development of randomized trials of PCI for SCLC treatment during the late 1980s and early 1990s, in which PCI consistently demonstrated improvement in preventing brain tumor relapse and trends toward improved survival but no signiﬁcant difference. The Prophylactic Cranial Irradiation Overview Collaborative Group was created to undertake a meta-analysis based on data on individual patients to evaluate the role of PCI in SCLC patients in complete remission. Trials eligible for inclusion in the meta-analysis were those in which patients who were treated with systemic chemotherapy until they reached complete remission were then randomly assigned to receive PCI or no PCI. Auperin et al.110 recently published the results of the meta-analysis, showing an absolute 5.4% improvement in three-year survival in patients who received PCI (20.7%) compared with those who did not receive PCI (15.3%). In addition, there was an absolute decrease of 25.3% in the cumulative incidence of brain metastasis at three years (33.3% in the PCI group versus 58.6% in the control group). This study provides substantial evidence for the survival beneﬁt of PCI in patients with either limited or extensive SCLC that is in complete remission. However, a major concern pertaining to PCI is delayed neurocognitive dysfunction. A decline in neurocognitive dysfunction has been suggested in older studies that used concurrent chemoradiation, neurotoxic nitrosoureas, and higher doses of radiation or a larger fraction size111, 112. Recently, two large randomized trials of PCI incorporated psychometric testing of patients prospectively before and after PCI81. A trial completed in France113 demonstrated that 41% of patients had a normal cognitive exam at the time of randomization after induction chemotherapy, and testing over a ﬁve-year period revealed no difference between those in the PCI group and the control group. Gregor et al.114 achieved similar results in another study. Surgical resection of brain metastases is a common form of treatment in NSCLC patients, whereas it is less common in SCLC patients because of the widespread cancer dissemination observed at diagnosis. The ﬁrst clinical series of surgically treated brain metastases from lung cancer was reported in 1930115. Myriad studies have demonstrated that radical treatment of the primary lung cancer is the most important predictor of survival in patients with completely resected single brain metastases. A multivariate analysis found that curative resection of primary lung cancer was associated with improved survival116. In 1976, Magilligan et al.117 conducted a study of 22 patients that marked the advent of combined primary lung cancer and brain metastasis resection. The study concluded that ﬁnding stage I disease at pulmonary resection, use of WBRT, and observing a longer interval between pulmonary resection and cerebral metastasis were factors that had a favorable bearing on outcome. Another study found a correlation between improved patient survival and curative resection of primary lung tumors, absence of tumor in the mediastinal nodes, and having systemic disease limited to the central nervous system18. Mandell et al.118 found that patients with the brain as the sole site of metastases from lung cancer had a median survival-time of 33 months when

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both the primary lung and brain lesions were resected. In 1989, a clinical series reported that 35 patients with stage I–III lung cancer had a one-year survival rate of 50% when both craniotomy and thoracotomy were performed119; the one-year survival rate dropped to 0–2% when only one operative procedure was performed or no surgery was done. Another series (185 patients) revealed that complete resection of both the primary lung lesion and the cerebral metastases resulted in prolonged survival, whereas tumor histology, interval to metastases, number of lesions, locoregional stage, and use of WBRT had no bearing on outcome9. This study provided compelling evidence that highstage lung cancer patients should be considered for the extirpation of surgically accessible brain metastases if the primary lung cancer can be resected. In 1995, a published report120 providing data on the Cox multivariate analysis of 231 consecutive NSCLC patients found that complete resection of the primary lung cancer, supratentorial location of lesion, female gender, absence of systemic lesions, and age less then 60 years were the strongest determinants of survival. The use of WBRT for treating cerebral metastases has been well-documented, but the role of SRS continues to be evaluated. SRS is a recommended treatment option for patients in whom extracranial disease is controlled or not evident and who have single or multiple (≤ 5) brain metastases. Gamma Knife and linear-accelerator-based radiosurgery have reportedly been used to treat such patients, with equivalent results. In 1997, Kim et al.121 reported the results of a retrospective study of 77 NSCLC patients with brain metastases treated with SRS (71 of them also received WBRT). Univariate and multivariate analyses were used to determine signiﬁcant prognostic factors affecting survival, which were extent of systemic disease, presence of neurologic deﬁcit, size of the intracranial tumor, initial imaging appearance of intratumoral necrosis, and initial resection of the primary lesion. The median survival interval was 10 months after SRS, and 15 months from the diagnosis of brain metastases. In a subgroup of these patients who had no extracranial metastases, no neurological deﬁcits, and a small lesion without necrosis, median survival was 26 months. The authors concluded that the early detection of brain metastases and treatment with SRS combined with WBRT provide the opportunity for extended high-quality survival. Li et al.122 conducted a study on 70 lung cancer patients with solitary brain metastases using WBRT, SRS, or both modalities. Multiple endpoints, including survival, Karnofsky Performance Scale (KPS) status, freedom from local progression (FFLP), and freedom from new brain metastasis (FFNBM), were measured from the date of treatment completion and compared using univariate and multivariate analyses. KPS scores exhibited improvement in 41.4%, 82.6%, and 88.9% of patients treated with WBRT, SRS, and SRS + WBRT, respectively. For patients treated with WBRT, SRS, and SRS + WBRT, the median survival times were 5.7, 9.3, and 10.6 months, respectively, the median FFLP intervals were 4.0, 6.9, and 8.6 months, respectively, the median FFNBM intervals were 4.1, 6.7, and 8.6 months, respectively, and the local tumor response rates were 55.6%, 87.0%, and 88.9%, respectively. The

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comparison between SRS alone and SRS + WBRT demonstrated that the addition of WBRT only improved the FFNBM interval. The authors concluded that SRS alone and SRS + WBRT appeared better in prolonging life and improving quality of life than WBRT alone for patients with solitary brain metastases, whereas SRS alone was comparable to SRS + WBRT in improving survival, local tumor control, and quality of life, except for a more favorable FFNBM interval with the combined modality treatment. Another retrospective study of 113 patients with lung cancer analyzed the efﬁcacy of SRS with or without WBRT in the management of newly diagnosed or recurrent single or multiple brain metastases123. The median patient survival time after SRS was 12 months overall, 13.9 months for 41 patients treated with SRS alone initially, 14.5 months for 19 patients treated with SRS and WBRT initially, and 10 months for 53 patients with recurrent brain metastases. Improved survival was associated with the absence of extracranial metastases and the presence of fewer brain metastases among newly diagnosed patients. Among patients with recurrent brain metastases, improved survival was associated with a higher KPS score, control of the primary cancer, and fewer metastases. One-year FFLP probabilities for patients were 81% with SRS, 86% with SRS + WBRT, and 65% with SRS performed after brain tumor recurrence. There was a signiﬁcantly greater risk of developing subsequent brain metastases in patients with newly diagnosed brain metastases being treated only with SRS in contrast to SRS + WBRT. The investigators concluded that SRS is an effective treatment for selected patients with newly diagnosed or recurrent brain metastases, whereas initial administration of WBRT + SRS improved brain tumor control but not survival. These studies have provided compelling evidence for the role of SRS in the treatment of lung cancer brain metastases, but prospective, randomized trials are necessary to further evaluate the role of SRS with and without WBRT in this clinical setting (Figure 12.1).

Conclusion Lung cancer has a propensity to metastasize to the brain, and the discovery of brain metastases is a common occurrence in advanced disease. MR image screening for brain metastases may be useful in neurologically asymptomatic patients with SCLC for staging, prognosis, and therapy. CT or MR image screening may also have clinical utility in asymptomatic stage III NSCLC, especially adenocarcinoma and large cell carcinoma, because of a higher probability of detecting brain metastases in contrast to asymptomatic stage I or II disease. Several treatment modalities, including surgical resection, WBRT, and SRS are available for the management of cerebral metastases, but current data support a greater improvement in survival when the primary lung cancer can be resected completely to obtain systemic control of the disease. Although treatment with chemotherapy until complete remission in combination with PCI improves survival, the prognosis for SCLC patients remains especially poor because the majority of patients have extensive disease at the time of

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Figure 12.1 Gadolinium contrast-enhanced images of a woman with brain metastases from nonsmall cell lung cancer. Prior to treatment, this patient had a right frontal mass (A, upper row, axial view) and a right thalamic mass (B, upper row, axial view) (C, upper row, saggital view of both lesions). The right frontal mass was treated surgically, and the thalamic mass was treated with stereotactic radiosurgery. The patient also underwent whole-brain radiation therapy immediately after her surgery and radiosurgery. Lower row: axial and sagittal images of the same patient 6 months after treatment.

diagnosis and are not candidates for surgical resection. Future prospective, randomized trials using SRS in the treatment of patients with brain metastases from lung cancer are needed to corroborate the effectiveness of this modality and further deﬁne its role.

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113 Arriagada R, LeChevalier T, Birie F, et al.: Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. J Natl Cancer Inst 1995; 87: 183 –190. 114 Gregor A, Cull A, Stephens R, et al.: Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicenter randomized trial. Eur J Cancer 1997; 33: 1752–1758. 115 Fried B, Buckley R: Primary carcinoma of the lungs. IV. Intracranial metastases. Arch Pathol 1930; 9: 483– 489. 116 Hankins J, Miller J, Salcman M, et al.: Surgical management of lung cancer with solitary cerebral metastasis. Ann Thorac Surg 1988; 46: 24 –28. 117 Magilligan D, Rogers J, Knighton R, et al.: Pulmonary neoplasm with solitary cerebral metastasis. Results of combined excision. J Thorac Cardiovasc Surg 1976; 72: 690–698. 118 Mandell L, Hilaris B, Sullivan M, et al.: The treatment of single brain metastasis from non-oat cell lung carcinoma. Surgery and radiation versus radiation therapy alone. Cancer 1986; 58: 641– 649. 119 Read R, Boop W, Yoder G, et al.: Management of nonsmall cell lung carcinoma with solitary brain metastasis. J Thorac Cardiovasc Surg 1989; 98: 884 –890. 120 Wronski M, Arbit E, Burt M, et al.: Survival after surgical treatment of brain metastases from lung cancer: A follow-up study of 231 patients treated between 1976 and 1991. J Neurosurg 1995; 83: 605 – 616. 121 Kim Y, Kondziolka D, Flickinger J, et al.: Stereotactic radiosurgery for patients with nonsmall cell lung carcinoma metastatic to the brain. Cancer 1997; 80: 2075 –2083. 122 Li B, Yu J, Suntharalingam M, et al.: Comparison of three treatment options for single brain metastasis from lung cancer. Int J Cancer 2000; 90: 37– 45. 123 Hoffman R, Sneed P, McDermott M, et al.: Radiosurgery for brain metastases from primary lung carcinoma. Cancer J 2001; 7: 121–131.

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Current management strategies in intracranial breast cancer metastasis Stacy Moulder, David H Johnson, Steven A Toms

Breast cancer is the most common malignancy in women, accounting for 32% of all female cancers. It is second only to lung cancer in incidence of cancer death and accounts for 18% of all cancer deaths in women1. The combination of early detection and advances in adjuvant hormonal therapy, chemotherapy, and radiation therapy have led to an improvement in survival for women with nonmetastatic breast cancer. Unfortunately, metastatic disease is found at presentation in 5–10% of patients with breast cancer, and 20–30% of patients treated for localized disease will suffer a systemic relapse. Disease detected outside the breast and local lymph nodes is considered incurable, and subsequent therapy focuses on improving survival and palliation of symptoms. Although metastasis to the bones, liver, and lungs is more common in breast cancer patients, central nervous system (CNS) metastases account for approximately 10–15% of the incidence of clinically apparent metastases2, 3. The widespread use of modern imaging techniques, aggressive surgical intervention, and innovative radiation and chemotheraputic strategies, has resulted in effective palliation and a decreased incidence of death from CNS metastasis4.

Epidemiology of breast cancer It was estimated that 175,000 cases of breast cancer would be diagnosed in the United States in the year 2000, and that 43,700 women would die from this cancer. The risk of developing breast cancer increases with age, with 0.8% of breast cancers occurring before age 30, 6.5% of breast cancers occurring at ages 30–40 yrs, and > 90% occurring after age 40. Although male breast cancer is uncommon (male to female ratio of 1:100), diagnosis is often delayed in males, who also tend to present with later stages of disease when compared to their female counterparts5. White and African American women have the same rate of premenopausal breast cancers; however, white peri- and postmenopausal women have a higher rate of breast cancer than African American women6. The incidence in United States Hispanic and Asian women is roughly half that of whites, and breast cancer is uncommon in Native American women. Women of higher socioeconomic and educational status have higher rates of 221

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breast cancer, which are probably due to lifestyle inﬂuences such as age at ﬁrst live birth7.

Pathology of invasive breast cancer The World Health Organization’s histological typing of breast tumors is the most widely used classiﬁcation system for invasive breast cancer. This classiﬁcation system is based on growth patterns and cytological features of the invasive cells and not on the site of origin within the mammary duct system. This is because most invasive breast cancers arise in the terminal duct lobular unit, regardless of the histological type8.

Inﬁltrating ductal carcinoma Inﬁltrating (invasive) ductal carcinoma is the most common histological type of invasive breast cancer by virtue of its deﬁnition as a type of cancer “not classiﬁed into any other categories of invasive mammary carcinoma”. Terms such as inﬁltrating ductal carcinoma, not otherwise speciﬁed, or inﬁltrating carcinoma of no special type have been coined to emphasize this diagnosis of exclusion8. These tumors most often present as a palpable mass or a clinically silent abnormality on screening mammography. Macroscopically, these tumors usually appear as a ﬁrm mass with a gray to white gritty surface on cut section. Most lesions have a spiculated contour with irregular margins, but a minority may be well circumscribed8. As would be expected, inﬁltrating ductal carcinomas are a histologically diverse group of lesions. The tumors may form glandular patterns or consist of dense sheets of cells. There is also wide variation in cellular pleomorphism, nuclear atypia, and mitotic activity. Some tumors may have minimal to absent stromal desmoplasia, whereas others show such prominent stromal desmoplasia that malignant cells may compose only a small portion of the tumor 8. Inﬁltrating ductal carcinomas are commonly associated with areas of ductal carcinoma in situ (DCIS), but can also present without evidence of DCIS. Because of the histological diversity associated with inﬁltrating ductal carcinoma, histological grading has been used to subclassify these tumors based on the assessment of tubule formation, mitotic activity, and nuclear pleomorphisms. The overall histological grade is determined by the sum of the scores for each parameter9, 10. Inﬁltrating ductal carcinomas have the poorest prognosis of all invasive breast cancers11. Because of the heterogeneity within this group, prognostically favorable subsets have been identiﬁed. Histological grade has been clearly shown to correlate with survival, and the prognostic value is independent of tumor size or lymph node status12, 13. Poorly differentiated tumors (higher grade) are associated with higher rates of distant metastasis and poorer overall survival. Some studies have indicated that histological grade appears to generate useful information regarding the response of tumors to chemotherapy as well, with higher grade lesions showing a better response to certain chemo-

Current management strategies in intracranial breast cancer metastasis 223

therapy regimens. Other histological factors, such as vascular invasion (a term that encompasses both lymphatic and blood vessel invasion)14 and tumor necrosis15, have been associated with either increased risk of axillary lymph node involvement or a higher grade of lesion, both of which portend a poorer prognosis.

Inﬁltrating (invasive) lobular carcinoma Inﬁltrating lobular carcinoma is the second most common type of invasive breast cancer, accounting for approximately 5–14% of the cases in most reported series16. These tumors have been associated with multifocal lesions in the ipsilateral breast17. Although there are reports of higher rates of bilateral synchronous breast cancers in patients who have inﬁltrating lobular carcinoma rather than other types of invasive breast cancer, follow-up studies in patients with surgically resected localized disease have found no difference in the rate of contralateral breast cancer between the two groups. Most cases (70–80%) are associated with foci of lobular carcinoma in situ18. Clinically, these tumors can present with characteristics similar to inﬁltrating ductal carcinomas (palpable mass on physical examination; spiculated mass on mammogram), and they may even have a similar appearance by gross pathological exam. Not uncommonly, however, these tumors will have a subtle presentation with a nonspeciﬁc thickening of the breast on physical examination and poorly deﬁned areas of asymmetric density on mammographic examination. There may be no grossly apparent mass by macroscopic examination, and the only hint of abnormality may be a rubbery consistency of the breast tissue8. Histologically, inﬁltrating lobular carcinomas have distinctive cytological features that include cells with small nuclei with little variation, low mitotic indexes, and cells that appear to be loosely cohesive. The classic form of lobular carcinoma is characterized by small cells invading the surrounding stroma in linear single-cell formations18. Some variant forms, such as solid, alveolar, and tubulolobular forms, have the same cytological features as the classic form but display different growth patterns of tumor cells. Other variant forms, such as signet ring and pleomorphic variants, display invasion patterns similar to the classic form but have different cytological features19. Inﬁltrating lobular carcinomas typically test positive for estrogen and progesterone receptors and negative for HER2/neu receptors according to immunohistochemical analysis8. The prognosis for patients with lobular carcinoma is not thought to differ from that of patients with ductal carcinoma. Interestingly, several studies have suggested differences regarding patient prognosis among the variants of invasive lobular carcinoma, with the tubulolobular variant having a better prognosis than the classic variant, which has a better prognosis than the solid variant20. Although the prognosis for patients with lobular carcinoma does not differ from that for patients with ductal carcinoma, a number of studies have noted differences in the pattern of metastatic propagation between these two forms

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of invasive breast cancer. Lobular carcinomas show a greater propensity to metastasize to bone, peritoneal surfaces, and leptomeninges relative to other types of invasive breast carcinoma8, 21, 22.

Less common pathological types Although ductal and lobular carcinomas make up the majority of invasive breast cancers reported in the medical literature, less common histological types also have importance in the assessment of prognosis. Mucinous, tubular, cribriform, papillary, adenoid cystic, and secretory histological types are associated with a lower histological grade, low rates of regional lymph node metastasis, and a more favorable prognosis8. The widespread use of screening mammography has increased the detection and reported incidence of many of these breast cancer types, especially tubular carcinomas. Although tumors with an invasive papillary histology have been associated with a more favorable prognosis, invasive micropapillary histology is associated with a higher rate of axillary nodal involvement and appears to signify a poorer prognosis8. Because of controversies among pathologists concerning the appropriate histological diagnostical criteria, the prognostic implications of medullary and metaplastic tumor histologies are uncertain.

Staging of breast cancer The most widely used system for staging breast cancer is that of the American Joint Committee on Cancer (AJCC) (Table 13.1). The TNM system is a representation of the anatomic extent of disease based on tumor size (T), extent of regional lymph node involvement (N), and the absence or presence of distant metastasis (M). This staging system applies to inﬁltrating, as well as microinvasive and in situ, carcinomas of the breast.

Primary tumor size The clinical measurement used for classifying the primary tumor (T) is the one judged to be the most accurate for that particular case (i.e., mammogram for calciﬁed lesions versus ultrasound for lesions not detected by mammogram versus magnetic resonance [MR] imaging for suspected chest wall lesions). Pathological tumor size for classiﬁcation (pT) is a measurement of only the invasive component as determined by microscopic examination of the resected tumor. For adequate pathological staging, there can be no macroscopically visible tumor tissue in any margin of resection. If there is tumor tissue in the margin of resection as viewed macroscopically, it is coded TX because the extent of the primary tumor cannot be assessed. If the margin of the tumor site is re-resected and found to be free of tumor tissue at its margins, the tumor size can be calculated as the sum of the measurement of the invasive component of the initially resected tumor plus the invasive component of the re-resected margin. A case can be classiﬁed as pT for pathologic stage grouping if there is only microscopic, but not macroscopic, tumor involvement of the margin23.

Current management strategies in intracranial breast cancer metastasis 225 Table 13.1 The American Joint Committee on Cancer criteria for the staging of breast cancer. Primary tumor (T) TX T0 Tis T1

T2 T3 T4

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ: Intraductal carcinoma, lobular carcinoma in situ, or Paget’s disease of the nipple with no tumor. Tumor 2 cm or less in greatest dimension T1mic Microinvasion 0.1 cm or less in greatest dimension T1a Tumor more than 0.1 but not more than 0.5 cm in greatest dimension T1b Tumor more than 0.5 cm but not more than 1 cm in greatest dimension T1c Tumor more than 1 cm but not more than 2 cm in greatest dimension Tumor more than 2 cm but not more than 5 cm in greatest dimension Tumor more than 5 cm in greatest dimension Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below: T4a Extension to chest wall T4b Edema or ulceration of the skin of the breast or satellite skin nodules conﬁned to the same breast T4c Both (T4a and T4b) T4d Inﬂammatory carcinoma (see deﬁnition in text)

Regional lymph nodes NX N0 N1 N2 N3

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis to moveable ipsilateral axillary lymph nodes Metastasis to ipsilateral lymph nodes ﬁxed to one another or to other structures Metastasis to ipsilateral internal mammary lymph nodes

Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis (includes metastasis to ipsilateral supraclavicular lymph nodes) Stage grouping Stage 0 Stage I Stage IIA

Stage IIB Stage IIIA

Stage IIIB Stage IV

Tis T1 T0 T1 T2 T2 T3 T0 T1 T2 T3 T3 T4 Any T Any T

N0 N0 N1 N1 N0 N1 N0 N2 N2 N2 N1 N2 Any N N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

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Multiple simultaneous primaries If multiple simultaneous ipsilateral primary carcinomas are present, the largest primary carcinoma should be used to classify (T), and the fact that multiple ipsilateral primaries were present should be recorded. Alternatively, if simultaneous bilateral breast carcinomas are present, each lesion should be staged as a separate primary23.

Microinvasion of breast carcinoma Microinvasion is the extension of cancer cells beyond the basement membrane into the adjacent tissues with no focus more than 0.1 cm in greatest dimension. When there are multiple foci of microinvasion, the size of only the largest focus is used to classify the microinvasion. (The sum of all the individual foci should not be used.) The presence of multiple foci of microinvasion should be noted23.

Inﬂammatory carcinoma Inﬂammatory carcinoma is a clinically diagnosed entity characterized by diffuse induration and erythema of the skin of the breast with an erysipeloid edge, which represents tumor inﬁltration and embolization of dermal lymphatics. Although imaging studies may detect a parenchymal mass along with the characteristic thickening of the overlying skin of the breast, there is usually no clinically palpable mass. Tumors that present with inﬂammatory carcinoma are classiﬁed as T4d. Edema, ulceration of the skin, or satellite skin nodules that are conﬁned to the same breast are classiﬁed as T4b. Other skin changes, such as dimpling of the skin or nipple retraction, may occur in T1, T2, or T3 without changing the classiﬁcation23.

Regional lymph nodes The breast lymphatics drain by three major routes: the axillary, transpectoral, and internal mammary nodes. Intramammary lymph nodes are considered and coded as axillary lymph nodes for staging purposes. Metastasis to any other lymph node is considered distant (M1), including supraclavicular, cervical, or contralateral internal mammary nodes23.

Prognostic indicators for metastatic disease In patients with metastatic breast cancer, selected predictive and prognostic factors can be used to recommend further treatment options. Interestingly, factors that are important for prognosis in localized disease do not necessarily hold the same predictive value at the time of metastatic recurrence. For example, TNM staging at the time of original diagnosis offers no indication of prognosis after metastatic relapse. Being less than 35 years old is also a very important prognostic indicator in localized disease, but the effect of age on time to progression and overall survival has not been well established in the metastatic setting.

Current management strategies in intracranial breast cancer metastasis 227

Alternatively, estrogen receptor expression and low tumor grade are favorable prognostic indicators for both the localized and metastatic disease forms24. Other clinical factors that predict rate of progression and decreased survival include length of the interval between primary diagnosis and relapse, the presence or absence of visceral organ involvement, and the number of sites of metastatic disease25. A time to tumor recurrence of greater than ﬁve years is considered to indicate a favorable prognosis, most likely because such tumors may have a more indolent biology25. The site of recurrence is also an important indicator, with patients showing involvement of nonvisceral tissues, such as bone or the chest wall, having a longer time to disease progression and a longer overall survival time compared with those who have hepatic or CNS involvement.

Therapy for metastatic breast cancer The median survival after detection of metastatic breast cancer is 18–24 months, and about 45,000 women die of metastatic breast cancer each year8. Although durable complete remissions have been documented with cytotoxic therapy, these cases are exceedingly rare, and therapy should focus on palliation of symptoms and improvement in survival rather than on curative intent. Patients with breast cancer make up a heterogeneous group with wide variation in survival in both treated and untreated patients. Several large randomized trials with systemic hormonal therapy and/or chemotherapy have proved a survival beneﬁt for these treatments in patients with metastatic disease26. The selection of treatment for patients with metastatic disease involves consideration of the clinical features of the disease and the patient’s coexisting medical conditions. Patients with indolent disease (deﬁned as having a disease-free interval of greater than two years; having metastasis to bone, soft tissue, or having non-life-threatening visceral organ involvement; and tumors showing estrogen receptor [ER] and progesterone receptor [PR] positivity) can be treated with hormonal therapy as initial treatment for metastatic disease. Patients with more aggressive disease or ER/PR-negative tumors usually receive cytotoxic chemotherapy26.

Hormonal therapy Hormonal therapy for metastatic breast cancer has been used since the early 1900s, when Beatson published his observation of tumor response in breast cancer patients undergoing oophorectomy27. These days, alternatives to oophorectomy in premenopausal patients include the use of ablative radiation therapy to the ovaries or the administration of luteinizing hormone releasing hormone (LHRH) agonists combined with tamoxifen28, 29. The efﬁcacy of tamoxifen, a selected estrogen-receptor modulator (SERM), has been documented as an effective therapeutic agent for metastatic breast cancer for the past two decades. Tamoxifen is an orally administered, synthetic

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estrogen antagonist that blocks estrogen binding to the cytoplasmic estrogen receptor (ER)30. As a consequence, tamoxifen regulates the expression of genes associated with estrogen receptor transactivation. These genes are involved with expression of growth factors that may stimulate growth by autocrine or paracrine mechanisms30. In patients with tumors that test positive for ERs and/or PRs, tamoxifen has shown tumor response rates of around 30%, which is as efﬁcacious as many chemotherapy regimens26, 30, 31. Conversely, less than a 10% tumor response rate has been reported in women with ER/PR-negative tumors. In addition to having a favorable hormone receptor status, patients most likely to respond to tamoxifen therapy include those who have a disease-free interval lasting two or more years after initial surgery, and those with soft tissue, bone, or nodular lung metastases. These patients may also beneﬁt from secondary and tertiary endocrine therapies after experiencing failure of tamoxifen in metastatic disease treatment or tumor recurrence during adjuvant tamoxifen therapy26, 30, 32. Case reports have also demonstrated antitumor activity of tamoxifen in patients with multiple brain metastases33. Chemotherapy is generally recommended for patients with rapidly progressing metastases, heavy tumor inﬁltration of visceral organs, or ER/PR-negative tumors. Tamoxifen “ﬂare” is a syndrome that is associated with hypercalcemia and increasing pain at metastatic sites during the ﬁrst weeks of therapy. During this time, it is often difﬁcult to distinguish tumor progression from a clinical scenario that signiﬁes a high likelihood of response to therapy. If possible, symptomatic management with pamidronate and analgesics should be utilized along with assuring the patient that this syndrome may represent a response to therapy. Tamoxifen is also associated with a slightly increased risk of cataracts, endometrial carcinoma, and venous thrombosis30. In postmenopausal women, virtually all estrogen is produced by aromatase, an enzyme found in brain, muscle, and peripheral fat that converts androgenic hormones to estrogens. Aminoglutethimide was one of the ﬁrst drugs used to inhibit aromatase; however, its nonspeciﬁc action also blocked the 11-, 17- and 21-hydroxylation necessary for the adrenal pathway of steroidogenesis, resulting in the reduced production of mineralocorticoids and glucocorticoids necessary for life31. Second-generation aromatase inhibitors were more speciﬁc but required injection, which limited their use. Third-generation aromatase inhibitors, such as anastrozole and letrozole, have an oral route of administration, and randomized clinical trials have demonstrated improvement in time to treatment progression and overall survival when they are used as second line agents after tamoxifen fails to inhibit metastatic tumors34. Preliminary studies have suggested that anastrozole may be equivalent (if not superior) to tamoxifen for ﬁrst line therapy in metastatic breast disease in postmenopausal women35–37; at present, a large randomized trial is underway in these women, comparing each drug as a single agent and evaluating combination therapy with both drugs. Based on currently available data, postmenopausal women with metastatic disease who are eligible for endocrine therapy should receive

Current management strategies in intracranial breast cancer metastasis 229 Table 13.2 Commonly used regimens for metastatic breast cancer. Cyclophosphamide 100 mg PO day 1–14 every 28 days or 600 mg/m2 IV day 1 every 28 days Methotrexate 40 mg/m2 IV days 1 and 8 every 28 days Fluorouracil 600 mg/m2 IV days 1 and 8 every 28 days Cyclophosphamide 600 mg/m2 IV day 1 every 21 days Doxorubicin 50 mg/m2 IV day 1 every 21 days Fluorouracil 500 mg/m2 IV days 1 and 8 (or 4) every 21 days Cyclophosphamide 600 mg/m2 IV day 1 every 21 days Doxorubicin 60 mg/m2 IV day 1 every 21 days Paclitaxel 175 mg/m2 IV every 21 days Trastuzumab (Herceptin) 4 mg/kg IV loading dose on day 1 followed by 2 mg/kg IV weekly Docetaxel 100 mg/m2 IV every 21 days Vinorelbine 20 mg/m2 IV every 7 days Capecitabine 1,500 mg/m2 PO divided BID

tamoxifen as initial therapy, followed by a third-generation aromatase inhibitor upon progression of disease.

Cytotoxic chemotherapy Breast cancer is moderately sensitive to many cytotoxic agents; in spite of this, single agent therapy is effective in only 20–30% of patients. The highest response rates for single agent regimens (30–60%) are seen with the anthracyclines, alkylating agents, and taxanes26. The most effective chemotherapy regimens involve combination therapy, usually with an anthracycline38. Table 13.2 lists the standard chemotherapy regimens commonly used to treat metastatic breast cancer. Several clinical factors, such as neurological performance status, tumor burden, and prior exposure to chemotherapy, predict response to chemotherapy. Patients with a good neurological performance status, small tumor burden, and no prior exposure to chemotherapy show response rates of 50–70%. On the other hand, patients with poor performance status and extensive tumor burden have an expected response rate of < 30%8.

Biological therapy Recently, new drugs have been introduced that target tumor-speciﬁc cellular pathways in order to inhibit tumor growth and/or induce cell death (apoptosis). The most extensively clinically tested of these new agents is trastuzumab (Herceptin™, Genentech Inc., South San Francisco, CA, U.S.A.), a humanized monoclonal antibody that targets the HER2/neu receptor. This receptor is a member of the epidermal growth factor receptor family and its overexpression

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has been associated with an aggressive tumor phenotype. Single agent trastuzumab has shown activity in patients with metastatic breast tumors demonstrated to overexpress HER2/neu receptors by immunohistochemistry or ﬂuorescence in situ hybridization (FISH), even in patients in whom chemotherapy has failed39. Trastuzumab has also shown synergistic activity when combined with standard chemotherapy agents, such as taxanes40, 41. Trastuzumab has been occasionally associated with hypersensitivity reactions and rarely associated with cardiomyopathy, which resolves with discontinuation of the drug42– 44.

Intracranial metastasis Intracranial metastasis from breast cancer still carries a poor prognosis. It is second only to lung cancer as the most common cause of brain metastasis in women. Approximately 10,000 cases occur in the United States each year45. Nearly 10% of women with metastatic breast cancer will have clinical evidence of central nervous system involvement46, 47. The overall percentage of breast cancer patients who develop intracranial metastases has been reported to be as high as 22% in autopsy series48, 49. Intracranial metastasis is most commonly seen in the face of widespread extracranial metastasis. CNS metastasis is more common in premenopausal women, who often have more aggressive tumors50. The prognosis of patients without treatment is dismalaonly a one to two month average survival time without therapeutic intervention46, 51, 52. Nonetheless, there are rare instances of long-term survival of 10 years or more with radiation treatment alone or with no treatment of known intracranial metastases53.

Pathophysiology of intracranial metastasis Intracranial metastasis of breast cancer occurs by the hematogenous spread of tumor cells. In metastasis to the skull or dura, tumor cells may exit the blood vessels directly and begin their growth. Within most of the CNS, however, there is a blood-brain and blood-cerebrospinal ﬂuid barrier formed by the endothelial cells. These extra basement membrane layers must be transgressed before breast cancer cells can escape the capillary bed and begin their growth. In order to maintain the growth of stromal tumor cells, neoangiogenesis must occur, and a tumor vascular network must be established. In these vascular networks, the blood-brain barrier is incompletely formed. The blood vessels are permeable, and there is often extensive edema. It has been suggested that the edema is secondary to vascular permeability in these lesions caused by vascular endothelial growth factor (VEGF) and other vasoactive peptides54, 55.

Skull Breast cancer is frequently involved in osseous metastasis. Intracranial metastases in breast cancer may involve either the calvaria56 or the skull base, where cranial nerve palsies are a frequent complication (Figure 13.1)57. Most commonly, these bony metastases of the skull are identiﬁed by local pain or as a

Current management strategies in intracranial breast cancer metastasis 231

Figure 13.1 Contrast-enhanced axial T1 MR image of a patient with an isolated breast cancer metastasis to the left sphenoid bone.

growing mass lesion. Most breast lesions are osteolytic, although occasional osteoblastic metastases may occur. Although no single molecular characteristic of breast cancer seems to predispose to osseous metastasis, animal models have suggested pathways common to the bony sites of breast cancer metastasis. It has become apparent that metastatic breast cancer cells release parathyroid hormone related protein (PTH-rP), which leads to osteoclastic bone resorption. The bone resorption leads to the release of the bone’s stored growth factors, including insulin-like growth factor (IGF) and transforming growth factor β (TGF-β), which act in a paracrine fashion to stimulate the growth of breast cancer cells. In turn, these stimulated cancer cells release more PTH-rP, perpetuating the cycle of tumor growth and bone resorption58 – 60.

Dura Isolated dural metastases have long been recognized as characteristic of breast cancer (Figure 13.2). Similar to the situation for parenchymal metastases, patients having them most commonly present with headache or other nonfocal symptoms. Again, however, no speciﬁc characteristic of the molecular biology of breast cancer has yet been tied to this phenomenon. As the dura is relatively hypovascular relative to the underlying grey matter, neoangiogenesis from or direct invasion of the tumor into the cortical surface is often encountered during surgical extirpation of these lesions, greatly complicating their removal61. In the surgical series of Rumana et al.61, 14% of patients having durally-based metastases relapsed with leptomeningeal disease, postoperatively.

Leptomeninges Leptomeningeal disease (LMD), or carcinomatous meningitis, is a frequent complication of late stage breast cancer. In fact, 30% of all cases of

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Figure 13.2 Contrast-enhanced axial T1 MR image of a patient with a durally-based breast cancer metastasis at the right cerebellopontine angle mimicking a meningioma.

leptomeningeal disease observed in metastatic cancer are related to breast tumors50. Among the histological subtypes of breast cancer, the variant with lobular architecture is most likely to produce LMD21, 62. The most likely entry point for tumor cells into the cerebrospinal ﬂuid (CSF) spaces is via the choroid plexus. Tumor cells traversing the endothelium of this extremely vascular organ have direct access to the CSF. However, the subarachnoid space may also become involved from dural or parenchymal metastases that secondarily invade the subarachnoid space. Rarely, isolated intraventricular metastases growing within the choroid plexus may be identiﬁed. More commonly, however, diffuse involvement of the intracranial and intraspinal CSF spaces is encountered.

Parenchyma Breast cancer metastases are most commonly found in the cerebral hemispheres (80–85%) (Figure 13.3). This is primarily a result of the larger size of the hemispheres relative to other CNS components and their blood ﬂow pattern. The next most common sites for these metastases are the cerebellum (10–15%), brain stem (3–5%) and spinal cord parenchyma (< 1%)49, 63, 64. Cortical hemispheric metastases are most commonly deposited at the junction of grey and white matter. This is thought to be secondary to the change in vessel caliber as blood vessels begin to leave the metabolically active grey matter and penetrate into the relatively hypometabolic deep cerebral white matter. It has also been noted that metastases tend to respect vascular territories, occurring more frequently in the higher-ﬂow middle cerebral artery territories, especially at watershed zones with other vascular distributions64, 65. Approximately 50–60% of parenchymal metastases are multiple upon clinical presentation64, 65.

Current management strategies in intracranial breast cancer metastasis 233

Figure 13.3 Contrast-enhanced saggital T1 MR image of a patient with a large cystic frontal-lobe breast cancer metastasis.

Clinical presentation of intracranial metastases The clinical presentation of intracranial breast cancer metastasis is largely dependent upon the intracranial compartment to which the tumor has metastasized as well as the patient’s overall tumor burden. Symptoms may be nonlocalizing secondary to increased intracranial pressure or localizing secondary to focal mass effect upon (or invasion of) neurological structures. Nonlocalizing symptoms may include headache, nausea, vomiting, shortterm memory lapses, alteration in the level of consciousness, or other changes in mental status. Such symptoms are most common in the case of multiple metastases, carcinomatous meningitis, or from focal obstruction of cerebrospinal ﬂuid circulation and hydrocephalus. Generalized seizures may occur secondary to metabolic abnormalities from systemic cancer. Focal signs less commonly herald the presence of intracranial metastasis. Local pain or a mass may occur with skull lesions. Cranial nerve palsies most commonly occur with carcinomatous meningitis but may also be a presenting sign of skull base metastases. Focal seizures, hemiparesis, aphasia, or other focal neurological signs are most prominent with dural-based or intraparenchymal metastases49, 66 – 68.

Imaging of intracranial metastases The diagnosis of intracranial metastasis is most often conﬁrmed with computed tomography (CT) or MR imaging scans. The most sensitive of these studies is gadolinium-enhanced MR imaging. However, it is important to remember that all regions of enhancement on MR images in patients with a known diagnosis of breast cancer do not correspond to metastatic tumors. In

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one study, 11% of single intracranial lesions in patients with systemic cancer were not metastatic tumors69. A second tumor, such as a meningioma or glioma, may mimic the imaging characteristics of an intracranial metastasis. Intracerebral abscess is occasionally found in patients with systemic cancer and mimics the imaging pattern of parenchymal metastases. Although a diagnosis based on a tissue sample remains the gold standard, it is not always necessary before treatment is initiated. In otherwise asymptomatic patients, skull lesions may be identiﬁed on bone scans. When a clinical sign or symptom is present, CT or MR imaging is indicated. For many bony lesions, CT is superior in terms of identifying the destruction produced by lytic lesions. Durally-based lesions are easily confused with meningioma as both present as focal, contrast-enhancing dural lesions. Leptomeningeal invasion of breast cancer is most commonly seen on MR images as abnormal linear dural enhancement. At other times, the abnormal pial enhancement or focal enlargement of regions such as the cavernous sinus are the MR imaging hallmarks of LMD.

Laboratory studies of intracranial metastases Serum markers such as carcinoembryonic antigen or CA-27.29 are sometimes monitored in patients with metastatic breast cancer. A rise in their levels may alert the clinician to otherwise occult disease progression. Widespread bony disease or skull lesions may be heralded by a rise in alkaline phosphatase. If carcinomatous meningitis is suspected, a lumbar puncture may be performed. Frequently, the opening pressure is high or the protein is elevated in the CSF sample. Cytological examination of cell pellets from centrifuged samples of CSF may reveal neoplastic cells. At least some abnormality in normal CSF indices is found in the CSF of nearly all patients who have LMD from breast cancer70, 71. The most precise laboratory test for conﬁrming the diagnosis of intracranial breast cancer metastasis is, of course, the pathological analysis of biopsy or excised material. Unfortunately, metastatic breast cancer is often poorly differentiated, and only a diagnosis of metastatic adenocarcinoma may be made. Histological analysis of the brain lesion should include the immunohistochemical analysis of estrogen and progesterone receptors, as this may heavily impact treatment options.

Treatment of intracranial metastases General The ﬁrst stage of treatment for patients with intracranial metastases is to address the symptoms that led to diagnosis. Often, this involves treatment of increased intracranial pressure caused by the mass lesions. Initial treatment often involves the administration of corticosteroids. In most cases, this is enough to stabilize a patient. Larger masses or more extensive swelling may require intubation and hyperventilation or the administration of mannitol or

Current management strategies in intracranial breast cancer metastasis 235

other diuretics until the antiedema effect of corticosteroids begins. If patients present with seizure, initial anticonvulsant therapy with diphenylhydantoin is required. More refractory seizures or diphenylhydantoin reactions may require the use of other anticonvulsants. Unfortunately, many chemotherapies alter the binding and metabolism of these drugs, and frequent monitoring of drug levels is required.

The undiagnosed patient It is likely that fewer than 10% of patients with breast cancer present with an intracranial lesion as the ﬁrst sign of cancer72. A patient presenting with a solitary brain lesion consistent with metastasis needs further imaging. Most commonly, a CT scan of the chest, abdomen, and pelvis is the diagnostic procedure of choice. A thorough breast and gynecological examination is necessary for female patients. The role of preoperative mammography in locating an occult primary is controversial. In general, mammography is not obtained unless a suspicious lesion is found during breast examination73. Often, a tissue diagnosis may be obtained from extracranial lesions. However, if the patient has good neurological performance status and the solitary brain lesion is resectable, then all attempts should be made to extirpate it. If the lesion is, for example, in the brainstem or a deep grey nucleus, and no other lesion is found upon systemic imaging and examination, consideration may favor biopsy. If, however, there is evidence of widespread systemic metastasis, then tissue diagnosis at the site of the primary should be undertaken, and irradiation of the CNS and chemotherapy should be initiated. The patient whose ﬁrst presentation is with multiple intracranial lesions necessitates a different approach. Although many women with two or three intracranial metastases can be managed as efﬁciently as those with a solitary lesion, multiple intracranial metastases more often portend widespread systemic disease. Fortunately, there are few occasions in which a patient with breast cancer will present primarily with multiple intracranial metastases. However, if no systemic site of disease is found after a thorough evaluation, then tissue diagnosis via biopsy may still be necessary. If all lesions are treatable with surgery or stereotactic radiosurgery (SRS), either of these modalities (or a combination of them) may be the preferred treatment.

Single (and solitary) metastases More often, CNS metastases will present in a patient with a known history of breast cancer rather than occurring as a primary presentation. In metachronous metastases, recent staging of the patient must be undertaken by performing CT of the chest, abdomen and pelvis. Examination of the patient’s overall course of treatment and response to therapy must be noted. If the patient’s systemic disease is controlled, the illness is not rapidly progressing, and the patient continues to maintain a good neurological performance status, then aggressive intervention should be entertained. If the patient is rapidly deteriorating due to progressive systemic disease, then palliative whole-brain

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radiation therapy (WBRT) may be an appropriate consideration. The treatment of the patient with a solitary metastasis and good neurological performance status has become polarized between those who believe in SRS versus those who favor surgery plus WBRT. Although it has become clear over the past decade that both treatments are superior to observation or WBRT alone, the most appropriate use of these two modalities remains subject to debate. Reports that speciﬁcally focus on patients with breast cancer metastases are even scarcer than well-controlled studies of patients with metastases in general. However, several important facts regarding the biology of breast cancer argue for an aggressive approach to these patients. First, metastatic breast cancer patients have long median survival times, approximately three years. This is probably because many breast cancers are both hormonally responsive and chemosensitive. Also, novel compounds, such as the antibody that targets the HER2/neu receptor (trastuzumab), are showing efﬁcacy even in advanced metastatic breast cancer. Moreover, a small percentage of metastatic breast cancer patients survive for 10 years or more, even without additional treatment. This further supports the role of hormonal or immunological inﬂuences on the survival of these patients. Caution should be exercised before assigning patients to palliative care before objective failure to biological therapy, hormonal therapy, and chemotherapy are documented. Until data from further well-controlled studies are available, it appears that, for smaller lesions (< 3 cm in maximum diameter), SRS and surgery plus WBRT are nearly equivalent in effect. SRS is probably superior in treating very small lesions (< 7 mm in maximum diameter), which can be difﬁcult to localize with frameless stereotaxy and intraoperative ultrasound guidance. SRS may also be superior in treatment of lesions of the brain stem and deep grey nuclei, but the risks and beneﬁts must be analyzed individually for each patient. Surgery is superior in treating large lesions (> 4 cm in maximum diameter), where SRS dosimetry becomes problematic. Surgery may be superior in treating tumors adjacent to eloquent areas, especially if there is extensive surrounding edema. However, these pros and cons and a multitude of other questions regarding the two modalities (SRS and surgery) await better controlled trials. In summary, the patient with a solitary brain metastasis is nearly always a candidate for aggressive therapy with SRS or surgery plus WBRT. A patient with a single metastasis and well-controlled systemic disease will almost always be a candidate for aggressive treatment of her CNS disease. Only in the rare case of a patient who has relapsed systemic disease and poor neurological performance status should palliative WBRT be the only therapy initiated for patients with a single lesion from breast cancer.

Multiple metastases The decision to treat a patient with multiple brain lesions aggressively is more controversial than it would be for a patient with only a single lesion. As in the case of a patient with a single lesion, the ﬁrst point of departure in management is determining whether the patient has a known cancer diagnosis. In

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patients without known extracranial disease, extracranial sites more often present themselves for tissue diagnosis when the cancer is widely spread. As with other cancers that produce multiple metastases, there is a role for aggressive treatment of breast cancer patients who have multiple intracranial lesions. At The University of Texas M. D. Anderson Cancer Center (M. D. Anderson), 11 of 56 patients who had two or three brain lesions were those who had breast cancer74. In the Memorial Sloan Kettering experience, 16 of 70 patients with breast cancer metastases had multiple brain metastases41. In fact, in this series, the patients with multiple metastases had a longer survival time (14.8 months) than those with single metastases (13.9 months). Although this undoubtedly represents a selection bias, it does highlight that even a subgroup of patients with multiple brain metastases can expect long-term palliation, if aggressive intervention is employed. In general, those with multiple brain lesions in whom aggressive treatment options for all lesions may be pursued with acceptable morbidity have a life expectancy that rivals those with a single lesion. Surgery plus WBRT, radiosurgery to all lesions, or a combination of surgery and SRS may be appropriate treatment for carefully selected breast cancer patients with multiple lesions.

Leptomeningeal disease As with other cancers, LMD from breast cancer carries a very poor prognosis. LMD is rarely the initial presentation of metastatic breast cancer. The interval from the initial diagnosis of metastatic cancer until LMD develops most often ranges from 3–17 months71, 75. Breast cancer makes up a high percentage of LMD patient series and can be as high as 6% at autopsy48, 76. About 30% of patients with symptomatic intracranial metastases also have evidence of intercurrent LMD48, 77. Treatment options for these individuals remain poor, and untreated patients usually die within six weeks of diagnosis71, 78, 79. Brain and spinal radiotherapy may be used here, but they carry signiﬁcant morbidity. More often, radiotherapy is used to treat bulky tumor deposits or symptomatic regions in these patients. Not infrequently, patients with LMD also present with hydrocephalus. These patients are often considered for surgery for their hydrocephalus, but they need ventricular access for intrathecal (IT) chemotherapy as well. These patients may be treated with a shunt that has an ON–OFF ﬂushing valve™ that permits the shunt to be turned off for a period of time after IT chemotherapy, thereby allowing the diffusion of the chemotherapy throughout the CSF and the CSF diversion to be resumed hours after the chemotherapy has been given. The mainstay of therapy in these patients has been intrathecal chemotherapy via an Ommaya reservoir. Most often, IT methotrexate has been used as the chemotherapeutic agent, but more recently, IT Ara-C and thiotepa have been employed for LMD control. Nonetheless, after Ommaya reservoir placement and treatment with IT chemo, the life expectancy of these patients remains at 4 to 7 months71, 79. A preliminary report suggests that IT hormonal

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therapy may be beneﬁcial in a subgroup of LMD patients with hormonally responsive tumors80. It remains to be seen whether the IT use of other agents for breast cancer treatment, such as small-molecule epidermal growth factor receptor (EGFR) inhibitors or IT trastuzumab (Herceptin™) may modulate the dismal prognosis for these patients.

Recurrent metastases Recurrent CNS metastases of breast cancer fall into two basic categoriesathose that arise from local treatment failure or those that occur as metastases distant from the original treatment site. Local treatment failure makes up 30 to 50% of all brain metastasis treatment failures81. The decision of whether or not to re-treat these patients hinges mostly on the status of their systemic disease. If the patient’s neurological performance status is poor, the systemic malignancy is progressing and life expectancy is limited, there is no compelling reason to consider repeat surgery or a SRS boost to affected areas. However, if these conditions are met, there is reason, especially in breast cancer patients whose cancer has a more indolent course, to continue to intervene aggressively with repeat surgery or SRS. In a study at M. D. Anderson, 10 of 48 recurrent metastatic (brain) tumors were found in breast cancer patients81.

Radiation therapy The overall survival time of patients with brain metastases from breast cancer that were treated with radiotherapy has ranged from three to seven months82– 84. Brain metastases in approximately 60% of those treated respond to this modality82–84. Rare long-term survival after WBRT alone has been reported, with several cases of survival in excess of 10 years in what is generally considered to be palliative treatment72. Most treatment protocols involve the administration of 30 to 45 Gy over an interval of two to three weeks, although the standard dose in the United States is 30 Gy given over a period of two weeks in 10 daily fractions85, 86. Although there are little data to suggest that certain histologic subtypes are more radiosensitive than others, there are some data on molecular markers of radiosensitivity of breast cancer cells. There is some evidence that the IGF receptor-1R, the BRCA1/2 proteins, and the HER2/neu receptor may all modulate in vitro radiosensitivity in breast cancer cell lines, but this correlation remains to be established, clinically.

Surgery There have been few series reviewing surgery for breast cancer metastatic to the brain. The largest and most complete of these are from the Memorial Sloan Kettering Cancer Center, reporting upon 70 patients treated from 1974–199387, and from M. D. Anderson, reporting on 63 patients treated between 1983 and 199288. Most other data were abstracted from other surgical series of brain metastases of various histological types. Median survival times ranged from 5.5 to 16 months in published reports, with the best results of 16 and 14.5

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months coming from the M. D. Anderson and Sloan Kettering experiences. These studies have veriﬁed for breast cancer, the improvement in survival observed in unselected surgical series for cancer metastatic to the brain. Importantly, several studies have shown that, when all lesions can be treated surgically, there is no difference in survival time between those who have single brain metastases and those with multiple brain metastases74, 87. The most important variables in extending survival appear to be receiving WBRT after surgical resection, the absence of LMD, age, preoperative neurological status, and preoperative systemic disease status87, 88.

Radiosurgery There have been only two reports to date speciﬁcally looking at SRS for treatment of breast cancer brain metastases. One is a cohort of 30 patients who were treated with single fraction Gamma Knife SRS at the University of Pittsburgh89. Median survival in these patients was 13 months, but this heavily selected group had a very small median tumor volume (4 cm3), and prior WBRT treatment had failed in 26 of 30 patients. A series of 60 patients who underwent fractionated radiosurgery for brain metastases from breast carcinoma had a median survival time of 7.5 months90. Although the survival was shorter, 30% of patients in this less highly selected group had > 6 brain metastases, and 50% had treatment volumes of > 10 cm3. These two studies mirror the SRS results from unselected series. Such studies have median survival times of 6.5 to 10 months and have been used to suggest that SRS treatment of metastatic brain lesions from breast cancer is equivalent to, and less costly than, surgical treatment followed by WBRT91, 92. Although the cost-beneﬁt analyses in these papers are suspect in terms of their methodologies, they do suggest that for selected patients who have brain metastases from breast cancer, especially metastases with diameters of less than 2 cm, that SRS is a viable treatment option with long-term results approaching that of surgery plus WBRT.

Chemotherapy and hormonal therapy Although multiple reasons exist for the failure of chemotherapy in treating CNS metastases, several studies have reported the response of brain metastases from breast cancer to systemic chemotherapy93, 94. The existence of the blood-brain barrier, the relative chemoresistance of metastatic tumors, and the likely previous exposure of these tumors to effective therapeutic agents would suggest that systemic chemotherapy is doomed to failure. However, there are important theoretical reasons to consider chemotherapy for these patients. First, the vast majority of these metastases are metachronous. The appearance of a new CNS metastasis suggests the presence of active systemic disease even when imaging studies do not ﬁnd evidence of new extracranial metastases. Conﬁning aggressive treatment to the CNS theoretically risks the occurrence of future CNS metastases distant from those treated with surgery and/or SRS.

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Fortunately, some CNS metastases from breast cancer are ER/PR positive. In the Sloan Kettering series of 70 surgical patients, the median survival time for those whose resected tumors were positive for hormonal receptors was 21.9 months versus 12.5 months for those whose brain lesions were ER/PR negative87. This suggests that a number of breast cancer patients with CNS metastases may beneﬁt from hormonal modulation.

Future directions Multiple therapeutic agents are becoming available that may beneﬁt patients with intracranial breast cancer metastases. EGFR antagonists, Ras pathway inhibitors, and angiogenesis inhibitors will probably be available to patients within several years. Unfortunately, many of them will still be of limited use because of the blood-brain barrier and resistance to these agents in tumors that metastasize. Local drug delivery systems with biodegradable polymers have proved efﬁcacious in extending the survival of animals who have experimental brain metastases from breast cancer95. New methods of drug delivery (including convection-enhancement) may help solve some of these difﬁculties and broaden the spectrum of agents available for these patients.

Summary Intracranial metastasis remains an important type of treatment failure in therapy for breast cancer. Increasing evidence suggests that aggressive treatment of CNS metastases with SRS or surgery plus WBRT vastly improves life expectancy of patients having such metastases. Although the ultimate survival of these patients is frequently complicated by CNS relapse, the majority of deaths in aggressively treated intracranial metastasis from breast cancer continue to occur from progressive systemic disease. Clearly, improvements in the systemic treatment of breast cancer will play an important role in any improvements in the quality and length of life for patients with intracranial breast cancer metastases.

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CHAPTER 14

Management of brain metastasis in malignant melanoma patients Andrew A Kanner, Gene H Barnett

Introduction Malignant melanoma is the third most common cause of brain metastasis, exceeded in most series only by lung and breast malignancies1, 2. Its importance as a source of neurological morbidity and mortality is compounded by an apparent increase in the incidence of both the systemic disease and brain involvement. Complicating this situation is the poor prognosis traditionally associated with malignant melanoma once it has metastasized to the brain. New approaches to the management of malignant melanoma metastatic to the brain often improve the outlook for affected patients and offer new hope. For example, aggressive treatment of these brain lesions often leads to extended local control. In this chapter we review the natural behavior of these tumors as well as the rationale, results, and strategies for the current treatment of this disorder.

Background Cutaneous melanoma The incidence of malignant melanoma (MM) is rising faster than that of any other malignancy in the United States (US)3, 4. Currently, the risk of developing MM is one in 74 for Americans during their lifetime. As the incidence has increased exponentially, the mortality rate has also risen by 2% annually. In the year 2000, it is estimated that 7,700 persons will die from MM in the US. Malignant melanoma is the third most common malignancy in Australia and comprises more than 10% of all cancers there5. Two-thirds of the melanoma occurring in Caucasians worldwide is attributed to ultraviolet (UV) radiation from the sun. Various reasons for the increasing incidence of MM have been proposed, but most relate to increased UV exposure due to the thinning of the atmospheric ozone layer or because people use topical UV blocking agents that provide insufﬁcient protection. Although the direct correlation of sun exposure and the incidence of MM is well-documented, the exact mechanism by which it contributes to the genesis of MM remains poorly understood6. 245

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Brain metastases from malignant melanoma Demographics Brain metastases are a common and often fatal complication in patients affected by cutaneous malignant melanoma. The diagnosis of central nervous system (CNS) involvement is established clinically in 12–60% of these patients, whereas the prevalence at autopsy is higher, at 36–90%7, 8. CNS involvement is the ﬁrst manifestation of malignant melanoma in 9–12% of patients9. The rise in the overall incidence of MM and improvements in controlling systemic disease (leading to long-term survivors) are thought to be responsible for the observed increase in brain involvement. The survival time of patients is directly related to the stage of the disease at diagnosis. In patients with early melanoma stages (deﬁned as lesions thinner than 1 mm), the ﬁve-year survival rate is 94%, whereas it is less than 50% in those with tumors thicker than 3 mm at the time of detection10. Remarkably, the overall 5-year survival rate has increased signiﬁcantly when comparing the periods 1974 to 1976 and 1989 to 1995 (80% and 88%, respectively, p < 0.05)4. The average age of presentation of patients with brain metastasis from MM is about 48 to 53 years, which is similar to that of patients with extracerebral metastasis11, 12. Three percent of cases occur in patients younger than 21 years old. The clinical behavior and natural history of the disease in these pediatric patients are similar to those seen in adults11, 13. A male predominance for cerebral metastasis of 52 to 64.3% is observed for MM patients1, 7, 11. At diagnosis, neurological symptoms and signs may be focal (40%) or nonfocal (25–50%) and often include seizures1, 7, 11. The pattern of presentation is unrelated to the number of brain metastases11. Metastasis to the brain occurs relatively late in the time course of malignant melanoma compared with lung carcinoma (3 months). The median interval between diagnosis of MM and cerebral metastasis is reported to be about 2.2 to 3.8 years (range, 2–120 months)1, 11, 14 –16. Eighteen percent of cerebral metastases from MM occur in the ﬁrst year, with the longest intervals reported being 18–29 years14, 15. The primary tumor site appears not to correlate with development of brain metastasis1, 17.

Biology of melanoma metastases to the brain The development of a metastasis depends on a series of sequential, interrelated events. This multistep process contributes to the survival and growth of a subpopulation of cells with metastatic potential. Angiogenesis is but one of multiple factors involved in this stage, as it is required to establish a sufﬁcient vascular network to sustain the expanding mass18. Seventy percent of MM metastases express melanoma cell adhesive molecule (MCAM) on their cell surfaces. This molecule is a mediator in the cell-to-cell/cell-to-matrix interaction, is an important predictor of metastatic potential, and seems to play a role in organ homing19–21. MCAM, however, represents only part of a more complex process, as several other intracellular

Management of brain metastasis in malignant melanoma patients 247

adhesive molecules and surface proteins have been identiﬁed (HLA-DR, GD2, GD3, and Mr 55,000), but the frequent absence of one or more of these factors suggests the involvement of additional mechanisms, too22, 23. Studies have shown that MM progression is associated with loss of c-KIT proto-oncogene expression. C-KIT receptors are involved in mediation of apoptosis. The loss of these receptors may lead to uncontrolled growth and contribute to further metastatic potential24, 25. Hematogenous propagation is believed to be the principal mechanism of systemic metastasis11. Thin-walled venules are postulated to provide the pathway for tumor cells into the circulation, but only about 0.1% of these embolic tumor cells survive to form metastases8, 26. Typically, metastatic cells invade the ﬁrst two zones of the blood-brain barrier (BBB)athe capillary endothelium and the basal membrane. Neutrophins are important factors in this process21. Thereafter, they establish interaction with astroglial cells. Several factors in this process have been identiﬁed that contribute to colonization. Cell surface receptors (p 75 NTR) appear to play a role in this process of establishment. Recently, heparanase (derived from astrocytes) has been shown to contribute to metastatic growth as soon as the BBB is violated and may also be a factor in the process of parenchymal invasion27. Organ-derived growth factors have been isolated that stimulate metastatic cell growth. It was shown that such transferrin-like glycoproteins act as mitogens. Tumor cells that metastasize to the brain express transferrin receptors in higher concentrations than tumor cells in other organs21. These ﬁndings suggest an inﬂuence of microenvironment on the biological behavior of tumor cells. Two mechanisms may account for the observation that brain metastases occur relatively late in the course of malignant melanoma. One explanation is that brain involvement is the result of a late metastatic event from another distant metastasis and represents the end of a metastatic cascade. An alternate mechanism is that, although the metastatic event occurs relatively early in the course of the disease, relatively slow growth of these deposits results in delayed appearance of a macroscopic tumor. The latter theory is supported by in vivo studies showing that MM cells from brain metastases tend to proliferate at a slower rate and exhibit lower metastatic potential8.

Location of metastasis The distribution of these melanoma metastases throughout the brain is proportionate to the contribution of the region to total central nervous system volume: Frontal lobe (22–36%), parietal (26.4–45%), temporal (18.9%), occipital (10.6%), cerebellum (5–7%), and brainstem (0.9%). On rare occasions, the spinal cord may be involved. Leptomeningeal invasion or melanomatous meningitis may also occur. About 75% of the lesions are found at the junction of the gray and white matter. With improvement in neuroimaging studies, most lesions are small at diagnosis7, 11. Initially, a single metastasis is found in 20–60% of cases7, 11, 12.

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The number of brain metastases and prevalence of CNS involvement may have been underestimated in the pre- and early-MRI eras11. Melanoma metastatic to the brain has a tendency to bleed, which may contribute to the onset of symptoms. In a series of 91 patients treated surgically for metastatic melanoma, bleeding was seen radiographically in 37.4% of metastases preoperatively, and signs of old hemorrhage were found in 25.3% of additional metastases28.

Imaging characteristics The imaging characteristics of malignant melanoma metastatic to the brain are quite variable. An appreciation of the spectrum of appearances may lead to earlier consideration of melanoma as the primary source of the tumor.

Computed tomography (CT) scanning The appearance of melanoma on nonenhanced computed tomography (CT) images is usually hyperdense (75%), with hypodense and isodense presentations accounting for only 22% and 3%, respectively29. The administration of a contrast agent to the patient results in a CT image with homogeneous nodular or ring enhancement29, 30. CT scanning has proved to be a good method for screening larger lesions (> 15 mm in maximum diameter), as well as for detecting tumoral hemorrhage and edema. CT scanning itself, however, is insufﬁcient to exclude intracranial disease or to determine the absolute extent of CNS involvement17.

Magnetic resonance (MR) imaging and other modalities The observation that magnetic resonance (MR) imaging (both with and without gadolinium) is generally more sensitive than CT scanning for the detection of most metastatic neoplastic diseases is also true for melanomas metastatic to the brain31, 32. MR imaging is particularly useful for detecting multiple and/or smaller lesions. Edema and hemorrhage are commonly observed features; tumoral cyst formation, however, is rarely seen33, 34 (Figure 14.1). Classic MR imaging ﬁndings for MM are unusual for brain metastases as there is shortening of T1-weighted and T2-weighted signals, resulting in hyperintensity (T1) and hypointensity (T2) in nonenhanced images30, 35. Stable free radicals within melanin pigment are thought to be responsible for the paramagnetic effect causing this characteristic MR pattern. Blood and its degradation products due to tumor-associated hemorrhage may also contribute to these signal alterations32. Detailed comparative studies correlating the melanin content of these lesions with the MR imaging characteristics have been conducted33, 36. It was found that only a minority of melanoma lesions (25%) presented with this classic melanotic MR pattern. Histopathological examination, however, showed that for most tumors, more than 10% of cells contained melanin and that the percentage of melanin-containing cells correlated with the image intensity.

Management of brain metastasis in malignant melanoma patients 249

(A)

(C)

(B)

(D)

Figure 14.1 (A) Axial T2-weighted MR image without contrast obtained in a patient with metastatic melanoma, showing a right postcentral melanoma metastasis, hypointense, and with perifocal edema. (B) Contrast-enhanced axial T1-weighted MR image obtained in a patient with metastatic melanoma, showing a right occipital cortical melanoma metastasis (inhomogeneously enhancing) and a deep-seated metastasis (homogeneously enhancing). (C) Contrast-enhanced axial T1-weighted MR image obtained in a patient with metastatic melanoma, showing a small left frontal metastasis with some enhancement. (D) Saggital T1-weighted MR image without contrast obtained in the same patient as in (A) showing a right postcentral melanoma metastasis, hyperintense, with a classic melanotic appearance.

The administration of an intravenous contrast agent to the patient typically resulted in either peripheral rim enhancement or inhomogeneously diffuse patterns of enhancement on the MR image of the brain lesion. Other radiographic imaging modalities (positron emission tomography [PET] with 18F-ﬂuorodeoxyglucose or 123I-iodoamphetamine scintigraphy) usually do not play a role in the diagnosis and imaging of malignant melanoma metastatic to the brain37–39. When used, they are capable of indicating hypermetabolism and partial disruption of the blood-brain barrier.

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Survival At present, no reliably curative treatment for brain metastasis from MM is available, and thus, the disease is almost always fatal. The aggressive metastatic potential of MM is well known (particularly to the lymph nodes, lungs and brain) and is an important contributor to this poor prognosis2, 7, 40. A patient’s disease-free interval prior to the occurrence of distant metastasis was found to be a signiﬁcant predictor of outcome41. Brain metastasis, causing neurological deterioration, has been identiﬁed as a major cause of mortality in the overall MM patient population4, 7, 41. The traditionally pessimistic view of the prognosis of these patients is reﬂected in historical survival statistics. Untreated patients with MM brain metastases have a median survival time of only a few weeks to two months, whereas the overall median survival time for treated patients with brain metastases of any type is four to seven months12. Survival percentages after diagnosis at one month, three months, six months, and 12 months are 75%, 53%, 32%, and 15%, respectively11. The prognosis is even worse in MM patients with disseminated disease or active systemic involvement. Patients with both brain and lung metastases have a median survival time of only 3.1 months11. In patients with metastatic melanoma, there was a fourfold difference in median survival time between different sites of primary metastasis, with the longest survival being found with skin or lymph node metastases (15 months) and the shortest survival with brain or liver lesions (4 months)41. Some factors associated with increased incidence of developing brain metastases (male gender, primary lesion on head, neck or mucosae) do not, in themselves, correlate with survival12. In general, survival for MM patients is directly related to early detection of the primary lesion.

Therapy Despite major advances over the last two decades in diagnosis, neuroimaging, neurosurgical technique, and adjuvant therapy for malignant melanoma metastatic to the brain, the cure for this disorder remains elusive. For the majority of patients with CNS involvement, treatment is largely palliative. The principal cause of death is the tumor’s resistance to conventional therapies, resulting in local recurrence at the resection site as well as disseminated growth at multiple sites within and outside the CNS8. Accurate tabulation of each patient’s characteristics and a good systemic work up for actual staging of the systemic disease are necessary. The age, neurological performance level (Karnofsky Performance Scale score [KPS]), and desires of the patient and his family should be the basis for decisions leading to an individual therapy strategy42 (Tables 14.1 and 14.2).

Radiotherapy Traditionally, the survival of patients with a tumor metastatic to brain has been limited predominantly by the progression of the CNS disease. Recent

Management of brain metastasis in malignant melanoma patients 251 Table 14.1 Factors inﬂuencing decision-making. Factor

Aggressive approach

Extent of systemic disease Number of CNS lesions Resectability of lesion Suitability for radiosurgery Karnofsky Performance Status Age

None 1 Good Good Excellent Young

Palliation Limited 2–4

Fair (60 years)

Extensive >4 Poor Poor Poor Elderly

Table 14.2 Primary therapeutic approach. 1. Stabilization 2. Neuroimaging/Staging 3. Treatment of edema (steroids) 4. Seizure prophylactics 5. Deﬁnitive Therapy: Surgery, Radiation, Radiosurgery, Chemo-/Immuno-therapy

trials, however, have shown that control of CNS metastases using whole-brain radiotherapy (WBRT) alone does not necessarily lead to signiﬁcantly prolonged survival. In a prospective randomized study, Patchell et al. demonstrated the efﬁcacy of surgical resection of solitary brain metastases followed by WBRT relative to that of WBRT alone43. In other trials44, the efﬁcacy of postoperative WBRT was examined, showing signiﬁcantly less recurrence at the original site than in those untreated (5 of 49 [10%] patients versus 21 of 46 [46%] patients) as well as less remote treatment failure in the brain (7 of 49 [14%] patients versus 17 of 46 [37%] patients). The timing of postoperative WBRT showed that there was no reduction in death from neurological causes in patients receiving WBRT only at recurrence of brain metastasis and not immediately postoperatively after the ﬁrst resection. Patients who received postoperative WBRT were also less likely to die from progression of CNS metastases than those who did not (6 of 43 [14%] patients versus 17 of 39 [44%] patients), but there was no survival beneﬁt from WBRT in the Patchell study44, whereas Noordijk et al.42 found prolonged survival in a group of patients treated with WBRT after surgery.

Whole-brain radiotherapy WBRT is considered the “gold standard” treatment for cancer metastatic to the brain and is, therefore, the most common therapy43, 45, 46. Numerous prospective and retrospective studies have shown an overall moderate prolongation of patient survival time from WBRT compared with no irradiation or with steroid therapy alone47. Also, symptom relief is often immediate. Although MM is considered to be a relatively radioresistant malignancy, it can be controlled by sufﬁciently high doses of radiotherapy, as seen in anatomic regions tolerant of these doses, such as soft tissue or bone14, 48, 49.

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Unfortunately, lower doses must be applied in the brain because of its more limited radiation tolerance, thereby mitigating the beneﬁt of WBRT for MM metastatic to the brain50. In the early 1970s, the Radiation Therapy Oncology Group (RTOG) conducted randomized trials that helped deﬁne the optimal dose fraction schemes for WBRT45, 46. WBRT was delivered in 10 to 20 fractions of 1.28 to 6 Gy for total doses of up to 30 to 60 Gy2, 12, 14, 48, 51. No difference in duration of therapeutic response or overall survival of patients was found in comparing the different protocols51, 52. Analysis of 60 patients with MM brain metastases in the RTOG studies revealed a median survival time of 10 to 14 weeks after WBRT53. It was observed that neurological improvement in patients after undergoing WBRT tends to be associated with a longer survival time15. Whole-brain radiotherapy has been shown to have additional positive effects on outcome when combined with surgery or radiosurgery (see below)44, 47, 52. In a retrospective study, Hagen et al. showed that postoperative radiation therapy signiﬁcantly delayed the time to CNS relapse after gross total resection for single metastases52. The rationale for WBRT as postoperative adjuvant therapy is the elimination of possible residual microscopic disease in the tumor bed or elsewhere in the brain parenchyma7, 14, 52. Sadly, the median survival time for patients with MM brain metastases treated with WBRT alone is on the order of 3 to 4 months (98–141 days)11, 47. Also, WBRT may produce substantial delayed complications. A signiﬁcant number of long-term survivors develop neurobehavioral sequelae, but disturbances to memory may occur soon after treatment54. As patients tend to survive longer, the effects of radiation-induced neurotoxicity become more evident50. The role of radiotherapy remains controversial, despite a number of randomized prospective trials and several retrospective studies7, 47, 52, 53. This has led to a recent tendency to withhold WBRT, especially in patients having surgically or radiosurgically treated solitary metastases. As a singular treatment modality, WBRT is reserved for patients with a low KPS score, extensive systemic disease, and contraindication for other treatments.

Surgery The feasibility of surgical resection of brain metastases has been improved in recent years. Advances in neuroimaging provide the neurosurgeon with better anatomic and functional brain visualization. The use of minimally invasive techniques and modern navigation methods helps to reduce surgical morbidity. As such, the option of surgery can now be extended to a larger patient population than in the past. Surgical morbidity and mortality for brain metastases have decreased from 7 and 27% to 0 and 5.4%, respectively, as reported for the 1980s and the 1990s28, 55 –59. Even early studies show some improvement in survival of patients with completely resected metastases, but not in those with partially resected tumors16. However, as different studies use various inclusion criteria for their patients, interpretations and comparisons should be made with caution.

Management of brain metastasis in malignant melanoma patients 253

Single brain metastases It is clear that surgical resection of a single brain metastasis (combined with radiotherapy and steroids) in general, and of a metastasis from malignant melanoma in particular, extends survival compared with radiotherapy or steroid administration alone1, 15, 42, 43, 55, 59 – 62. Retrospective reports and prospective, randomized trials comparing surgery with and without radiotherapy for single brain metastases have shown a prolonged interval prior to CNS relapse but little impact on overall survival44, 63 – 65. Based on this information, some centers no longer routinely perform WBRT after resection of single brain metastases, including those from MM. Recent prospective, randomized studies have shown that survival time in patients with completely resected single brain metastases is related to the extent of their extracerebral tumor burden and age. With more aggressive treatment of cerebral metastases, 50 to 90% of patients ultimately succumb to progression of their systemic disease42, 44, 66. The role of surgery for patients with multiple brain metastases remains poorly deﬁned. For years, the presence of multiple and recurrent cerebral metastases in a patient contraindicated surgical treatment67. In such cases, steroid administration, irradiation, or chemotherapy (alone or in combination) were offered. This approach to management has changed in the last decade68, 69.

Multiple and recurrent metastases Aggressive surgical and combined approaches are no longer restricted to solitary brain metastases. Retrospective reviews showed comparable survival in patients with single and multiple brain metastases when the lesions were resectedaespecially in younger patients69. Reoperation (and even second reoperation) for multiple brain metastases has been reported to prolong survival and improve quality of life70. The patient’s systemic disease status, neurological performance status (KPS score), time to tumor recurrence, and type of primary malignancy (lung versus breast or melanoma) were determined to correlate with survival time and served as guidelines for decision-making. In this particular study, focused on the issue of reoperation, no perioperative morbidity or mortality was noted. The outcome after reoperation was found to be similar to the prognosis after initial surgeryaan 11.5 months’ median survival compared with 10 to 13 months for patients who underwent resection of a single metastasis55, 59, 70. The number of metastases, however, does adversely affect the overall prognosis. As such, resection should be considered a realistic treatment option in patients with multiple or recurrent lesions, especially for large, symptomatic, and surgically excisable tumors68, 70.

Patient selection Patient selection guidelines for surgical resection of brain metastases are controversial9, 62, 68. However, patients with a single brain metastasis and with controlled or absent extracranial disease and a good neurological performance

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level are generally considered candidates for maximal therapy42. Although prolonged survival is possible in rare cases, palliation and improved quality of life are the best outcomes of therapy in the majority of patients, rather than cure65.

Radiosurgery Conventional radiotherapy exploits the differential repair capacity between normal and tumor tissues by delivering a series of radiation treatments wherein both tissues receive similar doses at intervals aimed to allow the repair of normal, but not tumor, tissues. In contrast to WBRT, stereotactic radiosurgery (SRS) delivers a comparatively high dose of radiation in a single session to a deﬁned intracranial volume while using a rapidly falling radiation dose gradient. This gradient is planned to be at the tumor margin or edge, thereby minimizing risk of damage to normal adjacent brain tissue. With this technique, a much higher dose delivery is possible than with conventional radiotherapy. Melanoma metastases to the brain are often optimal targets for SRS as they are typically small in volume, spherical and have limited brain invasiveness71, 72. Several recent studies have proved the efﬁcacy of SRS in achieving local tumor control, regardless of the primary tumor’s histology73, 74. Indeed, “radioresistant” tumors (e.g., melanoma, renal cell carcinoma) have SRS control rates equivalent to those of radiosensitive lesions73. The median survival rate for melanoma metastases treated with SRS is about 3 to 9.3 months, with a more favorable survival time for patients having a single metastasis (8.8 to 9.3 months) than for those with two lesions (3.5 to 8.3 months)75, 76. The local control (deﬁned as disappearance, shrinkage, or no progression of the tumor) rate for the reported follow-up period was 90 to 100%74, 77–79. Reports of median survival time and local control are dependent, in part, on the fraction of patients with multiple metastases within a given study group. Mori et al. showed no local recurrence when treating with a dose of > 17 Gy at the tumor edges72. The overall tumor volume seems to be the limiting factor with regard to response, as with greater tumor burden, the treatment dose is usually reduced and local control suffers. Procedure-related complications from SRS are mostly transient and include: nausea, vomiting, dizziness (in 5 to 6% of patients), deterioration of preexisting neurological symptoms, and seizures (in 1.6 to 8.8% of patients)72, 79. Some authors recommend the administration of prophylactic anticonvulsants to patients prior to SRS treatment51. The prescription of radiation dose for SRS should be in accordance with the tumor volume. To prevent damage to normal brain tissue, the prescribed dose should be selected based on the predicted dose-response relationship for brain necrosis of 3%80. In a randomized trial, Shaw et al. deﬁned safe SRS dose limits for patients who had previously received WBRT81. The beneﬁt of using WBRT in addition to SRS for a single melanoma metastasis is unclear,

Management of brain metastasis in malignant melanoma patients 255

Figure 14.2 Gamma Knife plan for treatment of a left occipital melanoma metastasis. Displaying isodose lines on a MR volume study.

although the realization of some beneﬁt has been suggested82 (Figure 14.2) and (Table 14.3). Mori et al. did not ﬁnd any improvement in survival or local tumor control in MM brain metastasis patients receiving SRS combined with WBRT compared with those receiving SRS alone72. Although there was a trend for fewer new brain metastases in patients treated with both modalities (23% versus 44% in those receiving SRS alone), it was not statistically signiﬁcant. Only 7% (four patients) died from CNS tumor progression72. Fuller et al., however, demonstrated in a very limited number of patients that the combination of WBRT and SRS was statistically superior to SRS alone in terms of local tumor control83. A randomized trial of SRS versus SRS + WBRT is needed to assess survival and prognosis84. Both retrospective and prospective trials have found survival beneﬁt for SRS and WBRT versus WBRT alone. This was true for multiple as well as for single metastases85. The use of SRS for treatment of patients having two brain metastases (including MM metastases) appears to result in a survival time identical to that achieved by using SRS for single brain metastases. The presence of multiple lesions, however (i.e., 3 or more), and poor neurological performance status have a strong, negative impact on patients’ survival73, 75.

Table 14.3 Retrospective studies on malignant melanoma brain metastases, treated with stereotactic radiosurgery (Gamma Knife). ExtraCNS

Complications

1 of 19 0.5%

97%

transient 13% seizures 0% delayed 0%

85%

4 of 60 7%

85%

transient 5% seizures 1.6% delayed 7%

49%

15 of 55 27%

89% at 6 months 77% at 1 year

transient 7% seizures 3.6% delayed 9%

4%

2 of 26 7.7%

97% median

transient 6.7% seizures 8.8% delayed 0%

Median survival

f/u

WBRT

21 32 17.4% multiple (91%)

2.5 cc mean 0.26–7.5 cc

7 months after SRS 9 months after DI of brain metastases 3–38 months 1 y survival: 26%

12 months mean

100%

118 40% multiple

36 (60%)

2.95 cc mean 0.1–25.5 cc

7 months after SRS 10 months after DI of brain metastases 1 y survival: 21% 2 y survival: 11%

9.6 months mean

55

140 62% multiple

49 (89%)

6.1 cc median 0.25–28.3 cc

8.75 months after SRS 18.8 months median 1 y survival 34%

45

93 31% multiple

35 (77.7%)

5.6 cc mean

8 months after SRS (1–20 months)

Pat Metastases

Somaza et al.74

23

Mori et al.72

60

Seung et al.76

Lavine et al.79

12 months median

Neurologic deaths

l/c

TTV

Study

Pat, number of patients included; Extra-CNS, number (percentage) of systemic metastases; TTV, treated target volume; f/u, follow-up interval; WBRT, percentage of patients treated with whole-brain radiotherapy; l/c, local control; SRS, stereotactic radiosurgery; DI, diagnosis; neurologic deaths, deaths from neurological causes.

Management of brain metastasis in malignant melanoma patients 257

Medical therapies Chemotherapy Most trials involving malignant melanoma and chemotherapy have excluded patients with brain involvement86 – 88. Dacarbazine (DTIC) is the only drug currently licensed by the Federal Drug Administration (FDA) for MM therapy 89. When this drug is used as a single agent against MM, a 20% response rate is observed with a median response duration of 5 to 6 months90. No single chemotherapeutic agent has proved to produce response rates greater than 10 to 20%, with a median duration of only 4 to 5 months in patients with systemic MM91. The mechanism of chemoresistance in MM is not clear, although impaired apoptotic mechanisms seem to play a role92. Still under investigation are multidrug protocols such as CBDT (DTIC, carmustine [BCNU], cisplatin, tamoxifen). Patients with systemically disseminated MM showed better response rates (52%) with CBDT treatment than with DTIC alone in smaller studies93. A recent randomized phase III trial, however, failed to demonstrate a statistically signiﬁcant difference in survival time between these two protocols94. Early CNS failure is thought to be responsible for the lack of survival advantage with CBDT treatment. A retrospective review61 demonstrated prolonged survival in patients receiving combined chemotherapy for MM metastasis to the brain (BCNU, DTIC, vincristine, procarbazine, cisplatin). A mean survival time of 11 weeks (2.75 months) was found. The necessity for adjuvant therapy after surgery was stressed. The authors suggested conducting a prospective randomized trial to compare surgery and WBRT with surgery and chemotherapy61. Intraarterial cisplatin-based chemotherapy was administered to 23 patients, most of whom had undergone previous irradiation and/or surgery for brain metastases from MM. Seven (30%) of the patients showed objective radiological improvement, the time to tumor progression was 8 to 34 weeks, and median survival time was 15 weeks. Middleton et al. compared the use of DTIC plus αinterferon with combination chemotherapy in a prospective, randomized fashion for treatment of advanced MM; no signiﬁcant difference in response rate (17.3% and 26.4%, respectively) or overall survival (199 days and 202 days, respectively) was demonstrated95. However, because of severe hematologic side-effects in the group receiving combination chemotherapy that necessitated prolonged hospitalization, DTIC was favored. In another report, seven of 15 (47%) patients with brain metastases from MM showed partial, but incomplete, responses to chemotherapy, with a median survival time of 6.5 months96. This small, nonrandomized and selected (no steroids administered) group was treated with chemotherapy combined with interleukin-2 and α-interferon. In similar patients, others have reported response rates with CBDT treatment of up to 55% and a complete response duration of up to 82 months90. A prospective randomized trial for front-line chemotherapy (cisplatin/ etoposide) did not achieve objective response in MM brain metastasis patients97.

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Twenty-ﬁve percent of patients (9 of 36) with brain metastases from MM responded to treatment with the nitrosourea fotemustine in a French multicenter phase II study98. The median duration of response was 22 weeks. The most promising new agent for brain metastases from malignant melanoma is temozolomide. Because it is taken orally, is generally well tolerated, has good BBB penetration (CSF level is 30 to 40% of the concentration seen in the plasma), and is metabolized to DTIC, it is suitable for upcoming trials for MM brain metastasis. Its role in future prevention and/or treatment of brain metastases is yet to be deﬁned87, 99.

Chemotherapy and WBRT Patients with multiple brain metastases not suitable for surgery may be treated with chemotherapy and adjuvant WBRT100. In this very limited study, seven of 12 patients experienced partial remission or stabilization, with a median survival time of six months. Severe hematological side effects were, however, common (in six of 13 patients). The addition of chemotherapy to radiation may not improve survival but can increase morbidity and mortality101.

Immunobiotherapy Melanoma is known to be one of the more immunogenic solid tumors and, as such, has served as a model for tumor vaccine investigation. In vivo, however, tumor cells tend to escape immune recognition102. Nonetheless, various types of immunotherapeutic approaches have been developed, with moderate clinical success. For example, the use of autologous tumor cells, inactivated by irradiation, as a vaccine produced a 12.5% response rate in patients with systemic MM103. The main limitation of immunotherapy for MM, as practiced today, is CNS involvement104. Patients with brain metastases from MM are often excluded from immunological treatments because they are taking steroids (which inhibit components of the immune system), because they are at risk for intracerebral hemorrhage, and because of the immunologically privileged status of the brain96. Further, although results are promising in treating systemic or disseminated disease, patients with such brain metastases usually do not respond. A very limited number of responders, however, have been reported who had failed to respond to conventional therapies105. Prospective randomized trials comparing chemoimmunotherapy to DTIC alone in treatment of systemic MM have failed to show either treatment to be superior, with just a few patients enjoying long-term beneﬁt from therapy86, 88. Only the 5% of MM patients with systemic dissemination who produce antibodies against cell surface glycolipids (gangliosides) experience prolonged survival when treated with immunotherapy105, 106. Unfortunately, patients responding to immunotherapy and/or IL-2 combined with chemotherapy trials often live long enough to develop CNS involvement and must discontinue their investigational treatment.

Management of brain metastasis in malignant melanoma patients 259

Anticonvulsants Prophylactic anticonvulsive therapy is recommended by some at diagnosis of brain metastases from MM. The rationale is the high incidence of seizures in affected patients and the concern of increased risk of seizure as the result of tumor treatment52, 107, 108.

Conclusions Melanoma metastatic to the brain continues to present a formidable challenge to the neuro-oncology team64. Over the past decades, dozens of studies analyzing prognostic factors in patients with metastatic disease have been reported71. Improvements in radiographic imaging and neurosurgical technique, as well as broader use of radiosurgery, have been applied to this disorder, producing beneﬁt to patients in certain cases. Future approaches will no doubt rely on the results of ongoing studies, with the aim of improving the rate of control of brain metastases from MM and prolonging survival time of good quality in patients. At present, many unanswered questions remain. For the clinician, 60 to 70% of patients with 1 to 3 metastases could be potential candidates for some form of focal CNS therapy11. Recent studies suggest that SRS may be used as an alternative or a ﬁrst-line treatment for deep-seated metastases and/or for those located in eloquent brain regions. The outcomes of patients with single metastases who undergo either surgical resection or stereotactic radiosurgery appear similar. To date, the optimal treatment is not known. There is a need for prospective trials comparing surgically suitable patients in a randomized fashion for treatment by surgery or radiosurgery. Also, the role of WBRT in patients with solitary brain metastases after surgical or radiosurgical therapy needs to be resolved. Treatment strategies in patients who have multiple (four or more) metastases are less controversial. Aggressive surgical approaches have not proved to prolong survival, although in well-selected patients the quality of life may improve2, 109. There is a trend, however, in the recent literature for increasing the number of brain metastases treated wherein up to three are treated as aggressively as a solitary metastasis. With such an approach, the survival time might depend more on the systemic activity of the malignancy and the neurological performance level of the patient. Progress in CNS treatment makes the need for systemic treatment more demanding, as patients with well-controlled brain metastases experience death from systemic progression. Unless the extracranial disease can be controlled effectively, the CNS will be at risk of metastasis. Reseeding the CNS from systemic foci may contribute to intracranial failure of tumor control following complete resection and adjuvant radiotherapy. Also, the role of adjuvant chemotherapy using temozolomide has yet to be deﬁned.

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Acknowledgements The authors wish to thank Ms. Martha Tobin for her assistance in the preparation of this manuscript. Support for the report was from the John Gagliarducci Brain Tumor Research fund.

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Management of brain metastasis in malignant melanoma patients 261 21 Nicolson GL, Nakajima M, Herrmann JL, et al.: Malignant melanoma metastasis to brain: role of degradative enzymes and responses to paracrine growth factors. J Neurooncol 1994; 18: 139–149. 22 Boukerche H, Baril P, Tabone E, et al.: A new Mr 55,000 surface protein implicated in melanoma progression: association with a metastatic phenotype. Cancer Res 2000; 60: 5848–5856. 23 Edward M: Integrins and other adhesion molecules involved in melanocytic tumor progression. Curr Opin Oncol 1995; 7: 185 –191. 24 Huang S, Luca M, Gutman M, et al.: Enforced c-KIT expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential. Oncogene 1996; 13: 2339 –2347. 25 Natali PG, Nicotra MR, Winkler AB, et al.: Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptor. Int J Cancer 1992; 52: 197–201. 26 Fidler IJ: Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I–5-iodo–2’-deoxyuridine. J Natl Cancer Inst 1970; 45: 773 –782. 27 Marchetti D, Li J, Shen R: Astrocytes contribute to the brain-metastatic speciﬁcity of melanoma cells by producing heparanase. Cancer Res 2000; 60: 4767– 4770. 28 Wronski M, Arbit E: Surgical treatment of brain metastases from melanoma: a retrospective study of 91 patients. J Neurosurg 2000; 93: 9 –18. 29 Weisberg LA: Computerized tomographic ﬁndings in intracranial metastatic malignant melanoma. Comput Radiol 1985; 9: 365 –372. 30 Dewulf P, Demaerel P, Wilms G, et al.: Cerebral metastatic malignant melanoma: CT and MR ﬁndings with pathological correlation. J Belge Radiol 1993; 76: 318 –319. 31 Davis PC, Hudgins PA, Peterman SB, et al.: Diagnosis of cerebral metastases: doubledose delayed CT vs contrast-enhanced MR imaging. AJNR Am J Neuroradiol 1991; 12: 293–300. 32 Woodruff WW Jr, Djang WT, McLendon RE, et al.: Intracerebral malignant melanoma: high-ﬁeld-strength MR imaging. Radiology 1987; 165: 209 –213. 33 Isiklar I, Leeds NE, Fuller GN, et al.: Intracranial metastatic melanoma: correlation between MR imaging characteristics and melanin content. AJR Am J Roentgenol 1995; 165: 1503–1512. 34 Reider-Groswasser I, Merimsky O, Karminsky N, et al.: Computed tomography features of cerebral spread of malignant melanoma. Am J Clin Oncol 1996; 19: 49–53. 35 Atlas SW, Grossman RI, Gomori JM, et al.: MR imaging of intracranial metastatic melanoma. J Comput Assist Tomogr 1987; 11: 577–582. 36 Premkumar A, Marincola F, Taubenberger J, et al.: Metastatic melanoma: correlation of MRI characteristics and histopathology. J Magn Reson Imaging 1996; 6: 190 –194. 37 Dietlein M, Krug B, Groth W, et al.: Positron emission tomography using 18Fﬂuorodeoxyglucose in advanced stages of malignant melanoma: a comparison of ultrasonographic and radiological methods of diagnosis. Nucl Med Commun 1999; 20: 255–261. 38 Tyler DS, Onaitis M, Kherani A, et al.: Positron emission tomography scanning in malignant melanoma. Cancer 2000; 89: 1019 –1025. 39 Watanabe N, Yokoyama K, Shuke N, et al.: Experimental investigation of I-123 iodoamphetamine in the detection of lung cancer. Lung Cancer 1999; 25: 1– 6. 40 Brand CU, Ellwanger U, Stroebel W, et al.: Prolonged survival of 2 years or longer for patients with disseminated melanoma. An analysis of related prognostic factors. Cancer 1997; 79: 2345–2353.

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41 Barth A, Wanek LA, Morton DL: Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Coll Surg 1995; 181: 193 –201. 42 Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al.: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994; 29: 711–717. 43 Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 44 Patchell RA, Tibbs PA, Regine WF, et al.: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998; 280: 1485 –1489. 45 Borgelt B, Gelber R, Larson M, et al.: Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: ﬁnal results of the ﬁrst two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981; 7: 1633 –1638. 46 Kurtz JM, Gelber R, Brady LW, et al.: The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981; 7: 891– 895. 47 Rate WR, Solin LJ, Turrisi AT: Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys 1988; 15: 859 – 864. 48 Katz HR: The results of different fractionation schemes in the palliative irradiation of metastatic melanoma. Int J Radiat Oncol Biol Phys 1981; 7: 907–911. 49 Katz HR: The relative effectiveness of radiation therapy, corticosteroids, and surgery in the management of melanoma metastatic to the central nervous system. Int J Radiat Oncol Biol Phys 1981; 7: 897–906. 50 Sundaresan N, Galicich JH, Deck MD, et al.: Radiation necrosis after treatment of solitary intracranial metastases. Neurosurgery 1981; 8: 329 –333. 51 Gaspar L, Scott C, Rotman M, et al.: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745 –751. 52 Hagen NA, Cirrincione C, Thaler HT, et al.: The role of radiation therapy following resection of single brain metastasis from melanoma. Neurology 1990; 40: 158 –160. 53 Carella RJ, Gelber R, Hendrickson F, et al.: Value of radiation therapy in the management of patients with cerebral metastases from malignant melanoma: Radiation Therapy Oncology Group Brain Metastases Study I and II. Cancer 1980; 45: 679 – 683. 54 Crossen JR, Garwood D, Glatstein E, et al.: Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 1994; 12: 627–642. 55 Brega K, Robinson WA, Winston K, et al.: Surgical treatment of brain metastases in malignant melanoma. Cancer 1990; 66: 2105 –2110. 56 Fell DA, Leavens ME, McBride CM: Surgical versus nonsurgical management of metastatic melanoma of the brain. Neurosurgery 1980; 7: 238 –242. 57 Ferrara M, Bizzozzero L, Talamonti G, et al.: Surgical treatment of 100 single brain metastases. Analysis of the results. J Neurosurg Sci 1990; 34: 303 –308. 58 Neuss M, Konig A, Herrmann HD: Intracranial melanoma metastases: surgical treatment and follow-up of 18 patients. Anticancer Res 1987; 7: 445 – 446. 59 Oredsson S, Ingvar C, Stromblad LG, et al.: Palliative surgery for brain metastases of malignant melanoma. Eur J Surg Oncol 1990; 16: 451– 456. 60 Byrne TN, Cascino TL, Posner JB: Brain metastasis from melanoma. J Neurooncol 1983; 1: 313–317.

Management of brain metastasis in malignant melanoma patients 263 61 Madajewicz S, Karakousis C, West CR, et al.: Malignant melanoma brain metastases. Review of Roswell Park Memorial Institute experience. Cancer 1984; 53: 2550 –2552. 62 Mendez IM, Del Maestro RF: Cerebral metastases from malignant melanoma. Can J Neurol Sci 1988; 15: 119 –123. 63 Mintz AH, Kestle J, Rathbone MP, et al.: A randomized trial to assess the efﬁcacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996; 78: 1470–1476. 64 Saha S, Meyer M, Krementz ET, et al.: Prognostic evaluation of intracranial metastasis in malignant melanoma. Ann Surg Oncol 1994; 1: 38 – 44. 65 Sundaresan N, Galicich JH: Surgical treatment of brain metastases. Clinical and computerized tomography evaluation of the results of treatment. Cancer 1985; 55: 1382–1388. 66 Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al.: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993; 33: 583 –590. 67 Hafstrom L, Jonsson PE, Stromblad LG: Intracranial metastases of malignant melanoma treated by surgery. Cancer 1980; 46: 2088 –2090. 68 Lang PG Jr: Malignant melanoma. Med Clin North Am 1998; 82: 1325 –1358. 69 Bindal RK, Sawaya R, Leavens ME, et al.: Surgical treatment of multiple brain metastases. J Neurosurg 1993; 79: 210 –216. 70 Bindal RK, Sawaya R, Leavens ME, et al.: Reoperation for recurrent metastatic brain tumors. J Neurosurg 1995; 83: 600 – 604. 71 Davey P, O’Brien P: Disposition of cerebral metastases from malignant melanoma: implications for radiosurgery. Neurosurgery 1991; 28: 8 –14. 72 Mori Y, Kondziolka D, Flickinger JC, et al.: Stereotactic radiosurgery for cerebral metastatic melanoma: factors affecting local disease control and survival. Int J Radiat Oncol Biol Phys 1998; 42: 581–589. 73 Alexander E 3rd, Moriarty TM, Davis RB, et al.: Stereotactic radiosurgery for the deﬁnitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995; 87: 34 – 40. 74 Somaza S, Kondziolka D, Lunsford LD, et al.: Stereotactic radiosurgery for cerebral metastatic melanoma. J Neurosurg 1993; 79: 661–666. 75 Joseph J, Adler JR, Cox RS, et al.: Linear accelerator-based stereotaxic radiosurgery for brain metastases: the inﬂuence of number of lesions on survival. J Clin Oncol 1996; 14: 1085–1092. 76 Seung SK, Sneed PK, McDermott MW, et al.: Gamma knife radiosurgery for malignant melanoma brain metastases. Cancer J Sci Am 1998; 4: 103 –109. 77 Auchter RM, Lamond JP, Alexander E, et al.: A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996; 35: 27–35. 78 Flickinger JC, Kondziolka D, Lunsford LD, et al.: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994; 28: 797–802. 79 Lavine SD, Petrovich Z, Cohen-Gadol AA, et al.: Gamma knife radiosurgery for metastatic melanoma: an analysis of survival, outcome, and complications. Neurosurgery 1999; 44: 59–64. 80 Flickinger JC, Lunsford LD, Kondziolka D: Dose prescription and dose-volume effects in radiosurgery. Neurosurg Clin N Am 1992; 3: 51–59. 81 Shaw E, Scott C, Souhami L, et al.: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: ﬁnal report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys 2000; 47: 291–298.

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82 Skibber JM, Soong SJ, Austin L, et al.: Cranial irradiation after surgical excision of brain metastases in melanoma patients. Ann Surg Oncol 1996; 3: 118 –123. 83 Fuller BG, Kaplan ID, Adler J, et al.: Stereotaxic radiosurgery for brain metastases: the importance of adjuvant whole brain irradiation. Int J Radiat Oncol Biol Phys 1992; 23: 413–418. 84 Sneed PK, Lamborn KR, Forstner JM, et al.: Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 1999; 43: 549 –558. 85 Kondziolka D, Patel A, Lunsford LD, et al.: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999; 45: 427– 434. 86 Atkins MB: The treatment of metastatic melanoma with chemotherapy and biologics. Curr Opin Oncol 1997; 9: 205 –213. 87 Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18: 158 –166. 88 Rosenberg SA, Yang JC, Schwartzentruber DJ, et al.: Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 1999; 17: 968 –975. 89 Cohen GL, Falkson CI: Current treatment options for malignant melanoma. Drugs 1998; 55: 791–799. 90 Serrone L, Zeuli M, Sega FM, et al.: Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res 2000; 19: 21–34. 91 Nathan FE, Mastrangelo MJ: Systemic therapy in melanoma. Semin Surg Oncol 1998; 14: 319–327. 92 Serrone L, Hersey P: The chemoresistance of human malignant melanoma: an update. Melanoma Res 1999; 9: 51–58. 93 McClay EF, Mastrangelo MJ, Berd D, et al.: Effective combination chemo/hormonal therapy for malignant melanoma: experience with three consecutive trials. Int J Cancer 1992; 50: 553–556. 94 Lattanzi SC, Tosteson T, Chertoff J, et al.: Dacarbazine, cisplatin and carmustine, with or without tamoxifen, for metastatic melanoma: 5-year follow-up. Melanoma Res 1995; 5: 365–369. 95 Middleton MR, Lorigan P, Owen J, et al.: A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer 2000; 82: 1158 –1162. 96 Richards JM, Gale D, Mehta N, et al.: Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. J Clin Oncol 1999; 17: 651–657. 97 Franciosi V, Cocconi G, Michiara M, et al.: Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 1999; 85: 1599 –1605. 98 Jacquillat C, Khayat D, Banzet P, et al.: Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases. Cancer 1990; 66: 1873–1878. 99 Agarwala SS, Kirkwood JM: Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncologist 2000; 5: 144 –151.

Management of brain metastasis in malignant melanoma patients 265 100 Brocker EB, Bohndorf W, Kampgen E, et al.: Fotemustine given simultaneously with total brain irradiation in multiple brain metastases of malignant melanoma: report on a pilot study. Melanoma Res 1996; 6: 399 – 401. 101 Feun LG, Lee YY, Plager C, et al.: Intracarotid cisplatin-based chemotherapy in patients with malignant melanoma and central nervous system (CNS) metastases. Am J Clin Oncol 1990; 13: 448 – 451. 102 Brinckerhoff LH, Thompson LW, Slingluff CL Jr: Melanoma vaccines. Curr Opin Oncol 2000; 12: 163–173. 103 Berd D, Maguire HC Jr, Schuchter LM, et al.: Autologous hapten-modiﬁed melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases. J Clin Oncol 1997; 15: 2359 – 2370. 104 Eton O, Talpaz M, Lee KH, et al.: Phase II trial of recombinant human interleukin-2 and interferon-alpha-2a: implications for the treatment of patients with metastatic melanoma. Cancer 1996; 77: 893 – 899. 105 Savas B, Arslan G, Gelen T, et al.: Multidrug resistant malignant melanoma with intracranial metastasis responding to immunotherapy. Anticancer Res 1999; 19: 4413 – 4420. 106 Schuchter LM. Melanoma and other skin neoplasms. Curr Opin Oncol 1997; 9: 175 –177. 107 Cohen N, Strauss G, Lew R, et al.: Should prophylactic anticonvulsants be administered to patients with newly-diagnosed cerebral metastases? A retrospective analysis. J Clin Oncol 1988; 6: 1621–1624. 108 DeAngelis LM, Mandell LR, Thaler HT, et al.: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 1989; 24: 798 – 805. 109 Hazuka MB, Burleson WD, Stroud DN, et al.: Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy. J Clin Oncol 1993; 11: 369–373.

CHAPTER 15

Brain metastases from renal cell carcinoma Fadi Hanbali, Jeffrey S Weinberg

Introduction Renal cell carcinoma (RCC) is the most common renal tumor, accounting for approximately 80% to 90% of adult kidney tumors and about 2% to 3% of all new cases of cancer diagnosis1– 4. Each year, 30,000 new cases in the USA and 20,000 in the European Union are detected5. The incidence of RCC has increased by more than 30% in the last decade. This increase may be attributed to environmental factors, better imaging techniques, and early diagnosis5, 6. Up to one-third of patients with RCC will have metastases at presentation7, 8. Metastatic RCC is one of the more therapy-resistant malignancies. Around 60% of the patients who are clinically diagnosed with RCC will die because of progressive disease and metastatic dissemination2, 9. Patients presenting with solitary metastases are considered candidates for resection, provided the primary tumor is resectable. This approach can provide a 5-year survival of 34% in highly selected patients10 –13.

Epidemiology The age-adjusted incidence rate of kidney cancer (per 100,000 persons) increased from 6.7 in 1973 to 9.0 in 1992 in the USA14. Males are affected twice as often as females, with the highest incidence in those aged 50–70 years5, 14, 15. The rates were also slightly higher in African American males than in white males. There were no differences in RCC rates between white and African American females. Several types of environmental and personal exposures have been identiﬁed as risk factors for kidney cancer. Diet has been suggested as a major factor in the etiology of RCC. Fried meat and poultry intake were associated with increased RCC risk, whereas protective effects were noted with frequent fruit and dark green vegetable intake. Consumption of vitamin C, vitamin E, and carotenoids was also found to have a protective effect against RCC14, 16 –20. Tobacco use has been linked to an increased risk of RCC, although the effects are moderate14, 21–26. Such risks have been identiﬁed in long-term or heavy smokers. 266

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There have been several reports describing a linear relationship between kidney cancer in women and the number of births14, 27, 28. How high parity might increase the risk of kidney cancer is still unclear. Unrelated factors were age at menarche and menopause, and estrogen replacement therapy. High body weight has been consistently linked to RCC in both sexes14, 15, 19, 29. Obesity increases estrogen production, and estrogens promote the development of kidney tumors in hamsters30. Whether obesity itself is a risk factor or whether some factor associated with obesity is responsible is still unclear. Hypertension or treatment for hypertension has also been linked to an increased risk of RCC in a number of studies14, 15, 19, 29. Some authors reported that hypertension in people not medicated for the condition does increase the risk of RCC31, whereas others noted that it does not increase the risk of kidney cancer32, 33. Antihypertensive medications may contribute to the risk of RCC, independently of the effects of hypertension. Alternatively, antihypertensive medications may act only as a marker for hypertension, potentially confounding a true association between hypertension and RCC15. Calcium channel blockers have been linked to an increased mortality from kidney cancer in some reports34 but not in others35. One study found a 1.8-fold risk of kidney cancer associated with use of beta blockers36. Angiotensin-converting enzyme (ACE) inhibitors have been associated with increases in risk36, no changes in risk37, and decreased risk38. Diuretic use has been shown to increase kidney cancer risk in a number of studies. In experimental studies, diuretic exposure induces tubular adenocarcinoma. Positive associations of RCC risk with diuretic use but not hypertension were reported in a cohort of women39.

Molecular biology Recent advances in the genetics involved in the pathogenesis of RCC have allowed the recognition of distinct types of tumors40. These tumors are characterized by heterogeneous morphology and heterogeneous behavior. Based on these genetic alterations, four different types of RCC have been identiﬁed: conventional (nonpapillary), papillary, chromophobic, and collecting duct carcinoma (Table 15.1). There is also a group of tumors that remains unclassiﬁed2, 41.

Table 15.1 Classiﬁcation of renal cell carcinoma (RCC). Tumor type

Incidence (%)

Origin

Conventional (clear cell) RCC Papillary RCC Chromophobic RCC Collecting duct carcinoma Medullary carcinoma RCC, unclassiﬁed

60–62 7–14 6–11 <1 – 6–7

Proximal convoluted tubule Distal convoluted tubule Intercalated cells Collecting ducts of renal medulla Distal collecting ducts of medulla Distal collecting ducts of medulla

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Conventional (nonpapillary) RCC is characterized by the occurrence of a deletion of chromosome 3p42. About 73% of the sporadic cases of RCC are associated with the loss of the terminal part of 3p15, 43. The loss of 3p heterozygosity has been identiﬁed in RCC, pheochromocytoma, and hemangioblastoma in patients with Von Hippel-Lindau (VHL) disease. The mutation of the VHL gene occurs exclusively in nonpapillary RCC44, and other characteristic alterations are the duplication of chromosome region 5q22 and the deletion of chromosome arms 6q, 8p, 9p, and 14q2, 45. Papillary RCC generally includes trisomies in different combinations, including the trisomy of chromosomes 7, 17, 8, 12, 16, 20, 3q, and the loss of the Y chromosome2, 40, 42, 46. Chromophobe RCC is characterized by the presence of a low chromosome number with a combination of monosomies of chromosomes 1, 2, 6, 10, 13, 17, 21, and X2, 47, 48, and a hypodiploid DNA content is frequently found49. Collecting duct carcinoma is a rare, highly malignant renal neoplasm, comprising 1% to 2% of the cases of RCC. No speciﬁc genetic alterations have been established for this tumor type. One study identiﬁed a loss of DNA sequences involving chromosomes 1, 2, 9, 11, and 18, detected by comparative genomic hybridization, as well as the gain of DNA sequences affecting chromosomes 16 and 2050. In contrast to alterations of the VHL gene, which appear to occur early in the tumor development, alterations in the p53 suppressor gene seem to be late events associated with malignancy and/or metastasis in RCC2, 51, 52. Shiina et al. reported p53 overexpression in advanced and poorly differentiated tumors53. Forty-four per cent of papillary RCCs showed p53 overexpression compared with around 15% for conventional and chromophobe RCCs. Epidermal growth factor receptor (EGF-r) expression in RCC was associated with the presence of a higher tumor growth fraction based on the observation of increased expression of cell proliferation marker Ki-67 in these tumors54. EGF binding capacity, along with tumor stage, nuclear grade, and tumor size, were also shown to correlate signiﬁcantly with overall survival34; 42 of 67 RCC patients with tumors that demonstrated EGF binding capacity died within ﬁve years, whereas all 25 patients whose tumors were negative for this trait were alive at ﬁve years (p = 0.0003). The paraneoplastic elevation of alkaline phosphatase (AP) was noted to have a signiﬁcant association with patient survival. Chuang et al. found that the ﬁve-year survival rate in RCC patients with a normal AP level was 71% compared with 50% for those with an abnormal AP level and no evidence of liver or bone metastasis55. In patients who had an elevated AP level and another paraneoplastic syndrome such as hypercalcemia, thrombocytosis, or erythrocystosis, the survival rate was 31%.

Imaging Conventional radiological imaging of RCC includes intravenous pyelography, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Angiography is no longer routinely used, and bone scintigraphy is

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unnecessary in asymptomatic patients with a small tumor, normal AP, and serum calcium levels. CT and MRI of the brain with contrast enhancement remain the best diagnostic tools for detection of brain metastases. Functional properties of viable tumor cells and recurrence or progression of the disease might be detected by positron emission tomography (PET)56. Clinical studies involved in detecting kidney-related antigens, such as using the murine monoclonal antibody (mAb) G250, in patients with RCC have shown excellent tumor-targeting ability in vivo57. These mAb scans have been useful in detecting metastatic sites that were missed using conventional imaging58.

Management Several factors potentially prognostic for RCC have been cited in the literature41 (Table 15.2). The standard treatment for localized RCC is radical nephrectomy because it cures most patients who have early-stage disease59. Traditionally, a radical nephrectomy involves the complete removal of Gerota’s fascia, including the perinephric tissue, ipsilateral adrenal gland, and regional lymph nodes. More recently, there has been a controversy about the components of a radical nephrectomy, particularly regional lymphadenectomy and ipsilateral adrenalectomy. Several authors recommend sparing the lymph nodes and the adrenal gland, particularly when the radiological images of these are negative for the presence of RCC5, 15, 60 – 62. With modern imaging technology, the number of patients who are diagnosed incidentally with RCC, before the onset of symptoms, has risen signiﬁcantly. These patients may be amenable to a partial or nephron-sparing nephrectomy. This parenchymal sparing approach may be equivalent to radical nephrectomy in patients with tumors of less than 4 cm in maximal diameter15. Several series have shown excellent local control rates with very low recurrences using this procedure63 – 65, in addition to an improved postoperative course, with patients experiencing less pain and a quicker recovery. Table 15.2 Factors potentially prognostic for RCC. Tumor-related factors

Patient-related factors

Pathological TNM stage Surgical margins Histological type Histological grade Number of tumors Solitary (unresectable) Metastases Location (lung, liver . . . ) Conventional (clear cell) Architecture (sarcomatoid)

Presentation Weight loss (> 10% body weight) Anemia ESR* (> 30) Hypercalcemia Increased alkaline phosphatase (AP)

*ESR, erythrocyte sedimentation rate.

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Metastatic disease About 25% to 30% of patients with RCC have metastatic disease at initial presentation13, 66 – 68, and in another 30%, metastatic lesions will develop during the course of the disease13. The most common sites of metastases are the lungs (55%), lymph nodes (34%), bones (32%), liver (32%), adrenal gland (19%), brain (4–13%), contralateral kidney (11%), and heart (5%)3, 4, 13, 66. In RCC, cytotoxic chemotherapy for metastatic disease has generally been disappointing, and most agents previously used gave response rates of less than 5%. Multidrug resistance (MDR)-1 gene expression and its protein product, p-glycoprotein, is the cause of chemoresistance. The use of agents that can reverse such drug resistance, such as medroxyprogesterone acetate, tamoxifen, cyclosporine, quinine, and verapamil, did not enhance the response rates5, 69, 70. Immunotherapy with interferon alfa-2a, interleukin (IL)-2, or a combination of both biological agents is the mainstay of medical management of metastatic RCC15. In 1,042 patients, Wirth reported an overall response to interferon alfa2a of 12%, with occasional complete remission71. However, the duration of the response rarely exceeded 2 years. Fisher et al. administered intravenous IL-2 to 255 patients who had metastatic RCC. They observed a 15% objective response, with a median duration of 15 months72. Both studies noted that the beneﬁts of interferon alpha and IL-2 appeared to occur only in groups of patients who had a good or moderate prognosis. In a prospective study of 425 patients with metastatic RCC who were randomized to receive continuous infusion of IL-2, subcutaneous interferon alpha, or both, Negrier et al. reported an overall response rate of 6.5% for patients receiving IL-2, 7.5% for those receiving interferon alpha, and 18.6% for those receiving both (p < 0.01)73. There was no signiﬁcant difference in overall patient survival time among the three groups. Using multivariate analysis, they determined ﬁve independent predictors of rapid disease progression (deﬁned as progression within 10 weeks): 1 number of metastases (two or more) 2 disease-free interval after the diagnosis of the primary tumor (< one-year versus > one-year) 3 presence of liver metastases 4 presence of mediastinal lymph node metastases, and 5 treatment group. They concluded that patients who had metastases to more than one organ, metastasis to the liver, and less than a one-year disease-free interval had a probability of rapid progression of at least 70%, even if they received combination therapy73. Several reports have shown signiﬁcant long-term survival in patients with solitary metastases after radical nephrectomy and metastatectomy10–12, 74 – 81. Other studies have shown that patients with multiple metastases who could undergo complete resection of their lesions were most likely to survive long-

Brain metastases from renal cell carcinoma 271

term. In addition, there was no signiﬁcant survival difference with respect to the number of lesions excised, provided all metastatic disease could be completely resected67, 75, 82.

Disease metastatic to the brain The earliest reports of brain metastases from RCC date back to more than 70 years ago13. In a review of 325 patients with RCC in Japan, Harada et al. reported a 5.5% incidence of metastasis to the brain66. The incidence of brain metastases in a large autopsy series of 1828 patients with RCC was 10%83. Marshall et al. reviewed 106 patients with clinically localized RCC who underwent brain CT scans and found brain metastases in 13% of them84. The dissemination of RCC to the brain is thought to develop via the pulmonary arterial circulation83, 85 or by passage of RCC cells into the spinal epidural plexus and vertebral veins as described by Batson86. The time interval between the diagnosis of the primary tumor and the occurrence of brain metastasis generally spans several years (range, 0–190 months)4, 13, 66, 87. Several authors have reported that brain metastases mostly occur at advanced stages of RCC, and the brain is likely to be the ﬁnal metastatic site of this tumor66, 87, 88. RCCs metastatic to the brain are notorious for intratumoral hemorrhage and the potential for an acute intracerebral hematoma requiring emergent intervention13, 89 –92. One series reported an incidence of intratumoral hemorrhage as high as 46%, with 4% of the patients requiring emergency craniotomy for hematoma evacuation13. The optimum treatment of RCC metastatic to the brain remains undeﬁned (Table 15.3). Decker et al. reported a mean survival time of 3 months for patients if the brain metastasis was left untreated, and only 4.2 months, if radiotherapy was administered93. The role of radiation therapy in the management of brain metastases from RCC has long been controversial. RCC is traditionally regarded as a radioresistant tumor. Onufrey and Mohiuddin reported that high doses of radiation, as measured by time-dose fractionation values higher than 70, can palliate local symptoms94. In contrast, Halperin and Harisiadis found no correlation

Table 15.3 Treatment options for RCC metastatic to the brain.

Treatment 1. 2. 3. 4. 5. 6. 7.

Supportive therapy (steroids) Chemotherapy/Immunotherapy WBRT* Surgical resection Surgical resection followed by WBRT* Radiosurgery Radiosurgery followed by WBRT*

*WBRT, whole-brain radiation therapy.

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(B)

Figure 15.1 A 57-year-old man who was diagnosed with renal cell carcinoma four years prior to presenting to the neurosurgery clinic. He had undergone a nephrectomy and chemotherapy for his known multiple lung metastases. He began to have symptoms of right hemiparesis and expressive speech dysphasia approximately two weeks before his clinic appointment. The magnetic resonance imaging (MRI) scan performed at that time demonstrated a 2.1 cm × 2.1 cm contrastenhancing lesion in the posterior left frontal lobe (A, coronal image). A craniotomy and gross-total resection of the lesion were performed with the aid of intraoperative ultrasound. The postoperative MRI scan demonstrated no residual tumor (B, coronal image). He recovered without difﬁculty and his neurological exam returned to normal.

between an equivalent time-dose fractionation of radiation and clinical response95. In a review of 46 patients with RCC metastatic to the brain who were treated at The University of Texas M. D. Anderson Cancer Center, the median survival time of patients treated solely with whole-brain radiation therapy (WBRT) and who responded to the treatment was 17 weeks compared with eight weeks for those treated solely with WBRT who did not have a favorable response. Patients who were managed initially with surgical resection followed by WBRT had a median survival time of 63 weeks. The authors concluded that in patients with brain metastases from RCC, WBRT is neither curative nor palliative3. Harada et al. reported their results in 18 patients with RCC metastatic to the brain who were treated by surgery (n = 12) or WBRT (n = 6)66. In the surgical group, the one-year survival rate was 64.8% and the three-year rate, 27.8%, whereas in the nonsurgical group, no patient survived for one year. This difference, however, was not statistically signiﬁcant. They concluded that surgical resection in selected patients with RCC metastatic to the brain might contribute to prolonged survival and better quality of life66. The best outcomes after surgical excision are usually achieved in patients with a solitary, surgically accessible brain tumor and in patients without systemic disease (Figure 15.1). Salvati et al. reviewed their results in 29 patients with asymptomatic or controlled primary disease who underwent complete removal of solitary brain metastases plus treatment with or without radiation therapy96. The median survival time was 28 months in the irradiated group

Brain metastases from renal cell carcinoma 273

and 23 months in the nonirradiated patients (not a statistically signiﬁcant difference). Death from neurological causes was noted in 28% of their patients. The results in 50 patients with brain metastases from RCC who were treated at Memorial Sloan-Kettering Cancer Center with surgery or with surgery followed by WBRT indicated an overall median survival time of 12 months13. This series included nine patients with multiple brain metastases. They noted that postoperative WBRT did not improve survival. Relapse in the brain was found in 38% of patients not treated with WBRT and in 48% of patients treated with WBRT after resection of the brain metastases. Death from neurological causes occurred in 42% of their patients. The authors have also noted that patients with cerebellar metastases showed a shorter median survival time than patients with supratentorial metastases (three versus nine months), although this difference was not statistically signiﬁcant13. The same ﬁndings, in general, were observed by Fujime et al. and Badalament et al.97, 98. Favorable prognostic factors included a good Karnofsky Performance Scale score, a lesser extent of systemic disease, metachronous appearance of the brain metastasis, and supratentorial location13. The largest reported radiosurgery study of RCC patients is from Mori et al.4, who reported the management results from a total of 52 RCC brain metastases in 35 consecutive patients, 28 of whom received WBRT as part of their treatment, who underwent radiosurgery treatment at the University of Pittsburgh. The median survival interval from the date of radiosurgery was 11 months. The local tumor control rate was 90%, with 21% of patients achieving complete tumor regression. Death from progression of disease in the central nervous system occurred in 12% of their patients. The addition of WBRT did not appear to improve survival. They concluded that WBRT combined with stereotactic radiosurgery may contribute to local control but did not prevent the development of new remote tumors. At the present time, the use of adjuvant WBRT in conjunction with either surgical resection or radiosurgery in the management of patients with RCC metastatic to the brain has to be individualized based on the projected overall survival time, local tumor control (control at the same site as the surgically or radiosurgically treated original lesion), distant tumor control (any new brain metastasis in a location distant from the original lesion), treatment toxicity, quality of life, and prolongation of treatment time and cost.

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51 Reiter RE, Anglard P, Liu S, et al.: Chromosome 17p deletions and p53 mutations in renal cell carcinoma. Cancer Res 1993; 53: 3092–3097. 52 Uchida T, Wada C, Wang C, et al.: Genomic instability of microsatellite repeats and mutations of H-, K-, and N-ras, and p53 genes in renal cell carcinoma. Cancer Res 1994; 54: 3682–3685. 53 Shiina H, Igawa M, Urakami S, et al.: Clinical signiﬁcance of immunohistochemically detectable p53 protein in renal cell carcinoma. Eur Urol 1997; 31: 73 – 80. 54 Moch H, Sauter G, Buchholz N, et al.: Epidermal growth factor receptor expression is associated with rapid tumor cell proliferation in renal cell carcinoma. Hum Pathol 1997; 28: 1255–1259. 55 Chuang YC, Lin AT, Chen KK, et al.: Paraneoplastic elevation of serum alkaline phosphatase in renal cell carcinoma: incidence and implication on prognosis. J Urol 1997; 158: 1684–1687. 56 Hoh CK, Seltzer MA, Franklin J, et al.: Positron emission tomography in urological oncology. J Urol 1998; 159: 347–356. 57 Lampe MI, Oosterwijk E: New developments in the use of monoclonal antibodies in the therapy of genitourinary cancer. BJU Int 2000; 86: 165 –171. 58 Steffens MG, Boerman OC, Oosterwijk-Wakka JC, et al.: Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250. J Clin Oncol 1997; 15: 1529 – 1537. 59 Kirkland Z: Limits of cure by surgery in renal carcinoma. In: Kurth KH, Mickisch GHJ, Schroder FH (eds): Renal, Bladder, and Prostate Cancer. Bath: Parthenon Publishing Group, 1999, pp. 15–22. 60 Blom JH, van Poppel H, Marechal JM, et al.: Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group. Eur Urol 1999; 36: 570 –575. 61 Kardar AH, Arafa M, Al Suhaibani H, et al.: Feasibility of adrenalectomy with radical nephrectomy. Urology 1998; 52: 35 –37. 62 Tsui KH, Shvarts O, Barbaric Z, et al.: Is adrenalectomy a necessary component of radical nephrectomy? UCLA experience with 511 radical nephrectomies. J Urol 2000; 163: 437–441. 63 Dunn MD, McDougall EM, Clayman RV: Laparoscopic radical nephrectomy. J Endourol 2000; 14: 849–855. 64 Van Poppel H, Bamelis B, Oyen R, et al.: Partial nephrectomy for renal cell carcinoma can achieve long-term tumor control. J Urol 1998; 160: 674 – 678. 65 Van Poppel H: Nephron sparing surgery. In: Petrovich Z, Baert L, Brady LW (eds): Carcinoma of the Kidney and Testes, Rare Urological Malignancies. Innovations in Management. Berlin: Springer-Verlag, 1999, pp. 79–93. 66 Harada Y, Nonomura N, Kondo M, et al.: Clinical study of brain metastasis of renal cell carcinoma. Eur Urol 1998; 36: 230 –235. 67 Kavolius JP, Mastorakos DP, Pavlovich C, et al.: Resection of metastatic renal cell carcinoma. J Clin Oncol 1998; 16: 2261–2266. 68 Takashi M, Takagi Y, Sakata T, et al.: Surgical treatment of renal cell carcinoma metastases: prognostic signiﬁcance. Int Urol Nephrol 1995; 27: 1– 8. 69 Northway RO, Ritenour CWM, Marshall FF: Management of advanced renal cell carcinoma. In: Kurth KH, Mickisch GHJ, Schroder FH (eds): Renal, Bladder, Prostate, and Testicular Cancer. New York: The Parthenon Publishing Group, 2001, pp. 75–78. 70 Yagoda A, Abi-Rached B, Petrylak D: Chemotherapy for advanced renal-cell carcinoma: 1983–1993. Semin Oncol 1995; 22: 42– 60. 71 Wirth MP: Immunotherapy for metastatic renal cell carcinoma. Urol Clin North Am 1993; 20: 283–295.

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96 Salvati M, Scarpinati M, Orlando ER, et al.: Single brain metastases from kidney tumors. Clinico-pathologic considerations on a series of 29 cases. Tumori 1992; 78: 392–394. 97 Badalament RA, Gluck RW, Wong GY, et al.: Surgical treatment of brain metastases from renal cell carcinoma. Urology 1990; 36: 112–117. 98 Fujime M, Akaza H, Yoshida M, et al.: Cerebellar metastasis from renal cell carcinoma. Nippon Hinyokika Gakkai Zasshi 1986; 77: 1164 –1168.

CHAPTER 16

Metastatic colorectal carcinoma Vijayabalan Balasingam, Ian E McCutcheon

Metastatic colorectal carcinoma Colorectal carcinoma gives rise to brain metastasis infrequently. However, intracranial metastasis (IM) from such tumors poses a signiﬁcant oncologic challenge for the care of these patients as they tend to have concomitant liver and/or pulmonary metastasis. Improvements in diagnostic techniques, better acceptance of screening, and improved therapy for systemic disease have led to a measurable increase in patient survival over the past three decades, with an associated increase in the incidence of IM from colorectal cancer. This chapter provides insight into the risk, pattern of occurrence, and management strategies for such tumors, as well as survival time of patients they afﬂict, in the light of presently available surgical and adjuvant therapies. Colorectal cancer is presently the third most common cause of cancerrelated deaths in both men and women. Death is usually attributed to progression of the disease, with local recurrence and distant metastases. On average, asymptomatic individuals have a 6% risk of developing colorectal cancer. The peak incidence of colorectal cancer and its associated IM occurs in the 6th and 7th decades of life (Figure 16.1). The median interval from initial diagnosis of a colorectal lesion to IM is approximately two years. The Surveillance Research Program of the American Cancer Society has estimated that 148,300 new cases of colorectal cancer will be diagnosed in the year 2002 and that 56,600 individuals will succumb to the disease1. However, despite complete resection of the primary colorectal tumor, a signiﬁcant number of patients will manifest local and distant recurrrences. Ten to 15% develop distant metastasis as a mode of recurrence2–5. Brain metastasis is a relatively rare occurrence in colorectal cancer. The incidence of (IM) from colorectal carcinoma represents 3–5% of all new brain metastases6 –11. About 2–3% of all patients with colorectal carcinoma harbor central nervous system (CNS) metastases and another 10% develop intracranial metastases during the course of their illness. In these patients with IM, the incidence of multiple metastases is reported to be 50% by Cascino et al.11, and 36% by Hammoud and colleagues12. Autopsy studies reveal that 60–85% of patients with IM have multiple lesions13. These observations suggest that isolated solitary metastasis from colorectal carcinoma is not common; the 279

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91–100 81–90

Age of Patient

71–80 61–70 51–60 41–50 All colorectal carcinomas Brain metastasis

31–40 0–30 0

20 Number of Patients

40

Figure 16.1 Bar graph based on data from 8,632 patients registered at The University of Texas M. D. Anderson Cancer Center with adenocarcinoma of the colon and rectum between January 1, 1980 and June 30, 1994. The age of patients with a diagnosis of primary colorectal cancer was compared with the age of patients who developed intracranial metastasis from their colorectal cancer. Used with permission from Hammoud MA, McCutcheon IE, Elsouki R, et al. Colorectal carcinoma and brain metastasis: distribution, treatment, and survival. Ann Surg Oncol 1996; 3: 453–46312.

extent of IM can be shown by magnetic resonance imaging of the brain at the time of initial work-up. The incidence of distant metastasis and particularly of IM from colorectal lesions is dependent on the site of the primary disease and the stage of the disease. The majority of colorectal primary lesions occur in the distal colon (which includes the sigmoid colon and the rectosigmoid junction) as well as the rectum. The incidence of primary colon carcinoma in the proximal colon (which includes the cecum, ascending colon, transverse colon, and descending colon) is much lower (Table 16.1). Location of the primary disease is a signiﬁcant prognostic indicator of survival after IM is detected. Patients with proximal lesions survive for a shorter time than those with distal lesions, with a median survival time of three months versus six months, respectively14. Patients with tumors extending through the bowel wall (Dukes stage B) and/or involving the lymph nodes (Dukes stage C) have a higher incidence of distant metastasis2, 15. The most frequently diagnosed metastatic sites include the liver (20% to 30%) and lungs (10% to 20%)16 –19. Less commonly, these patients show dissemination of the tumor to such other sites as the spine, lymph nodes, uterus, adrenal glands, pancreas, bones, and the CNS15, 16, 20, 21. In a study of 18 patients with colorectal cancer metastatic to the CNS, Chyun et al.22 found the incidence of IM to be comparable, irrespective of Dukes stage at presentation. On the contrary, Hammoud and colleagues12, in a series of 150 patients, observed that patients with stage C disease are more prone to develop colorectal brain metastases than those with stage D disease (48% versus 24%, respectively). The apparent discrepancy may reﬂect the fact that people with more advanced disease succumb to their systemic disease rapidly despite therapeutic intervention. On the other hand, those with less advanced

Metastatic colorectal carcinoma 281 Table 16.1 Primary tumor location in patients with colorectal cancer*.

Location

Patients with brain metastasis

Proximal Cecum Ascending colon Transverse colon Descending colon Distal Sigmoid Rectosigmoid Rectum Other Total

n 35 15 15 1 4 65 23 9 33 0 100

Patients with colon cancer % 35% 15% 15% 1% 4% 65% 23% 9% 33% 0% 100%

n 3,011 1,157 883 300 671 5,084 2,100 921 2,063 537 8,632

% 34.9% 13.4% 10.2% 3.5% 7.8% 58.9% 24.3% 10.7% 23.9% 6.2% 100%

The above data were based on 8,632 patients registered at The University of Texas M. D. Anderson Cancer Center with adenocarcinoma of the colon and rectum between January 1, 1980 and June 30, 1994. *From Hammoud MA, McCutcheon IE, Elsouki R, et al.: Colorectal carcinoma and brain metastasis: distribution, treatment, and survival. Ann Surg Oncol 1996; 3: 453–46312.

disease have the opportunity to beneﬁt from therapeutic intervention, leading to increased survival, and are thus more prone to IM. An appreciation of the distant metastatic pattern of colorectal cancer requires an understanding of the venous vascular drainage pattern. The proximal colon, which includes the cecum, ascending colon, transverse colon, and descending colon, sends its venous outﬂow into the superior and inferior mesenteric veins. These veins drain into the hepatic portal system, which conveys blood from these viscera to the liver (Plate 16.1a, facing p. 82). This intrahepatic system ramiﬁes like an artery and ends in sinusoids, from which vessels again converge to reach the inferior vena cava en route to the lung for oxygenation. This venous drainage pattern then explains the high incidence of liver metastasis and the concurrent discovery of lung metastasis prior to IM (Plate 16.1a). On the other hand, the distal colon, which includes the sigmoid colon and rectosigmoid junction as well as the rectum, has additional venous drainage routes (Plate 16.1b). In addition to the hepatic portal system to which it sends blood via the superior rectal vein and inferior mesenteric vein (Plate 16.1b(C)), the distal colon also drains blood into the inferior and middle rectal veins, which in turn drain into the inferior vena cava via the internal iliac vein (Plate 16.1b(A)). This effectively allows metastases to bypass the liver and shows how distal lesions can predispose a patient to a higher incidence of pulmonary than hepatic metastases. Colorectal cancer patients without liver metastasis generally survive longer, which then gives them time to develop brain metastasis. In a study of 163 patients, Patanaphan et al.18 observed that primary tumors located in the proximal colon showed a higher incidence of

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Table 16.2 Distribution of patients with intracranial metastases from colorectal cancer and either pulmonary or hepatic metastases.

Reports

Number of patients

% of pulmonary metastases

% of hepatic metastases

Chyun et al. 198022 Cascino et al. 198311 Farnell et al. 199636 Hammoud et al. 199612 Wronski & Arbit 199914

18 40 150 100 73

55 85 57 71 74

22 50 29 42 49

hepatic metastasis than lesions located in the distal colon, which show a higher incidence of lung metastasis. IM might also arise by way of the intervertebral veins (Batson’s plexus, Plate 16.1b(B)) and their connections with pelvic veins, where blood ﬂow has been shown to be temporarily reversed by raised intraabdominal pressure or postural alterations23. However, the rarity of vertebral or spinal cord metastases in patients with IM argues against this last hypothesis. Hammoud and colleagues12 noted a higher incidence of pulmonary than hepatic involvement (71% versus 42%, respectively) in patients with IM and that lesions originating from the distal colon and rectum (with a predilection for pulmonary metastasis) had a higher incidence of IM than was seen with more proximal colonic sites, with their afﬁnity for hepatic metastasis (65% versus 35%, respectively). This disproportionately higher incidence of IM from patients with pulmonary metastasis versus hepatic metastasis has been reported by others (Table 16.2). This difference in metastatic proﬁle probably occurs because 30% of proximal colonic lesions are associated with hepatic metastasis (Dukes stage D) at initial diagnosis24; patients with such tumors die from liver failure before developing brain metastasis, which in previous series has been considered a late event in the natural course of the disease8. These observations strongly support the notion that the risk of developing IM is higher from primary disease in the distal colon and rectum (Figure 16.2) and that tumor cells arrive in the brain through a hematogenous route. However, for patients with IM but without pulmonary metastasis, the route into the brain is less clear. It is possible that such patients actually harbor micrometastases in the lung that are difﬁcult to detect on a chest x-ray. As Batson’s plexus of vertebral veins bypasses the lung, it offers another possible mechanism for the creation of IM. The intracranial distribution of metastatic colorectal cancer is not congruent with the relative volumes of different brain regions as has been assumed for brain metastasis in general. Although the weight of the cerebrum is nine times that of the cerebellum25, in colorectal cancer the supratentorial region does not account for 80–90% of all lesions. The literature reports a higher rate of metastasis to infratentorial sites from colorectal lesions than would be expected if regional brain volumes were the main determinant of metastatic distribution

Metastatic colorectal carcinoma 283

Figure 16.2 The percentage incidence of intracranial metastases arising from different regions of the colorectal system. For an appreciation of the incidence of primary cancers at these sites, see Table 16.1.

Table 16.3 Colorectal cancer metastatic to infratentorial locations.

Reports

Number of patients

% infratentorial metastases

Cascino et al. 198311 Alden et al. 199637 Hammoud et al. 199612 Farnell et al. 199636 Wronski & Arbit 199914

40 19 100 150 73

35 55 52 29 35

(Table 16.3). The overrepresentation of colorectal infratentorial metastases has been attributed to a number of factors, including access from the vertebral artery system to the cerebellum26, propagation via Batson’s venous plexus27, and a special afﬁnity of these tumor cells for locations within the cerebellum or brainstem28. Proof of these hypotheses is still sought, as this trend is observed but not explained. In addition, colorectal cancer can metastasize to unusual sites: metastases to the sella turcica29 (which is generally considered a site for breast or pulmonary metastases) and to the pineal region30 have been reported. The signs and symptoms of colorectal intracranial metastases are no different from those seen with other intracranial mass lesions and reﬂect both increased intracranial pressure (ICP) and the creation of local irritative foci. Commonly seen symptoms include (in decreasing frequency) gait changes/ ataxia, headache, hemiparesis, speech changes, memory loss, and seizures. The high incidence of gait changes/ataxia is indicative of the ampliﬁed occurrence of cerebellar lesions with colorectal cancer. Patients with cerebellar lesions can also present with acute neurological decline due to increased intracranial pressure from aqueductal or ventricular obstruction, leading to hydrocephalus.

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Metastatic lesions, as seen on imaging studies, are generally well demarcated and spheroidal, located at the gray-white matter junction, and associated with an extensive zone of edema. The size of the tumor does not necessarily correlate with the extent of the edema. Tumor angiogenesis contributes to a defective blood-brain barrier, and experimental evidence suggests that increased permeability occurs with tumors that exceed 1 mm in maximum diameter31. Intraoperatively, these tumors generally appear pinkish-gray and have been reported to be ﬁrm and scirrhous in some instances and on other occasions, soft and granular. Larger lesions tend to possess a central core of necrosis as the tumor outgrows its vascular supply. Less commonly, lesions have been described as cystic, hemorrhagic, and on rare occasions, vascular. Despite shared common characteristics among intracranial metastases of varying etiologies that allow successful surgical removal in many patients, the excision of colorectal carcinomas is generally less clear and more difﬁcult than in other forms of IM. This may be attributed to their microscopic inﬁltrative proﬁle32, to the friability of colorectal metastases, and to their tendency to show a coloration quite similar to that of the adjacent brain. The degree of inﬁltration is not as extensive as that seen with malignant gliomas, but it is an important explanation of recurrence when resection of these metastases is carried out in a piecemeal versus an en bloc fashion. Such technical factors can be critical in determining the completeness of removal and thus, the likelihood of local recurrence. Adenocarcinoma that metastasizes to the brain from either pulmonary or colorectal primary sites can pose challenges to the pathologist attempting to differentiate between them microscopically in patients with an unknown primary site of disease. Ultrastructurally, both have brush borders with rootlets and can be distinguished from each other by immunohistochemical staining for cytokeratins and villin. Metastases from colorectal cancer33 are negative for cytokeratin 7, positive for cytokeratin 20, and profusely positive for villin, with well formed roots; however, lung metastases are cytokeratin 7 positive, cytokeratin 20 negative, and only focally villin positive. Serum carcinoembryonic antigen (CEA) is of great value in detecting the systemic (extracranial) recurrence of primary or intra-abdominal metastatic colon cancer, even before the appearance of a radiographically detectable lesion. CEA levels in the cerebrospinal ﬂuid (CSF) of patients have also been shown to correlate with the presence of leptomeningeal disease from colorectal (and other) carcinomas34, 35. However, serum or CSF CEA levels have not been helpful in the evaluation of progressive intraparenchymal disease from colorectal cancer11. The disease course of untreated IM in general is grim; the median survival time of patients without therapy is one month. The therapeutic goal for all patients should be to palliate symptoms while improving survival without compromising the patient’s quality of life. Presently, the management options for metastatic lesions include: 1 the administration of corticosteroids 2 whole-brain radiotherapy (WBRT)

Metastatic colorectal carcinoma 285

3 surgical extirpation, and 4 radiosurgery. These treatment modalities can be used alone or in various combinations, with the use of radiosurgery being restricted to lesions < 3 cm in maximum diameter. The optimal treatment strategy for a given patient will depend on the patient’s prognostic factors for long-term survival, which are: 1 Karnofsky Performance Scale (KPS) status 2 status of the primary disease at its original site and at sites of extracranial metastasis 3 neurological symptoms 4 surgical accessibility of the tumor, and 5 number of intracranial metastases. Patients with uncontrolled systemic disease and widespread IM can be adequately palliated from adverse neurological signs and symptoms for their limited life expectancy by either of two options: 1 supportive care and administration of corticosteroids, and/or 2 WBRT36, 37. Palliation with corticosteroids may reduce intracranial swelling, but the median survival time of patients infrequently exceeds six weeks (Table 16.4). Supportive care with WBRT remains the standard of care for patients with multiple symptomatic intracranial metastases or with isolated brain metastases in the presence of uncontrolled extracranial disease. In general, 30 Gy delivered in 10 fractions over two weeks is the normal treatment pattern for WBRT. Higher doses of radiation have been used by some groups, but none has indicated any improved survival, given the relative radioresistance of these lesions38. The median survival time after WBRT is four months and rarely exceeds one year (Table 16.4 and Figure 16.3). Consequently, the long-term

Table 16.4 Comparison of patient survival times following different management strategies for intracranial metastases.

Reports

Treatment

Number of patients

Median survival time from diagnosis of IM* (months)

Cascino et al.198311 Farnell et al. 199636 Hammoud et al. 199612 Cascino et al. 198311 Alden et al. 199637 Farnell et al. 199636 Hammoud et al. 199612 Alden et al. 199637 Cascino et al. 198311 Farnell et al. 199636 Hammoud et al. 199612 Wronski & Arbit 199914

Corticosteroids Corticosteroids Corticosteroids WBRT WBRT WBRT WBRT Craniotomy Craniotomy + WBRT Craniotomy +/− WBRT Craniotomy +/− WBRT Craniotomy +/− WBRT

2 21 7 29 14 79 57 5 7 50 36 73

0.5 1.5 1 2.25 2.6 3.6 3 4.9 9.25 10 9 8.7

IM, intracranial metastasis; WBRT, whole-brain radiotherapy.

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Proportion surviving

1.00

0.75

No brain surgery (median 3 months) Brain surgery (median 9 months)

0.50

0.25

0.00 0 10 5 15 20 25 30 35 40 Survival after diagnosis of brain metastasis (months) Figure 16.3 Graph showing Kaplan-Meier estimates of survival of patients with intracranial metastasis after surgical versus nonsurgical treatment. The patient series is as described in Figure 16.1. Used with permission from Hammoud MA, McCutcheon IE, Elsouki R, et al. Colorectal carcinoma and brain metastasis: distribution, treatment, and survival. Ann Surg Oncol 1996; 3: 453–45612.

complications and potential delayed side effects (e.g., cognitive decline) of radiation can be ignored. Patients who have relatively well-controlled primary cancer with extracranial metastasis and also have a good KPS score are generally treated with either surgery or stereotactic radiosurgery. Surgery is the ideal mode of treatment, even for as many as two to three intracranial metastases39. Resection offers improved local rates of tumor control, overall survival, and functional independence compared with WBRT alone. In general, for intracranial metastases of any etiology, postoperative radiation as an adjunct has yielded lower intracranial relapse rates but has not improved survival time40. This also appears to be the case for brain metastasis from colorectal cancer (Figure 16.4 and Table 16.4). Currently, the median survival time after surgical extirpation of such intracranial metastases with/without WBRT is 9–10 months (Table 16.4). Lesions that are 3 cm and smaller in maximum diameter can also be treated via stereotactic radiosurgery as an alternative to surgery. Presently, controversy exists in the literature regarding the efﬁcacy of surgery and radiosurgery for IM treatment, pending the completion of a randomized controlled Phase III trial comparing the two modalities. Survival data are not presently available for brain metastases from colorectal cancers treated via radiosurgery. However, this modality is being used for the treatment of surgically inaccessible lesions and in patients wishing to avoid operation. In summary, the median interval from diagnosis of a colorectal lesion to IM is approximately two years (Table 16.5), and in general, colorectal brain

Metastatic colorectal carcinoma 287

Proportion surviving

1.00

No treatment (median 1 month) Radiotherapy (median 3 months) Surgery (median 9 months) Surgery and radiotherapy (median 9 months)

0.75

0.50

0.25

0.00 0 10 20 30 40 Survival after diagnosis of brain metastasis (months) Figure 16.4 Graph showing Kaplan-Meier estimates of survival of patients with intracranial metastasis according to type of treatment. The patient series is as described in Figure 16.1. Used with permission from Hammoud MA, McCutcheon IE, Elsouki R, et al. Colorectal carcinoma and brain metastasis: distribution, treatment, and survival. Ann Surg Oncol 1996; 3: 453–45612.

Table 16.5 Time from initial diagnosis of primary colorectal cancer to intracranial metastasis.

Reports

Number of patients

Time to diagnosis of IM* (months)

Chyun et al. 198022 Cascino et al.198311 Farnell et al. 199636 Hammoud et al. 199612 Wronski & Arbit 199914 Ko et al. 199941

18 40 150 100 73 53

27.4 24.5 23 26 27.6 36

*IM, intracranial metastasis.

metastases occur during the 6th and 7th decades of life (Figure 16.1). Based on a literature survey, this two-year interval is increasing and reﬂects increased awareness, early diagnosis, and aggressive adjuvant therapy after surgical resection of the primary lesion. This time interval between the diagnosis of the primary cancer and subsequent IM depends on two important factors: primary disease stage at diagnosis (Table 16.6), and treatment of noncerebral metastases (Table 16.7). Patients with more widespread disease develop brain metastases more quickly. However, the only treatment that affects survival after the diagnosis of IM is surgical extirpation of the CNS lesion (Figures 16.3 and 16.4). The median survival time of patients from the diagnosis of a primary colorectal tumor that leads to IM has been reported to be 35–37 months12, 14. On average, the median survival interval from the time of craniotomy was 8.7– 10 months (Table 16.4). In conclusion, the one-year and two-year survival

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Number of Median Dukes stage patients (months)

p

B C D

0.03 < 0.0001

28 48 24

40 26 8

Table 16.6 Time from diagnosis of primary colorectal tumor by Dukes stage to diagnosis of intracranial metastasis*.

*Data from Hammoud MA, McCutcheon IE, Elsouki R, et al.: Colorectal carcinoma and brain metastasis: distribution, treatment, and survival. Ann Surg Oncol 1996; 3: 453–46312.

Table 16.7 Time from treatment of primary colorectal tumor to appearance of intracranial metastases (months).

Treatment

Number of patients

Median time interval (months)

p

None Chemotherapy only Radiotherapy only Both

31 53 7 9

13.0 27.0 49.0 30.0

0.001 0.0001 0.08

times after craniotomy are only reached by one third and one-ﬁfteenth of the cohort, respectively. Length of survival is not signiﬁcantly different for patients with brain metastases from colorectal cancer, within the following four groups14: 1 men and women 2 craniotomy patients who undergo a thoracotomy for pulmonary metastasis and patients whose pulmonary lesion is not resected surgically 3 patients with metastatic lesions > 3 cm in diameter and those with lesions < 3 cm in diameter 4 those undergoing en bloc tumor resection and those undergoing piecemeal resection. The resection of pulmonary metastases was seen as a favorable prognostic factor in patients having brain metastases from other types of cancer, but in the case of those arising from colorectal tumors, it does not matter. This could be attributed to the simultaneous presence of hepatic and pulmonary metastases (Plate 16.1) in patients with colorectal cancer, which detracts from survival. The presence of cerebellar intracranial metastases from colorectal cancer portends a poorer survival interval relative to that seen with supratentorial lesions. The median survival time was noted to be ﬁve months for patients having infratentorial metastases and 9.1 months for patients with supratentorial lesions, with a one-year survival rate of 15.4%14 for patients with cerebellar lesions. These lesions also tend to present with a higher frequency of obstructive hydrocephalus.

Metastatic colorectal carcinoma 289

Screening for IM in asymptomatic individuals should be performed no later than 24 months after the initial diagnosis of a colorectal cancer. This time frame is in keeping with the average median time interval from the diagnosis of a primary colorectal tumor to the appearance of CNS involvement (Table 16.5). Close and careful attention to any new neurologic complaints is important for earlier detection in these patients. Furthermore, the presence of pulmonary lesions in colorectal cancer patients should warrant earlier and more frequent performance of neuroimaging studies.

Conclusions The incidence of IM in colorectal cancers is small but such metastasis is more prevalent from lesions occurring in the distal colon and rectal region. IM is generally associated with other organ involvement, principally the lungs and/or the liver. The two most important factors inﬂuencing progression from the diagnosis of the primary cancer to IM are the stage of the primary disease and the treatment status of noncerebral metastatic disease. However, given the more aggressive therapies available in this millennium and the great strides in the arena of cancer chemotherapy, one can be optimistic that brain metastases will begin to occur beyond two years from diagnosis of the primary colorectal tumor. Cerebellar intracranial metastases are more frequent, present with a higher incidence of obstructive hydrocephalus, and portend a poorer survival time in comparison with supratentorial lesions. Radiation alone is capable of relieving symptoms, but only for a short period of time; it should be the ﬁrst line of treatment for patients with multiple intracranial lesions, multiorgan involvement, and/or poor neurological status. Surgical intervention is by far the best treatment alternative in patients with limited, accessible intracranial metastases from colorectal cancer and provides for extended quality of survival in what is still, unfortunately, a palliative effort.

References 1 American Cancer Society. Cancer Facts & Figures 2002, United States, 2002, pp. 5–6. (http://www3.cancer.org/eprise/main/docroot/STT/stt_0, accessed January 4, 2002). 2 Olson RM, Perencevich NP, Malcolm AW, et al.: Patterns of recurrence following curative resection of adenocarcinoma of the colon and rectum. Cancer 1980; 48: 2969 –2974. 3 Dawson LE, Russel AH, Tong D, et al.: Adenocarcinoma of the sigmoid colon: sites of initial dissemination and clinical patterns of recurrence following surgery alone. J Surg Oncol 1983; 22: 95 –99. 4 Galandiuk S, Wieand HS, Moertel CG, et al.: Patterns of recurrence after curative resection of carcinoma of the colon and rectum. Surg Gynecol Obstet 1992; 174: 27–32. 5 Obrand DI, Gordon PH: Incidence and patterns of recurrence following curative resection for colorectal carcinoma. Dis Colon Rectum 1997; 40: 15 –24. 6 Aronson SM, Garcia JH, Aronson BE: Metastatic neoplasms of the brain: their frequency in relation to age. Cancer 1964; 17: 558 –563.

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7 Takakura K, Sano K, Hojo S, et al.: Metastatic Tumors of the Central Nervous System. Tokyo, Igaku-Shoin, 1982, 346pp. 8 Wright DC, Delaney TF, Buckner JC: Treatment of metastatic cancer to the brain. In DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. 4th edn. Philadelphia, JB Lippincott, 1993, pp. 2170–2186. 9 Winston KR, Walsh JW, Fischer EG: Results of operative treatment of intracranial metastatic tumors. Cancer 1980; 45: 2639 –2645. 10 Cairncross JG, Kim J-H, Posner JB: Radiation therapy for brain metastasis. Ann Neurol 1980; 7: 529–541. 11 Cascino TL, Leavengood JM, Kemeny N, et al.: Brain metastasis from colon cancer. J Neurooncol 1983; 1: 203 –209. 12 Hammoud MA, McCutcheon IE, Elsouki R, et al.: Colorectal carcinoma and brain metastasis: distribution, treatment and survival. Ann Surg Oncol 1996; 3: 453 – 463. 13 Chason JL, Walker FB, Landers JW: Metastatic carcinoma in the central nervous system and dorsal root ganglion. A prospective autopsy study. Cancer 1963; 16: 781–787. 14 Wronski M, Arbit E: Resection of brain metastases from colorectal carcinoma in 73 patients. Cancer 1999; 85: 1677–1685. 15 Minsky BD, Mies C, Rich TA, et al.: Potentially curative surgery of colon cancer: patterns of failure and survival. J Clin Oncol 1988; 6: 106 –118. 16 Floyd CE, Stirling CT, Cohn I: Cancer of the colon, rectum, and anus: review of 1687 cases. Ann Surg 1966; 166: 829 – 837. 17 Welch JP, Donaldson GA: The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg 1979; 189: 496 –502. 18 Patanaphan V, Salaazar OM: Colorectal cancer: metastatic patterns and prognosis. South Med J 1993; 86: 38–41. 19 Benotti P, Steele G Jr: Patterns of recurrent colorectal cancer and recovery surgery. Cancer 1992; 70(Suppl 5): 1409–1413. 20 Weiss L, Grundmann E, Torhorst J, et al.: Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 1986; 150: 195 –203. 21 Philipsen SJ, Heilweil M, Quan SHQ, et al.: Patterns of pelvic recurrence following deﬁnitive resection of rectal cancer. Cancer 1984; 53: 1354–1362. 22 Chyun Y, Hayward E, Lokich J: Metastasis to the central nervous system from colorectal cancer. Med Pediatr Oncol 1980; 8: 305 –308. 23 Batson OV: The vertebral vein system. AJR Am J Roentgenol 1957; 78: 195 –212. 24 Foster JH: Survival after liver resection for secondary tumors. Am J Surg 1978; 35: 389 –394. 25 Ask-Upmark E: Metastatic tumors of the brain and their localization. Acta Med Scand 1956; 154: 1–9. 26 Delattre JY, Krol G, Thaler HT, et al.: Distribution of brain metastasis. Arch Neurol 1988; 45: 741–744. 27 Batson OV: Functions of vertebral veins and their role in the spread of metastases. Ann Surg 1940; 112: 138–149. 28 Cairncross JG, Posner JB: The management of brain metastases. In: Walker MD (ed): Oncology of the Nervous System. Hingham, MA, Martinus Nijhoff Publishers, 1983, pp. 341–378. 29 Neroni M, Artico M, Pastore FS, et al.: Diaphragma sellae metastasis from colon carcinoma mimicking a meningioma. A case report. Neurochirurgie 1999; 45: 160 –163. 30 Ramina R, Coelho NM, Mariushi WM, et al.: Pineal metastasis as ﬁrst clinical manifestation of colorectal adenocarcinoma. Case report. Arq Neuropsiquiatr 1999; 57: 92–95.

Metastatic colorectal carcinoma 291 31 Hasegawa H, Ushio Y, Hayakawa T: Changes of the blood-brain barrier in experimental metastatic brain tumors. J Neurosurg 1983; 59: 304 –310. 32 Sundaresan N, Galicich JH: Surgical treatment of brain metastases. Clinical and computerized tomography evaluation of the results of treatment. Cancer 1985; 55: 1382–1388. 33 Sharma S, Tan J, Sidhu G, et al.: Lung adenocarcinomas metastatic to the brain with and without ultrastructural evidence of rootlets: an electron microscopic and immunohistochemical study using cytokeratins 7 and 20 and villin. Ultrastruct Pathol 1998; 22: 385 –391. 34 Bresalier RS, Karlin DA: Meningeal metastasis of rectal carcinoma with elevated cerebrospinal ﬂuid carcinoembryonic antigen. Dis Colon Rectum 1979; 22: 216 –217. 35 Schold SC, Wasserstrom WR, Fleisher M, et al.: Cerebrospinal ﬂuid biochemical markers of central nervous system disease. Ann Neurol 1980; 8: 597– 604. 36 Farnell GF, Buckner JC, Cascino TL, et al.: Brain metastases from colorectal carcinoma. Cancer 1996; 78: 711–716. 37 Alden TD, Gianino JW, Saclarides TJ: Brain metastases from colorectal cancer. Dis Colon Rectum 1996; 39: 541–545. 38 Galicich JH, Arbit E: Metastatic brain tumors. In: Youmans JR (ed): Neurological Surgery. 3rd edn. Philadelphia, WB Saunders, 1990, pp. 3204–3222. 39 Bindal RK, Sawaya R, Leavens ME: Surgical treatment of multiple brain metastases. J Neurosurg 1993; 79: 210 –216. 40 Patchell RA, Tibbs PA, Regine WF: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998; 280: 1485 –1489. 41 Ko F-C, Liu JM, Chen W-S, et al.: Risk and patterns of brain metastases in colorectal cancer. Dis Colon Rectum 1999; 42: 1467–1471.

CHAPTER 17

Brain metastasis from cancer of an unknown primary site Robert J Bohinski, Ronald E Warnick

Introduction Cancer of an unknown primary site is diagnosed when metastatic lesions are discovered and no primary site can be identiﬁed. More speciﬁcally, these patients are deﬁned as those who have: 1 a histologically proved cancer and 2 no detectable primary site despite having a complete medical history and having undergone a comprehensive physical examination and screening laboratory and diagnostic work-ups1. In other words, the diagnosis of cancer of an unknown primary site is not made at the time of presentation; rather, it is a diagnosis of exclusion. A subset of patients with cancer of an unknown primary site are diagnosed as a result of symptoms referable to one or more brain metastases and appear to represent a distinct clinical entity. Overall, patients with cancer of an unknown primary site, regardless of whether the brain is involved, represent 3–10% of all cancer patients2. Therefore, of the estimated 1,220,100 new cases of cancer (including non-solid cancers) in the United States in the year 2000, between 37,000 and 122,000 patients would have metastatic disease from an undetected primary site3. As a group, median survival is merely six months, but identiﬁable subgroups of patients with favorable clinicopathological characteristics have signiﬁcantly better survival and some may be cured4 – 6. Much of the recent clinical effort dealing with the management of patients with cancer of unknown primary site has focused on identifying subgroups of patients who are candidates for speciﬁc treatment modalities and who have a more favorable prognosis than the group as a whole. However, the extreme heterogeneity of patient clinical presentation, tumor histology, and disease natural history has made systematic evaluation of these patients difﬁcult, and established protocols for diagnostic work-up, treatment, and clinical monitoring have evolved slowly. In particular, the subset of these patients affected by brain metastasis has been discussed only in the neuro-oncological literature7–18. Although these latter studies are helpful for guiding the brain-speciﬁc care of these patients, the management of metastatic disease outside of the central nervous system must be carefully extrapolated from guidelines outlined in the general oncological literature2, 4 – 6. 292

Brain metastasis from cancer of an unknown primary site 293

The neurosurgeon is often involved in the care of patients with cancer of an unknown primary site, because many patients having metastatic cancer present with a neurological symptom caused by brain metastasis as the ﬁrst sign of their cancer (i.e., a precocious presentation). Patients who present with brain metastasis and whose primary cancer site is unknown represent a wellrecognized but poorly deﬁned clinical entity. It is estimated that between 3% and 35% of all patients who present clinically with brain metastasis have an unknown primary cancer site7, 12, 14, 19–24; however, most estimates range between 5% and 12%7, 12, 14, 19–23. In many of these clinical series, an unknown primary cancer site ranks third in frequency of occurrence behind lung and breast cancer as primary sites19, 20, 22. The broad estimated range may result largely from the inconsistent application of terminology used to deﬁne this patient population. Clinical series encompass heterogeneous patient populations, making comparisons among studies problematic. Studies that report a high incidence of patients for whom the primary cancer site is unknown typically include all patients who present with precocious brain metastasis. Many of these patients will have a primary neoplasm identiﬁed during the course of the initial diagnostic evaluation and do not accurately represent the subgroup of patients with brain metastasis and an undetectable primary tumor. There is a further distinction between patients who present with brain metastasis and an undetected tumor and those who present with brain metastasis as the only manifestation of cancer14, 16. In the former situation, the patient may have extracerebral metastases at the time of diagnosis whereas, in the latter situation, the patient demonstrates no evidence of metastasis outside of the brain. Brain metastases may be single, multiple, or solitary. The phrase single brain metastasis refers to the detection of only a single brain metastasis without any implication regarding the existence of a primary site or extracerebral metastatic disease. The phrase solitary brain metastasis is more restrictive and refers to the unique situation in which a single brain metastasis is the only known site of metastasis in the body and no inference is made about the existence of a primary site. Given these deﬁnitions, it is important to recognize that brain metastasis from an unknown primary site can be single, solitary, or multiple.

Clinical presentation The mean age of patients who present with brain metastasis from an unknown primary site is in the ﬁfth or sixth decade (Table 17.1). The presentation of these patients does not appear to differ from that of the general population of patients with brain metastasis22, 25. Most series report a slight male predominance. Presenting neurological symptoms include headache, weakness, seizure, mental disturbances, language difﬁculty, gait difﬁculty, incoordination, nausea, emesis, and numbness. Headache and weakness are typically the most common presenting complaints, present in approximately 30–50% of patients. Focal motor weakness and alterations in the level of consciousness associated

Table 17.1 Summary of clinical series that report the demographics, clinical work-up, treatment, and outcomes of patients who present with brain metastasis and an unknown primary cancer site.

Authors, publication year

Time period of clinical series

Number of patients

Mean patient age

% male

% female

Most common presenting symptom or sign

Patients with antemortem Distribution of metastases (%) diagnosis of primary site Single Multiple Cerebellar (%) NS

NS

NS

32

Tumor histology

Patients alive at 6 months (%)

Patients alive at 12 months (%)

Cause of death

Lung (67%), kidney, parotid

NS

NS

NS

NS

NS

NS

NS

Primary tumor sites identiﬁed

Ebels & van der Meulen, 1978

1966–74

19

53

63

37

NS

Dhopesh & Yagnik, 1985

NS

26

59

65

34

Headache, motor deﬁcit

58

42

15

67

Lung (67%), testes

NS

Le Chevalier et al., 1985

1959–79

120

54

74

26

Elevated ICP, motor deﬁcit

77

23

12

44

Lung (45%), GI, melanoma, thyroid, breast, kidney

Adeno (44%), UC, SCC

52

18

NS

Eapen et al., 1988

1970–82

43

60

70

30

Elevated ICP, motor deﬁcit

63

37

26

16

Lung (45%), melanoma, bladder, liver, prostate

Adeno (56%), SCC, UC

52

20

Brain metastasis

Merchut, 1989

1977–87

56

59

54

46

Motor deﬁcit

57

43

30

84

Lung (68%), GI, bladder, thyroid, melanoma, lymphoma

Adeno (46%), UC, SCC

55

13

NS

Chee, 1990

1973–84

33

60’s

61

39

Focal neurological deﬁcit

52

48

15

NS

NS

Adeno (47%), UC, SCC, sarcoma, TCC

NS

NS

NS

Debevec, 1990

1973–87

75

(40–59)

77

23

NS

41

59

NS

63

Lung (53%), breast, skin, esophagus, kidney, parotid

UC, Adeno (21%), SCC

NS

18

Brain metastasis

Salvati et al., 1995

1976–88

100

50’s

75

25

Headache, focal signs

100

Excluded 26

64

Lung (65%), GI, melanoma, kidney, breast, UG

Adeno NS (65%), SCC, melanoma, UC

30

NS

van de Pol et al., 1996

1987–94

72

65

64

36

NS

NS

NS

NS

75

Lung (72%), breast, colon, melanoma

NS

~ 40

~ 20

Khansur et al., 1997

1982–89

32

57

75

25

Headache, paresis

44

56

9

3

Lung (100%)

NS

40

9

Nguyen et al., 1998

1977–96

39

55

54

46

Headache, weakness

49

51

33

31

Lung (83%), GI

Adeno (79%), small cell, other, SCC

~ 80

56

Systemic disease

Maesawa et al., 2000

1988–98

15

57

47

53

Focal neurological deﬁcit

60

30

40

27

Lung (75%), liver

Adeno (67%), SCC, clear cell, UC

NS

~ 65

Systemic disease

Systemic disease

NS

NS, not stated; ICP, intracranial pressure; GI, gastrointestinal; UG, urogenital; Adeno, adenocarcinoma; UC, undifferentiated carcinoma, SCC, squamous cell carcinoma; TCC, transitional cell carcinoma. Reproduced with permission from Mayﬁeld Clinic.

296

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with increased intracranial pressure are the most common presenting signs followed by other focal neurological deﬁcits. Signs and symptoms of extracerebral metastasis may be present and can provide valuable clues to the location of a primary tumor site and to overall tumor burden15, 18. The clinical presentation is also similar for the smaller subgroup of patients who present with brain metastasis as the only manifestation of an undetected tumor, except that signs of posterior fossa involvement may occur more frequently16.

Extent and distribution of metastatic disease Patients with brain metastasis and an unknown primary cancer site may have extracerebral metastatic disease present in their lymph nodes, bones, liver, or lungs. When extracerebral metastasis is present, the brain metastases are classiﬁed as either single or multiple. Alternatively, the brain may represent the only site of metastasis in the body, harboring either a solitary metastasis or multiple metastases. In one series of 421 patients referred for radiosurgical treatment of brain metastasis14, 15 patients (3.6%) had brain metastasis without a known primary cancer site, despite having undergone intensive diagnostic evaluation at the time of presentation. Ten of these 15 patients (75%) also presented with synchronous metastatic disease outside of the brain (e.g., in the lungs or lymph nodes). In a recent study, only 39 of 220 patients (18%) with brain metastasis and an unknown primary tumor site were without evidence of extracerebral metastasis at the time of presentation16. Therefore, more than 75% of patients with brain metastasis and an undetected primary tumor are likely to have coexistent systemic metastasis. This is important because one of the most signiﬁcant predictors of patient outcome is the extent of extracerebral tumor burden21, 23, 26. This estimate of extracerebral disease burden is comparable with the results of a series in which the primary site was known27. Most patients with undetectable systemic disease develop extracerebral metastasis a few months after the clinical presentation of the brain metastasis, regardless of whether the primary site becomes known or remains occult16, 27. As already mentioned, when the primary tumor site remains unknown, the brain metastases may be single, solitary, or multiple. Single brain metastases occur at a frequency of 41% to 77% in patients whose primary tumor site is unknown (Table 17.1). This range is similar to that reported for brain metastases found in the setting of a known primary tumor site13, 25. When the primary site remains unknown, parenchymal brain metastases may be found in the cerebral hemispheres, diencephalon, brainstem, or cerebellum7, 12, 14, 16, 17. One potentially signiﬁcant difference between patients with a known primary cancer site and those in whom it is unknown is that the cerebellum appears to be overrepresented as a site of brain metastasis when the primary site remains unknown. In the general population of patients with brain metastases, the cerebellum is involved in approximately 12% to 15% of the cases19, 22. In the majority of studies in which the primary tumor site is unknown, the cerebellum is involved (but not necessarily the only site of brain involvement) in 26%

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to 40% of cases (Table 17.1). Interestingly, the two most recent studies, which excluded patients in whom a primary site was identiﬁed within two to three months of the presenting brain metastasis, demonstrated cerebellar involvement in 33% and 40% of the cases, respectively14, 16. Tumors that arise in the abdomen and pelvis are known to metastasize preferentially to the posterior fossa19. The mechanism underlying this preference may be explained either by retrograde venous dissemination of tumor emboli to the posterior fossa by virtue of its connections with Batson’s plexus28 or by the ability of the cerebellum to preferentially support the growth of tumor cells from certain organs29. This latter effect may be attributed to cerebellum-speciﬁc growth factors or to permissive extracellular matrix components. Therefore, when the cerebellum is involved, the abdomen and pelvis may represent an important primary source of metastasis in patients with an unknown primary tumor. The overall occurrence of brain metastasis with an unknown primary tumor site or extracerebral metastasis may also be explained by the ability of brain parenchyma to support aggressive growth of metastatic tumor deposits compared with the primary cancer site or other body sites. A few patients with this distribution of disease have been observed to survive for several years. Their long-term survival appears to be based on effective treatment of the brain metastases and lack of development of extracerebral disease14 –16. Other patients die of overwhelming intracranial disease, and in some, even autopsy fails to disclose a primary cancer site10, 17.

Relationship with speciﬁc systemic cancers When the primary tumor site is ultimately identiﬁed after additional patient follow up, histopathological analysis, or autopsy in patients in whom it was previously unknown, most studies have shown a different frequency distribution with respect to the organ of origin relative to that for patients in whom the primary tumor site is known from the outset. In patients with an unknown primary cancer site, the lung represents the most frequent primary tumor site discovered antemortem, accounting for between 45% and 83% of primary sites (Table 17.1). The lung appears to represent the most common primary site, regardless of whether it becomes known within two months of the diagnosis of brain metastasis or later16, 18. In contrast, when the primary cancer site is discovered only at autopsy, there does not appear to be a predominant organ of origin11, 13, 15. In the general population of patients with brain metastases, the lung is identiﬁed as a primary site in 50% to 70% of patients and is followed in order of frequency by breast metastases in women20, 22, 23. In comparison, the breast appears to be underrepresented as a primary cancer site in the population of patients in whom the site is initially occult or remains so until autopsy11, 13 –16, 30. In these studies, organs from the abdomen and pelvis typically surpass the breast as the second most common site of primary cancer metastasizing to the brain. This difference may be a result of the earlier diagnosis of primary breast cancer or of the tendency of breast tumors to

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metastasize at a more advanced stage of the primary. Other primary cancers that become manifest include those derived from the skin and upper aerodigestive tract (melanoma, squamous cell carcinoma, and adenocarcinoma), thyroid gland, hematologic system, and reproductive organs in men and women. The fact that lung cancers predominate among primary cancers determined antemortem for patients who initially presented with unknown primaries is not surprising, given the high incidence of lung cancer in general, the greater ease of detection of lung masses, and the direct vascular connection between the lungs and the brain, providing a convenient route for hematogenous dissemination. However, it is also possible that a discovered lung mass actually represents metastatic disease from another organ rather than a primary lung tumor, because tumors from most organs that metastasize to the brain do so by ﬁrst metastasizing to the lungs31, 32. Therefore, ﬁnding a lung mass by the use of chest radiography should be interpreted cautiously.

Diagnostic evaluation Until recently, it has been unclear how far to carry the initial diagnostic evaluation in patients with cancer of an unknown primary site. Both general oncological and neuro-oncological studies have shown that an exhaustive diagnostic evaluation typically yields no more useful information than a screening diagnostic evaluation1, 2, 4, 5, 15. The goals of evaluation should be to identify patients with favorable clinical and histopathological features for whom speciﬁc treatment is available. For example, speciﬁc regional and systemic treatment is available for certain patients with metastatic cancer arising from primary tumors of the breast, prostate, and other reproductive organs1, 2, 4, 5. Following the completion of contrast-enhanced magnetic resonance imaging of the brain that adequately assesses the extent of intracranial disease, the initial evaluation of patients who present with brain metastasis as the ﬁrst sign of a cancer should include a complete review of the patient’s physiological systems. A thorough review of these systems not only helps to locate the primary site of most symptomatic brain metastases15, 18 but also ascertains the general functional status of the patient, which is critical before further treatment decisions can be made. In many cases the patient’s medical history reveals organspeciﬁc complaints that should be used to guide further diagnostic work-up. The work-up should also include a comprehensive physical examination, a screening laboratory test panel, and a limited radiographic imaging evaluation. The physical examination should include evaluation of all lymph node basins in the groin, axilla, and head and neck. Palpation of the thyroid gland, a digital rectal examination, and a careful skin examination should be performed. In men, the testes and prostate need to be examined. In women, it is necessary to perform a thorough breast and gynecologic examination. In a study of 72 patients presenting with symptomatic brain metastases from undiagnosed primary sites, 57% had complaints suggesting an underlying malignancy18. Symptoms indicating a primary lung tumor were most fre-

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quent, including an altered coughing pattern, hoarseness, and dyspnea. In 31% of these patients abnormalities were found by physical examination that accurately suggested the location of a primary tumor. Other important signs and symptoms of a primary extracerebral tumor include anorexia, weight loss, abdominal pain, dysphagia, ﬂank pain, hematuria, or a new skin lesion. In another study of patients presenting with single brain metastases as the ﬁrst sign of systemic cancer, only 18% of patients had organ-speciﬁc complaints suggesting a primary malignancy; however, in 83% of these patients a primary tumor site was identiﬁed on the basis of the patient’s symptoms17. In summary, the medical history and physical examination may provide useful information that leads to the identiﬁcation of a primary tumor site in 18–57% of patients who present with precocious brain metastasis17, 18. The essential laboratory work-up should include a complete blood count, an electrolyte panel, calcium concentration determination, liver function tests, determination of amylase and lipase levels, testing of stool for occult blood, and a urinalysis. Tumor markers that are detectable in serum, such as prostate-speciﬁc antigen (PSA), CA-125, and carcinoembryonic antigen (CEA), may be nonspeciﬁcally increased in patients with cancer, and in general, they lack sufﬁcient sensitivity or speciﬁcity to be used as screening tools1, 30, 33. Determination of such markers should be reserved for patients who are separable into one of several speciﬁc subgroups based on individual clinical characteristics and histopathology1. For example, serum PSA may be useful in men with brain metastasis and diffuse metastatic disease to bone or lungs. In general, tumor markers are more valuable for following the effects of treatment than for making a speciﬁc diagnosis. In the absence of organ-speciﬁc signs or symptoms, the initial radiographic work-up should include a chest radiograph and computed tomography (CT) scans of the chest, abdomen, and pelvis15, 18. Although mammography rarely detects an occult primary tumor site in patients with brain metastasis, the implications for treatment may justify its use in women, as effective treatment for breast cancer does exist. In a study that included 72 patients presenting with brain metastasis as the ﬁrst sign of cancer, a chest radiograph detected abnormalities in 56 patients (78%), and 47 of these patients proved to have primary lung tumors18. Similar ﬁndings were obtained in another study in which 71% of patients presenting with brain metastasis as the ﬁrst sign of cancer had abnormal chest x-rays. The diagnostic yield obtained from a simple chest x-ray is not surprising, given the high prevalence of metastatic lung cancer among men and women. However, as mentioned previously, the ﬁnding of a lung mass must be interpreted cautiously, because many other tumors that metastasize to the brain do so by ﬁrst metastasizing to the lungs31, 32. A chest CT scan may disclose lung masses not shown by chest radiography. In a retrospective study of 32 patients with brain metastasis as the ﬁrst sign of systemic cancer, 38% of patients with positive ﬁndings on a chest CT image had negative or unclear ﬁndings when chest radiography was used34. CT imaging of the abdomen and pelvis may identify a primary tumor site in as

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many as 35% of patients in whom the medical history, physical examination, and chest radiograph are negative for cancer and may demonstrate additional or unsuspected disease in 65%35. Contrast studies of the gastrointestinal tract, nuclear medicine studies (e.g., bone scans), panendoscopy, bronchoscopy, lymph node dissections, and ﬁne needle biopsies should be limited to patients with organ-speciﬁc complaints or ﬁndings and who may beneﬁt from additional therapy directed at those organs. 18F-ﬂuorodeoxyglucose positron emission tomography (FDG-PET) scanning of the whole body is a new diagnostic modality that in some cases may identify a primary tumor site after an unsuccessful conventional diagnostic work-up. However, its routine use in the work-up of patients with cancer of an unknown primary site is not well established, and there are conﬂicting reports of its clinical utility36, 37. In a recent case report, FDG-PET demonstrated a hypermetabolic lesion 1.5 cm in maximum diameter in the left upper lung lobe of a 66-year-old man who initially presented with a solitary brain metastasis38. The lung lesion in this patient was not detected using conventional CT and radiography. No other metastatic disease was detected in this patient. Surgical resection of the brain metastasis and the involved lung lobe resulted in a disease-free status for the patient at a follow-up visit 2 years later. In patients with a single supratentorial lesion, the differential diagnosis must include primary central nervous system tumors and nontumor masses, and extensive diagnostic testing in search of a primary tumor site outside of the brain is even less rewarding. In a study by Voorhies et al., it was established that the probability of a metastatic lesion in patients without a known history of cancer was only 7% if their chest radiograph and intravenous pyelogram were negative39. Therefore, in patients with a single supratentorial mass lesion, it is even more important to limit the extent of preoperative diagnostic studies aimed at examining the body for a primary tumor site. The fraction of patients in whom a diagnostic evaluation demonstrates a primary tumor site varies between 3% and 84% among clinical series (Table 17.1). This substantial range of diagnostic yield is probably a consequence of several factors. First, earlier clinical series made use of less-sophisticated diagnostic modalities (in the pre-CT era). Second, individual investigators used diagnostic protocols of varying rigor to evaluate patients. Third, earlier studies typically included all patients who presented with brain metastasis as the ﬁrst sign of cancer. Most of these patients had a primary tumor site identiﬁed after the initial screening evaluation, and therefore, do not actually represent patients with undetectable primary sites. This last point again emphasizes the need to clearly deﬁne this patient population in clinical studies. Of 56 patients in one study, 71% had a probable primary tumor site identiﬁed during the initial diagnostic evaluation15. Of the remaining 16 patients, 44% had a primary site identiﬁed at between four and 11 months after presentation. In the two most recent studies that excluded patients whose primary cancer site was identiﬁed within two or three months of presenting with brain metastasis, the primary site was eventually identiﬁed in 27% and 31% of patients, respect-

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ively14, 16. Median times to diagnosis of a primary site in these two studies were 11.75 and 22 months, respectively (range 2–35). Therefore, it appears that a primary cancer site becomes known antemortem by using contemporary diagnostic modalities in 27–44% of patients in whom the primary site is not identiﬁed within the ﬁrst two–three months of evaluation.

Neurosurgical intervention Histopathological analysis is critical to the appropriate management of patients with cancer of an unknown primary site. Therefore, the decision to operate is strongly favored when the brain is the only known site of metastatic disease or when the diagnosis of brain metastasis is in doubt. A tissue diagnosis may be obtained by stereotactic biopsy or resection. If stereotactic biopsy is performed, care must be taken to provide an adequate sample for both routine and specialized histopathological evaluations. A cauterized sample is typically inadequate for specialized studies. If metastatic disease is present outside of the brain, then biopsy of a peripheral site should be considered, especially if the peripheral biopsy procedure is predicted to be less morbid than the neurological procedure (e.g., supraclavicular lymph node biopsy versus biopsy of a deep-seated brain metastasis). The brain-speciﬁc treatment of patients with brain metastasis from cancer of an unknown primary site has been similar to that for patients with brain metastasis in whom the primary site is known7, 12, 14, 19 –24. Therapeutic decisions require careful evaluation of numerous factors, including tumor size, location, multiplicity, histology, the overall functional status of the patient, the extent of systemic disease, and the response or potential for response of systemic disease to treatment. For patients who are surgical candidates, the extent of systemic disease and their overall functional status are the two most important variables that correlate the most with patient survival23. If a patient is determined to be an operative candidate and tissue is needed to make the diagnosis of cancer metastatic to the brain, then surgical considerations are based mainly on the accessibility and multiplicity of the brain lesions. Surgical resection combined with whole-brain radiation therapy (WBRT) has proved superior to WBRT alone for patients with single brain metastases40, 41. If surgical resection is performed, frameless stereotaxis is an important technical adjuvant for trajectory planning and tumor localization. Although it is controversial, most patients who undergo surgical resection or stereotactic radiosurgery (SRS) are also treated with WBRT 42, 43. Stereotactic biopsy followed by SRS is an alternative to surgical resection of a single brain metastasis that is small in size and deep-seated or located in eloquent cortex. Survival beneﬁt has also been shown for patients who undergo surgical resection for multiple brain metastases44. Bindal et al. showed that the survival of patients who underwent craniotomy for multiple metastases was similar to patients who underwent surgery for single brain metastases if all lesions could be removed44. If, however, it is not possible to remove all brain lesions with

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acceptable operative morbidity, then resection or biopsy of one lesion should be performed only if it is necessary to provide tissue for specialized histopathological studies, i.e., tissue is not available from another body site. These patients may then be treated with SRS and WBRT45, 46. One important additional indication for craniotomy in patients with multiple brain metastases is an accessible lesion with overwhelming mass effect that is causing symptoms likely to improve after resection.

Histopathological studies Evaluation of tissue obtained from the metastatic site is essential to appropriately plan both general oncological and neuro-oncological strategies. In the absence of a clinically identiﬁable primary tumor site, histopathological characteristics of the lesion can provide valuable information that may 1 indicate a likely organ of origin for the metastasis 2 guide further specialized diagnostic work-up, and 3 assign the patient to a clinicopathological subgroup that may beneﬁt from speciﬁc treatment1, 2, 4, 5. For these reasons, histopathological studies should be performed as soon as possible after the completion of the screening clinical evaluation. In the absence of organ-speciﬁc signs or symptoms, biopsy or resection of the metastasis and histopathological evaluation should be performed prior to considering further clinical diagnostic testing4, 47, 48. The use of routine light microscopy is often sufﬁcient to conﬁrm the diagnosis of metastatic neoplasm and to classify most brain metastases of unknown origin into one of the following four histological subgroups: 1 adenocarcinoma 2 squamous cell carcinoma 3 poorly differentiated carcinoma, or 4 other poorly differentiated malignant neoplasm5. In the case of brain metastases that are well-differentiated and retain speciﬁc cellular characteristics of the organ of origin, their source may be evident using only light microscopy48, 49. For example, the presence of abundant cytoplasmic glycogen is characteristic of renal cell carcinoma and has been speciﬁcally referred to as “clear cell carcinoma”48, 49. Melanotic or squamous cell differentiation may be obvious. For some well-differentiated adenocarcinomas, subtle glandular or microvillus architecture may also provide clues to the identity of the primary tumor site48, 49. However, most metastatic adenocarcinomas and carcinomas are too poorly or insufﬁciently differentiated to allow speciﬁc diagnosis by conventional light microscopy alone49 –51. Thus, evaluation of the tumor specimen usually involves the application of specialized ancillary techniques such as immunoperoxidase staining, electron microscopy, and cytogenetic studies. For practical reasons (e.g., convenience, cost, and diagnostic yield), immunoperoxidase staining is usually performed prior to electron microscopy and cytogenetic studies. The success of these studies depends to a

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great extent on the technical expertise and experience of the pathologist in dealing with cancer of an unknown primary site. Because clinical information is used to guide these studies, the clinician and pathologist need to communicate regularly. Immunoperoxidase staining is based on the detection of tissue-, organ-, or tumor-speciﬁc antigens using monoclonal or polyclonal antibodies. Many antibodies are available for this type of analysis. The choice of antibody for a particular specimen is based on the results of the initial examination of the specimen with the light microscope and clinical information. The use of additional antibody staining is guided by the results of the ﬁrst antibody panel. For example, in the case of undifferentiated adenocarcinoma, the respective patterns of cytokeratin-7 and cytokeratin-20 staining can often distinguish tumors derived either from the lung or the breast from those originating in the gastrointestinal tract51. In women, further differentiation of breast from lung primary tumor sites may be accomplished on the basis of the pattern of staining with antibodies directed against estrogen receptors, progesterone receptors, gross cystic disease ﬂuid protein-15 (GCDFP-15), and thyroid transcription factor-1 (TTF-1)51, 52. Recently, TTF-1 was shown to be a highly speciﬁc marker for adenocarcinomas derived from either the thyroid gland or the lung52. To date, no breast tumor has stained positively for TTF-1; therefore, if TTF-1 staining is positive, it is reasonable to exclude the diagnosis of a treatable breast cancer in a woman and thus avoid interventions designed to establish this diagnosis. Speciﬁc antibodies are also available for detection of melanoma (HMB-45), prostate carcinomas (prostate-speciﬁc antigen, PSA), germ cell tumors (alpha-fetoprotein, AFP; human chorionic gonadotropin, beta-HCG), and lymphoid tumors (common leukocyte antigen, CLA)50. If immunoperoxidase staining of the tumor specimens gives an inconclusive result, electron microscopy or cytogenetic studies may provide useful information48.

Patient outcome and adjuvant treatment of systemic disease The survival of patients with brain metastases is generally poor. The median survival of patients selected to undergo neurosurgical resection followed by radiotherapy was only 8.9 months in a recent study that included 1292 patients with brain metastases23. Even class I patients with good prognostic indicators (patient age < 65 years, Karnofsky Performance Scale [KPS] score ≥ 70, a controlled primary tumor, and the brain metastasis as the only site of metastasis) have median survival times of only 7.1 months26. Although several groups have reported the outcome of patients with brain metastasis from an unknown primary cancer site, the authors derived differing conclusions from their results. Some authors reported that the prognosis of patients whose primary tumor site remained occult was worse than that of patients in whom it was known at the time of ﬁrst presentation because appropriate treatment of the

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primary tumor was delayed13. Others argued that these patients had a better overall outcome due to the relative lack of signiﬁcant extracranial disease14 –17. In two recent studies, the median survival times for patients treated for brain metastasis from an unknown primary site were 13.4 and 15 months, respectively14, 16. The approximate doubling of median survival time in these studies compared with that of all brain metastasis patients is probably because one study excluded patients with extracranial metastasis present at the time of initial diagnosis16, whereas the other study selected patients with brain metastases that were no larger than 3.5 cm in maximum diameter (suitable for radiosurgical treatment), and nearly all of these patients had KPS scores of 80 or more14. In addition, both studies excluded patients whose primary site became known within two months of their presenting with brain metastasis. The authors state that in some cases a two-month interval was necessary to allow urgent treatment of the brain metastasis and to ensure that a complete diagnostic work-up had been completed. However, this two-month interval naturally excluded patients with biologically aggressive tumors who would have experienced a rapidly progressive clinical course. Older studies with less stringent patient inclusion criteria demonstrate survival times similar to the brain metastasis group as a whole8, 10, 12, 13, 15, 18. In all studies in which contemporary aggressive treatment was performed for the brain lesion in patients who have brain metastasis and an unknown primary tumor, the cause of death was progression of systemic disease14, 16, 18. Even patients with brain metastasis as the only manifestation of an undetected tumor ultimately die most frequently from the eventual development of systemic neoplastic disease16. Because intracranial disease can be controlled in many of these patients14, 16, efforts should be directed toward identifying the patients for whom effective systemic treatment is available. Cooperation with a medical oncologist experienced in the care of patients with systemic metastasis from an undetected primary cancer site is imperative. Several studies indicate that a subgroup of patients with brain metastasis from cancer of an unknown primary site survives long term without developing systemic metastatic disease or a known primary site. As already mentioned, the biology of the primary tumor in these patients remains an enigma. The essential characteristics of these few patients are that they are in good performance status at the time of presentation and undergo effective brainspeciﬁc treatment (surgical resection and/or SRS plus WBRT). In one study, seven of 39 patients were alive eight years after treatment of their metastatic brain tumors16. In another study, three of 15 patients with multiple brain metastases were reported to be alive between 26 and 51 months after treatment of their brain metastases with radiosurgery14. The causes of death for other patients in these two studies were progression or development of uncontrollable systemic disease, despite effective control of disease metastatic to the brain. After treatment of disease metastatic to the brain, decisions regarding the general oncological care of the patient must be made. There is no information available in the literature that adequately addresses the subsequent care of this

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speciﬁc population of patients. The evolution of systemic treatment strategies for patients with cancer of an unknown primary site is largely a result of clinical work performed on the population of patients who present with metastatic disease from an undetected primary tumor outside of the central nervous system. These patients have heterogeneous clinical presentations, and therefore, it is not advisable to generalize treatment strategies and prognoses. As already mentioned, clinicopathological characteristics can be used to classify patients with unknown primary tumors into subgroups1, 2, 4, 5. The method that has evolved is to identify the patients belonging to clinicopathological subgroups for which an effective systemic treatment strategy exists. For example, the prognosis of women with breast cancer in whom adenocarcinoma is found in an axillary lymph node is signiﬁcantly better than for the group as a whole after modiﬁed radical mastectomy and adjunctive radiotherapy and chemotherapy4, 5. Similarly, patients with squamous cell carcinoma in a high- or midcervical lymph node appear to beneﬁt from local surgical treatment and speciﬁc adjunctive therapies4, 5. Currently, it is unclear whether empiric systemic treatment is beneﬁcial for patients whose metastases have unfavorable epithelial histologies, such as those reﬂective of lung or gastrointestinal origin2, 53. The applicability of treatment strategies that have evolved for cancer of an unknown primary site outside of the central nervous system to the treatment of patients with brain metastasis has not been studied directly. However, because the most signiﬁcant cause of death in patients with treated brain metastasis and an unknown primary site is progression or development of extracranial disease, it is important to treat the systemic disease as aggressively as possible. A unique situation arises in patients who present with brain metastasis as the only manifestation of systemic disease. As shown in the study by Nguyen et al., most of these patients ultimately die from causes related to the development of systemic cancer16. It is unknown whether this group of patients would have beneﬁted from earlier and empiric treatment with chemotherapy or other site-speciﬁc interventions. For patients with brain metastasis, discovery of the primary cancer site after treatment of the brain disease does not appear to alter the clinical course of the patient group as a whole14 –17. This may be due to the presence or development of signiﬁcant extracerebral metastases or to the low number of neoplasms metastatic to the brain that lend themselves to effective systemic treatment. Because of the unlikelihood of discovering a treatable systemic neoplasm, further diagnostic testing of these patients should be kept to a minimum. Additional diagnostic tests may be ordered, based either on careful clinical monitoring for new signs or symptoms or on the results of specialized pathological studies. Periodic whole-body imaging is not recommended.

Summary Cancer of an unknown primary site is not uncommon. Patients with this diagnosis have heterogeneous clinical presentations. The diagnosis is made

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only after a screening clinical and diagnostic work-up fails to disclose a likely primary site. A subset of these patients may ﬁrst present with a symptomatic brain metastasis. This subset of patients has been considered separately in the literature and appears to represent a distinct clinical entity. The clinical characteristics of patients with brain metastasis from an undetected primary tumor do not appear to differ signiﬁcantly from the general group of all patients with brain metastasis. In the absence of organ-speciﬁc signs or symptoms, diagnostic studies should be kept to a minimum. A primary lung tumor will ultimately become manifest in most patients, and this carries a poor prognosis. A few patients will have primary tumors discovered for which effective therapy is available. Specialized histopathological evaluation is essential to plan further diagnostic and therapeutic interventions and should be aimed at identifying treatable subgroups. Brain-speciﬁc treatment using contemporary neurosurgical modalities results in a median survival time equal to or better than that for patients in whom the primary is known. A unique situation occurs when the brain metastasis represents the only manifestation of an undetected tumor. Although most such patients ultimately develop tumor manifestations outside of the brain, a few will survive for several years after treatment of their brain metastases alone. The biology of primary tumors that metastasize only to the brain and remain occult for several years is not understood and represents an intriguing area for molecular research.

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34 Latief KH, White CS, Protopapas Z, et al.: Search for a primary lung neoplasm in patients with brain metastasis: Is the chest radiograph sufﬁcient? AJR Am J Roentgenol 1997; 168: 1339–1344. 35 McMillan JH, Levine E, Stephens RH: Computed tomography in the evaluation of metastatic adenocarcinoma from an unknown primary site. A retrospective study. Radiology 1982; 143: 143–146. 36 Kole AC, Nieweg OE, Pruim J, et al.: Detection of unknown occult primary tumors using positron emission tomography. Cancer 1998; 82: 1160 –1166. 37 Greven KM, Keyes JW Jr, Williams DW 3rd, et al.: Occult primary tumors of the head and neck: lack of beneﬁt from positron emission tomography imaging with 2-[F-18]ﬂuoro-2deoxy-D-glucose. Cancer 1999; 86: 114 –118. 38 Torre W, Garcia-Velloso MJ, Galbis J, et al.: FDG-PET detection of primary lung cancer in a patient with an isolated cerebral metastasis. J Cardiovasc Surg 2000; 41: 503 –505. 39 Voorhies RM, Sundaresan N, Thaler HT: The single supratentorial lesion. An evaluation of preoperative diagnostic tests. J Neurosurg 1980; 53: 364 –368. 40 Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 41 Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al.: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993; 33: 583 –590. 42 Patchell RA, Tibbs PA, Regine WF, et al.: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998; 280: 1485 –1489. 43 Mintz AP, Cairncross JG: Treatment of a single brain metastasis: The role of radiation following surgical resection. JAMA 1998; 280: 1527–1529. 44 Bindal RK, Sawaya R, Leavens ME, et al.: Surgical treatment of multiple brain metastases. J Neurosurg 1993; 79: 210 –216. 45 Breneman JC, Warnick RE, Albright RE Jr, et al.: Stereotactic radiosurgery for the treatment of brain metastases. Results of a single institution series. Cancer 1997; 79: 551–557. 46 Maor MH, Dubey P, Tucker SL, et al.: Stereotactic radiosurgery for brain metastases: results and prognostic factors. Int J Cancer 2000; 90: 157–162. 47 Hammar S, Bockus D, Remington F: Metastatic tumors of unknown origin: an ultrastructural analysis of 265 cases. Ultrastruct Pathol 1987; 11: 209 –250. 48 Mrak RE: Origins of adenocarcinomas presenting as intracranial metastases. An ultrastructural study. Arch Pathol Lab Med 1993; 117: 1165 –1169. 49 Hammar SP: Metastatic adenocarcinoma of unknown primary origin. Hum Pathol 1998; 29: 1393–1402. 50 Takahashi JA, Llena JF, Hirano A: Pathology of cerebral metastases. Neurosurg Clin N Am 1996; 7: 345–367. 51 Perry A, Parisi JE, Kurtin PJ: Metastatic adenocarcinoma to the brain: an immunohistochemical approach. Hum Pathol 1997; 28: 938 –943. 52 Bohinski RJ, Bejarano PA, Balko G, et al.: Determination of lung as the primary site of cerebral metastatic adenocarcinomas using monoclonal antibody to thyroid transcription factor-1. J Neurooncol 1998; 40: 227–231. 53 Greco FA, Hainsworth JD: Poorly differentiated carcinoma or adenocarcinoma of unknown primary site: long-term results with cisplatin-based chemotherapy. Semin Oncol 1994; 21: 77–82.

CHAPTER 18

Leptomeningeal carcinomatosis: diagnosis and management Morris D Groves, Jr

Introduction Neoplastic meningitis and leptomeningeal carcinomatosis (LC) refer to the dissemination of cancer to the pia mater, subarachnoid space, cerebrospinal ﬂuid (CSF) and arachnoid membrane. LC is a metastatic manifestation of many different malignancies, especially adenocarcinomas, and it carries a poor prognosis. The current management of LC is multidisciplinary and requires the expertise of neuro-oncologists, medical oncologists, neurosurgeons, and radiation oncologists. There has been very little improvement in the overall prognosis for patients with LC over many years. The current goal of treatment is primarily palliation and prevention of neurological deﬁcits. Because of improvements in treatment for many cancers, LC is likely to become a more frequently encountered clinical problem. This chapter will focus on LC secondary to the presence of solid tumors, but many of the concepts are relevant to the diagnosis and treatment of leptomeningeal involvement of leukemia and lymphoma.

Epidemiology Most patients with LC from solid tumors have disseminated cancer at the time of diagnosis1, although 20 to 35% of patients may not have identiﬁably active malignant disease outside the nervous system2, and 6 to 38% of patients may have no history of known malignant disease2, 3. Approximately one-third of patients with LC will have evidence of metastatic extension to other areas of the central nervous system (CNS) such as the brain, spinal cord, or the epidural space2, 4, 5. In patients with cancer who eventually undergo autopsy, as many as 19% of those who had neurological symptoms will have evidence of meningeal involvement of their cancer6. The incidence of LC varies depending upon the primary cancer histology. Approximately 2 to 5% of breast cancer patients eventually develop LC4, 7. Over the duration of their illness, small cell lung cancer (SCLC) patients have a

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6 to 11% risk of developing LC, although if patients with SCLC survive for three years, the incidence climbs to 25%8. Non-small cell lung cancer (NSCLC) patients have an estimated risk of LC of 1–5%9. Melanoma patients can have up to a 23% risk of developing LC10. Lymphoma and leukemia may involve the meninges in up to 6.3 and 10% of cases, respectively11, 13. Other malignancies, including gliomas, renal and other genitourinary cancers, gastrointestinal tumors, and sarcomas can also metastasize to the leptomeninges. Estimating conservatively, in the US, 30 to 40,000 individuals per year will be diagnosed with LC. Due to improvements in cancer treatments, the increasing sensitivity of modern diagnostic tests, and the relative isolation of the CNS and CSF from systemic therapies, the numbers of people diagnosed with LC each year will probably increase.

Pathophysiology The blood-brain barrier, which prevents large, hydrophilic chemotherapeutic agents from entering the CNS, results in this region becoming a sanctuary for malignant cells. Once malignant cells gain access to the spinal ﬂuid pathways, the cells can be dispersed throughout the CNS by direct extension along the meninges, or they can exfoliate and be carried to other parts of the CNS by CSF ﬂow. New metastatic deposits invade the subpial parenchyma, penetrate spinal nerve roots, and produce subarachnoid masses. The basal cisterns, posterior fossa, and cauda equina are the most frequently affected regions of the CNS, most likely from the effect of gravity on CSF ﬂow in these areas. Malignant cells can gain access to CSF pathways by a variety of routes, including: direct extension from parenchymal or epidural metastases (synchronous intraparenchymal brain metastases occur in 28 to 75% of patients with LC)2, 4, 6, 14; perineural growth along cranial or spinal nerves15; hematogenous propagation through arachnoid vessels, the choroid plexus, or the internal spinal venous (Batson’s) plexus; or perivenous extension from bone marrow metastases16. Intraoperative propagation is also possible17. A pattern of progressive involvement in leukemic meningitis has been described where there is progressive disease extending from the walls of the superﬁcial arachnoid veins to the surrounding adventitia, reaching the CSF18 and extending into the brain to the Virchow–Robin spaces. Similarly, in LC from SCLC, patients have been noted to have ﬁlling of the Virchow–Robin spaces from perivascular extension of the tumor and involvement of perineural and perivascular lymphatics and invasion of endoneural and perineural sheaths within the intervertebral foramina6, 8, 14, 19. The proximity of tumors to CSF pathways may play a part in their propensity to enter the CSF, as demonstrated by the fact that primary brain tumors such as ependymomas, pineoblastomas, and medulloblastomas are more often associated with LC than the more common intraparenchymal primary brain tumors20, 21.

Leptomeningeal carcinomatosis: diagnosis and management 311 Table 18.1 Symptoms and signs of leptomeningeal carcinomatosis at time of presentation. Neuraxis level

Symptoms

%

Signs*

%

Cerebral

Headache Mental changes Gait difﬁculty Nausea/vomiting Incoordination Loss of consciousness Dizziness

51–66 26–33 27 22–34 20 4 4

Mental changes Seizures/syncope Papilledema Diabetes Insipidus Hemiparesis Cerebellar signs

27–62 11–18 11 4 2 15

Cranial Nerve

Diplopia Visual loss Facial numbness Tinnitus/hearing loss Hypogeusia Dysphonia/dysphagia Vertigo

20–36 9–10 10 10–14 4 2–7 2

III,IV,VI II V VII VIII IX/X XII

5–36 6–19 6–10 10–30 7–18 2–6 5–10

Spinal

Lower motor neuron weakness Paresthesias Radicular pain Back/neck pain Bowel/bladder dysfunction

34–46 33–42 26–37 31–37 16–18

Nuchal rigidity Weakness Sensory loss Positive straight leg raise test Anal sphincter dysfunction

9–13 73 32 15 5–14

%, percent of patients affected 2, 4. *Roman numerals indicate cranial nerve(s) involved.

Diagnosis Symptoms and signs2– 4, 22 LC symptoms and signs are referable to the speciﬁc neural structures involved by tumor and the degree to which they are involved. Symptoms and signs are usually assigned to three neuro-anatomic groups: cerebral, cranial nerve, and spinal. The most common symptoms and signs of LC and their incidence at the time of presentation are listed in Table 18.1. Headache, mental status changes, diplopia, back pain, and leg weakness or numbness are the most common complaints. Headache can be due to elevated intracranial pressure from CSF ﬂow obstruction at the level of the arachnoid granulations or the ventricular foramina with resulting communicating or noncommunicating hydrocephalus. Head pain can also result from inﬂammation of the pain-sensitive dura. Cognitive changes resulting from LC can include memory loss, lethargy, extreme somnolence or even loss of consciousness. Seizures occur in 15% of patients with LC. Cancer cells near the cortex may cause impairment by brain invasion or by a metabolic stealing phenomenon whereby the malignant cells use glucose that would otherwise be available for nearby neurons. Symptoms referable to involvement of the cranial nerves and lumbosacral roots are

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common because of the frequent accumulation of malignant cells around the gravitationally dependent skull-base and lumbo-sacral regions.

Diagnostic studies Cerebrospinal ﬂuid (CSF) If LC is considered a diagnostic possibility and it is safe to perform lumbar puncture, CSF must be evaluated for malignant cells. A cytological examination identifying malignant cells in a patient’s CSF is the sine qua non of diagnosis in LC, but the sensitivity of a single CSF cytological examination can be as low as 45%3. Several physician-dependent variables have been shown to minimize false-negative CSF results, including: 1 withdrawing at least 10.5 mL of CSF for cytological analysis 2 processing the CSF specimen immediately 3 obtaining CSF from a site adjacent to areas suspected of LC involvement, and 4 repeating this procedure once if the initial cytological test is negative23. The sensitivity of CSF cytological testing is improved to > 77% if more than one CSF analysis is performed1–3, 22. The variability of test results on CSF drawn from the lumbar space versus that drawn from a ventricular reservoir is high enough that it is important to obtain lumbar CSF, particularly for assessment of response to treatment24, 25. In patients being evaluated for LC, the presence of neuroimaging ﬁndings suggestive of LC increases the likelihood of obtaining a cytological test positive for LC to > 60%, whereas if neuroimaging reveals no suggestion of LC, the odds of obtaining a positive CSF cytological test drop to 25%5. Other routine CSF studies that may support the diagnosis include: measurement of CSF opening pressure, cell count, and protein and glucose determinations. CSF pressure is elevated above 150 mm H2O in 30 to 57% of patients at the time of their initial lumbar puncture3, 26. The CSF WBC count is elevated in > 50% of patients who have LC and usually consists of lymphocytes or PMNs2, 3, 26, although CSF cell count can be normal in as many as onethird of patients whose CSF tests positive for malignant cells1. Elevation of CSF protein above 50 mg/dL occurs in > 70% of patients with LC3, and in patients with known cancer and multifocal neurological deﬁcits who are negative for LC on cytological tests, elevated protein levels may be helpful in establishing a diagnosis2, 27. A CSF glucose level of less than 60 mg/dL is found in up to 77% of LC patients3, and if infection can be excluded, this is highly suggestive of an LC diagnosis. A variety of methods are in use to increase the sensitivity of CSF analysis. Biochemical CSF markers such as alpha-fetoprotein (α-FP), human chorionic gonadotrophin (β-HCG), and carcinoembryonic antigen (CEA) are useful in the case of selected tumor histologies to help identify the presence of LC and are sometimes used to follow the course of the disease and response to treatment28. When these markers are used to assist with the diagnosis of LC, the baseline ratio of the CSF:serum marker level must be determined to insure that any level of a marker discovered in the CSF is not due to normal leakage across

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the blood-brain barrier. The less speciﬁc CSF markers such as β-glucuronidase, LDH, and β2-microglobulin are occasionally helpful in diagnosis but, unfortunately, are not speciﬁc for LC and can be elevated in inﬂammatory or infectious CNS processes, although some investigators suggest their use for evaluation of response to therapy25, 29. The sensitivity of these markers in LC detection can be as low as 22%.30 Immunohistochemical studies of the CSF employing monoclonal antibodies to surface antigens on malignant cells may aid in the diagnosis of some difﬁcult cases, particularly in patients with lymphomas and leukemias31, 32. The use of other methods, such as ﬂuorescence in situ hybridization33, 34, has also been suggested to increase the sensitivity of CSF analysis.

Neuroimaging In patients suspected to have LC, imaging of the symptomatic areas of the nervous system is useful for identifying areas suggesting the presence of LC, and imaging of the entire neuraxis is usually necessary. Radiographic abnormalities consistent with or suggestive of LC include leptomeningeal, subependymal, dural, and cranial nerve enhancement, as well as superﬁcial cerebral lesions, and communicating hydrocephalus5. Neuroimaging ﬁndings are more likely to be abnormal in patients with LC from solid tumors than in those with hematological malignancies (90% versus 55%, respectively)5. Approximately 50% of patients with LC and spine-related symptoms will have abnormal imaging studies2. Magnetic resonance (MR) imaging is more sensitive in detecting leptomeningeal enhancement than imaging by computed tomography (CT)35, 36. In patients who cannot undergo MR imaging, contrast CT or a CT myelogram can also provide diagnostic information. Because areas of enhancement suggest but are not diagnostic for LC, one must consider the presence of other conditions that can result in meningeal enhancement, such as changes seen post craniotomy or post lumbar puncture, skull lesions, subacute stroke, subdural hematoma, or infection or inﬂammation35. There is evidence that patients with positive CSF cytology and negative neuroimaging may have a better prognosis37.

CSF ﬂow studies Once the diagnosis of LC has been established, evaluation of CSF ﬂow by injection of a radioactive tracer (usually 111Indium-DTPA) is recommended to assess for areas of occult CSF ﬂow obstruction or loculation, because up to 70% of patients with LC can have CSF-ventricular-outlet obstructions. CSF ﬂow evaluation is usually performed after placement of an intraventricular catheter. Focal radiotherapy treatment administered to areas of CSF ﬂow obstruction has been shown to improve survival outcomes38, 39. Improvements in survival times of four to six months were noted in these studies. Interestingly, the best overall survival (13 months) occurred in patients in whom discovered blocks to CSF ﬂow were opened with radiotherapy39.

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When CSF analysis does not conﬁrm results of neuroimaging When imaging is suggestive of LC but no malignant cells can be found in the CSF, or when imaging is negative and only indirect tests such as elevated protein or hypoglycorrachia are found on CSF testing, assays for additional markers such as α-feto protein, β-HCG, CEA, or β-2 microglobulin may be useful. Up to three lumbar puncture samples may increase the sensitivity of such tests, and rarely, meningeal biopsy is necessary. Sampling of the CSF from the cisternal area can increase the diagnostic yield and should be considered when signs and symptoms are referable to the brain or cranial nerves40. The passage of time, use of repeat imaging, and CSF assessment usually resolve the diagnostic dilemma. Occasionally, in the presence of clinical features and neuroimaging typical of LC and repeatedly non-diagnostic CSF testing, a presumptive diagnosis can be declared and treatment instituted without the sine qua non cytological results.

Management The management of patients with LC is difﬁcult and complicated due to the associated poor prognosis and the risk of toxicity from treatment. Fixed neurological deﬁcits rarely improve, and survival is often short, although early diagnosis and treatment before the development of signiﬁcant neurological disabilities may improve quality of life and prevent death from neurological causes. Survival with LC is poor, and treatment is considered palliative, but there is evidence that aggressive treatment (radiotherapy and intrathecal [IT] chemotherapy) directed at the meningeal disease can improve survival time by anywhere from three weeks to three months4. The goals of treatment for patients with LC should be to improve or stabilize neurological deﬁcits and to prolong survival. With no therapy, the median survival time of LC patients is four to six weeks, and death most often results from progressive neurological decline2. Therapy for LC can provide effective local tumor control so that most patients eventually succumb to systemic rather than neurological complications of their cancer 2, 26, 41. Treatment of LC should include the entire neuraxis because tumor cells are disseminated throughout the CSF. Both bulky disease and malignant cells ﬂoating in the CSF must be addressed; therefore, focal and more systemic treatments are needed. Proper management of the patient’s underlying systemic malignancy should accompany any treatments directed to the CSF. Patients who may derive the most beneﬁt from treatment are those whose underlying tumor is quiescent or is known to be responsive to the available treatments. Guidelines recently published by the National Comprehensive Cancer Network suggest poor and good risk stratiﬁcation of patients to determine whether or not aggressive treatment should be instituted. This report deﬁnes poor risk patients as those with 1 low Karnofsky Performance Scale (KPS) scores 2 multiple, serious, ﬁxed neurological deﬁcits, and 3 extensive systemic disease with few treatment options.

Leptomeningeal carcinomatosis: diagnosis and management 315

It deﬁnes good risk patients as those with high KPS scores no ﬁxed neurological deﬁcits minimal systemic disease, and reasonable systemic treatment options, if needed. In these guidelines, supportive care and radiotherapy to symptomatic sites of disease are suggested for poor risk patients42. Patients can be physically or cognitively impaired and may require more assistance than the immediate family can provide. For practical and safety reasons, modiﬁcations of the home as well as special means of transportation may be necessary. Addressing the psychological burden of LC on the patients and their caregivers is also an integral part of the care of each patient. 1 2 3 4

External beam irradiation Areas of the nervous system where LC causes CSF ﬂow obstruction, symptoms of weakness or pain, or where bulky disease is identiﬁed, are usually treated with external beam irradiation. LC resulting in CSF ﬂow obstruction requires involved-ﬁeld radiation to open CSF pathways and to allow for IT drug passage opposite to the blockage to ﬂow. Typical radiation doses are 30 Gy in 10 fractions, with patients with LC resulting from breast cancer, leukemia, and lymphoma are considered the best candidates for this therapy. The role for craniospinal irradiation in patients with LC has not been determined, but it is rarely used because of the signiﬁcant myelosuppressive and gastrointestinal toxicities with which it is associated43. Palliative radiation therapy to areas of symptomatic disease may be given to patients not considered good candidates for more aggressive approaches.

Intrathecal (IT) chemotherapy IT chemotherapy is given to treat subclinical leptomeningeal deposits and tumor cells suspended in the CSF and to prevent further seeding of the leptomeninges. There is debate regarding the use of IT chemotherapy versus systemic chemotherapy. At least one report has suggested that IT chemotherapy increases toxicity without adding beneﬁt over radiation therapy and systemic chemotherapy44. Another study showed a better survival outcome for patients treated with systemic rather than IT methotrexate45.

Route of Adminstration of IT Chemotherapy For patient comfort and better CSF distribution of chemotherapeutic agents, most patients undergo Ommaya reservoir placement for drug delivery. Intralumbar delivery of chemotherapy may result in drug placement outside of the thecal sac and increased variability of ventricular drug levels46. In CNS leukemia, chemotherapy delivery via an Ommaya reservoir appears to result in improved durability of remission relative to intralumbar drug delivery47, 48. The reservoirs are usually well tolerated, but complications such as misplacement, catheter tip occlusion, or infection can occur in as many as 5% of patients41, 49.

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Commonly used IT chemotherapy agents Standard IT chemotherapy drugs used in the treatment of LC include methotrexate (MTX), cytarabine (ara-C), liposomal cytarabine, and thiotepa. Very few randomized trials have been performed to compare the respective efﬁcacies of these drugs. Grossman et al., compared the effect of intrathecally administered MTX to that of IT thiotepa in 59 solid tumor patients who had neoplastic meningitis; there was no difference in survival time between the two groups50. In another study comparing treatment with IT MTX to that with IT MTX plus IT ara-C, there was no signiﬁcant difference in the outcomes in 44 patients7. MTX is the drug most commonly used intrathecally LC treatment. It is a cellcycle phase-speciﬁc antimetabolite that acts primarily during S phase. Typical dosing schemes use MTX (10–12 mg) mixed with preservative-free normal saline and deliver IT twice per week for a total of eight doses. If a response is noted in terms of the clearing of malignant cells from the CSF, then treatment is administered once per week for a total of four doses, then twice monthly for four doses, and then monthly treatments are given for a variable period of time. Intraventricular injections result in therapeutic concentrations (> 1 μM) that persist for 48 hours41, 46. The use of MTX along with radiation as needed, has shown that up to 50% of patients can stabilize or improve2, 7, 41, 51. MTX toxicities such as myelosuppression and mucositis can be prevented by administering folinic acid, which, conveniently, does not enter the CNS and leaves the MTX within the CNS unantagonized. Thiotepa is an alkylating agent that has demonstrated therapeutic responses in some patients52. It is usually administered intrathecally in 10–15 mg doses on a schedule similar to that used for IT MTX. Intrathecal administration of thiotepa was prospectively compared with IT administration of MTX, and no difference in efﬁcacy was noted between drugs, although thiotepa was more myelosuppressive50. Ara-C is a synthetic pyrimidine analog that is relatively S-phase speciﬁc. It is used most commonly in patients with meningeal leukemia or lymphoma. The half-life of ara-C in the CSF is much longer than that in the serum because of the low levels of cytidine deaminase in the CSF. A new method of delivery for ara-C was recently developed, tested, and approved by the FDA for lymphomatous meningitis. The drug, marketed under the name DepoCyt® by Chiron (Emeryville, CA), is an injectable sustained-release formulation of cytarabine that extends the terminal half-life of free cytarabine in the CSF from 3.4 hours to 140 hours, allowing for treatment twice monthly instead of twice weekly53 –55. Measurable ara-C concentrations can be maintained in the lumbar and ventricular CSF for up to two weeks after one dose of DepoCyt®. A randomized trial published by Glantz and colleagues demonstrated the superiority of DepoCyt® over standard ara-C in the setting of lymphomatous meningitis56. This small study of 28 patients demonstrated a number of improvements of DepoCyt® over standard ara-C. Patients’ response rates, times to neurological progression, and survival times were 71% and 53%, 78.5

Leptomeningeal carcinomatosis: diagnosis and management 317

days and 42 days, and 99.5 days and 63 days, with DepoCyt® treatment versus standard ara-C treatment, respectively. DepoCyt®was also associated with an improved mean change in KPS score at the end of the induction period. The most common adverse events with DepoCyt® were headache, arachnoiditis, nausea, vomiting, and fever. Even though combination chemotherapy improves outcomes in many systemic cancers, this same beneﬁt has not been seen when combination IT chemotherapy has been used to treat LC. Studies that combined MTX with thiotepa or ara-C, MTX with thiotepa and ara-C, and MTX with thiotepa, ara-C, and hydrocortisone have failed to improve response rates or survival percentages if compared with single drug regimens7, 57–59. Patients in two of these studies showed increased degrees of myelosuppression or neurotoxicity relative to single drug regimens58, 59.

Experimental IT Treatments for LC Temozolomide An IT formulation of temozolomide, an orally administered alkylator with sufﬁcient bioavailability to show activity against a variety of tumors, has been tested in a leptomeningeal cancer model system in athymic rats, with evidence of beneﬁt and good tolerance of the therapy60. Topotecan Topotecan is a water-soluble semisynthetic campothecin analog that inhibits topoisomerase I, causing single-strand breaks in DNA. In primates, the concentration of the active lactone form is much higher with IT administration than with systemic administration, making IT use of the drug the logical choice61, 62. A phase I study of intrathecally delivered topotecan was recently completed and suggests that IT topotecan may be active against leptomeningeal extension of leukemia and brain tumors. Phase II studies of this compound are ongoing. Mafosfamide Mafosfamide is a bifunctional alkylator, not requiring activation by hepatic microsomal enzymes, with a broad spectrum of activity in solid tumors. IT doses of 20 mg given once or twice weekly have been used. A phase I study of mafosfamide in pediatric patients demonstrated some efﬁcacy in meningeal leukemia63, and a report of 16 children with LC from primary brain tumors treated with IT mafosfamide also shows promise64. In this report, eight of nine patients evaluable for response achieved complete responses, although all of the patients were simultaneously treated with systemic chemotherapy, so deﬁnitive evidence of efﬁcacy could not be ascertained64. An ongoing phase I study is evaluating the pharmacokinetics of alternate intralumbar and intraventricular drug dosing. The only toxicities noted were transient headache and nausea and vomiting around the time of drug administration. A randomized study to compare the results of IT administration of mafosfamide

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with those from IT administration of MTX in patients with LC is being contemplated. Diaziquone Diaziquone (AZQ) is an alkylating agent that readily crosses the blood-brain barrier and has been tested as systemic therapy for primary brain tumors65. Cumulative myelosuppression in patients treated with AZQ precluded further evaluation of this compound for systemic use. Favorable pharmacokinetics resulted in the investigation of AZQ as a possible IT agent66. In a phase I/II study, the safety and efﬁcacy of AZQ after IT administration were evaluated in 39 patients with refractory meningeal malignancies67. Dose-limiting toxicity (consisting of headache, nausea, or vomiting) occurred in only three patients at the highest dose. The overall response rate was 62%. Complete responses (CRs) occurred in 14 of 37 courses of chemotherapy with AZQ (38%), and partial responses (PRs) occurred in nine of 37 courses (24%). Among patients with meningeal leukemia, CRs were observed in 11 of 26 courses (42%) of AZQ administered and PRs, in nine of 26 courses (35%). AZQ may merit further study for treatment of LC. Nimustine (ACNU) Nimustine (ACNU) is an alkylator that has shown activity when administered intrathecally in a model system of LC in rats, although it did not penetrate as deeply into tumor masses as other drugs tested68. A phase I/II study of 27 patients with LC who were treated intrathecally with ACNU demonstrated good drug tolerance; eight of 21 patients (38%) who presented with a cytological exam positive for LC became negative on this test, with response durations ranging from one to 20 or more months69. Two other patients showed additional indirect evidence of response to treatment. The authors concluded that IT administration of ACNU was safe, had minimal toxicity, demonstrated efﬁcacy in some patients with LC, and warranted further evaluation of alternative dosing and delivery approaches. ACNU has also been given to patients via ventriculolumbar perfusion as therapy against CSF seeding from primary brain tumors; patients’ reponse rates and median survival times were: 17% and 12 months, 29% and 12 months, and 88% and 25 months for anaplastic glioma, glioblastoma multiforme, and PNET/medulloblastoma, respectively70.

Immunotherapy Immunotoxins The use of monoclonal antibodies coupled with protein toxins to target tumor cell-surface antigens is an attractive scheme to improve the selectivity of IT toxin delivery. A number of animal model systems have been used to test this method of treatment. In a model system utilizing mice with both severe combined immunodeﬁciency and CNS leukemia, IT administration of B43 (anti-CD19)-pokeweed antiviral protein, an anti-B-lineage acute lymphocytic leukemia immunotoxin directed against the pan-B-cell antigen

Leptomeningeal carcinomatosis: diagnosis and management 319

CD19/Bp95, signiﬁcantly improved survival of the mice and was superior to IT MTX71. A nude rat model system of SCLC LC was used to study IT administration of monoclonal anticarcinoma antibodies MOC-31 and NrLu10 and the growth factor transferrin when conjugated, respectively, to Pseudomonas exotoxin A. This IT therapy increased the symptom-free latency in the rats by 35–46%72. An athymic rat model system of LC from LOX melanoma-derived cells was used to test IT administration of transferrin-Pseudomonas exotoxin A. At a dose of 1 μg, there was a delay in the onset of paraplegia of ﬁve days (31%) when compared with the control animals73. A single-chain antibody speciﬁc for the epidermal growth factor receptor (EGFR)vIII mutation, expressed with a modiﬁed form of the Pseudomonas exotoxin, was used to form the immunotoxin MR1scFvPE38KDEL (MR-1), and this was tested in an athymic rat model system of LC induced by the EGFRvIII-expressing human glioma cell line, U87MG.deltaEGFR. In MR-1 treated rats, there was an estimated increase in median survival of > 657% compared with the saline-treated control group and an increase of 430% relative to the group treated with the control immunotoxin speciﬁc for the interleukin-2 receptor, anti-Tac74. A human trial has been conducted using the immunotoxin 454A12-rRA, delivered intrathecally in eight patients with LC. 454A12-rRA is a conjugate of a monoclonal antibody to the human transferrin receptor and the recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. The highest doses used in this study caused a CSF inﬂammatory response associated with headache, vomiting, and altered mental status, which was responsive to steroids and CSF drainage. Four patients had a greater than 50% reduction of tumor cell counts in the lumbar CSF; however, no patients experienced clearing of tumor cells from the CSF, and clinical or magnetic resonance imaging demonstrated evidence of tumor progression in seven of the eight patients after treatment75.

Radiolabeled monoclonal antibodies Tumor-speciﬁc monoclonal antibodies (Mabs) may improve delivery of radiotherapy to tumor cells, and a number of studies have demonstrated proof of this concept. In several studies, small numbers of patients with LC have been treated intrathecally with the 131I-labeled monoclonal antibody, HMFG1. Clinical responses to this therapy were seen, and a long term survivor (32 months) was observed, but serious toxicities occurred, including aseptic meningitis, seizures, and myelosuppression76, 77. 131I-labeled antibodies directed toward tenascin and the proteoglycan, chondroitin sulfate, have been delivered intrathecally to patients, producing some therapeutic responses, maintenance of stable disease, survival prolongation, and little toxicity78. One study that used tumor-speciﬁc Mabs in patients with diffuse LC, achieved a clinical response rate of approximately 33%; better results were observed in more radiosensitive tumors79. To try to overcome the dose-limiting toxicity of myelosuppression caused by passage of the radioimmunoconjugate from the CSF to the blood, instead of performing dose escalation and hematopoietic rescue, repeated IT administration

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of the radioimmunoconjugate to patients was attempted. It was found that the therapeutic index of the radioimmunoconjugate was signiﬁcantly increased by the development of an anti-mouse Ig response in the blood80. In a large review of 40 LC patients who had failed to respond to conventional therapy and who were treated intrathecally with 131I-labeled Mabs, there was evidence of Mab localization to the tumor, and minimal toxicity. The best results were seen with patients who had primitive neuroectodermal tumors (n = 22), where 53% of evaluable cases showed clinical responses, and 11% had stable disease. Three exceptional survival times were recorded; after therapy, one patient led a normal life at 10 years and 11 months, one patient was alive and normal at three years and two months, and a third patient survived in good condition for eight years. The mean survival time was 39 months for responders and 4 months for nonresponders. In the total series, 50% of patients survived for at least one year, and there were two long-term survivors81. An approach using IT 131I-labeled antibody speciﬁc for disialoganglioside (GD2) was used in ﬁve patients who had GD2-positive LC, resulting in minimal side-effects and a favorable CSF/blood ratio of 131I. Tumors known to have GD2 expression that might be candidates for this treatment include medulloblastoma/PNET, malignant glioma, neuroblastoma, retinoblastoma, ependymoma, sarcoma, melanoma, and SCLC82.

IT immunotherapy Because the subarachnoid space may serve as an immunological sanctuary for tumor cells from antitumor immune reactions, treatments with immunomodulating cytokines might beneﬁt patients with LC. Cytokines may enhance the immune response directed against some tumors. A small number of studies of patients with LC from melanoma, squamous cell carcinoma, and primary brain tumors have shown clinical responses to interleukin-2 (IL-2) alone or combined with lymphokine-activated killer (LAK) cells, but overall the results of immunotherapy in LC have not been encouraging. The CSF in all 12 patients treated with high-dose IL-2 administered intrathecally could be made tumor cell free and would again respond to IT IL-2 at relapse83. Melanoma was the most responsive tumor, whereas NSCLC, medulloblastoma, and glioblastoma patients showed no major responses to this therapy. When intravenous IL-2 is used in combination with IT administration of LAK cells, no signiﬁcant improvement in response is seen, although long-term remissions have been observed in small numbers of patients who have LC from medulloblastoma or squamous cell carcinoma84 – 86. The side-effects of IT IL-2 include fever, confusion, and seizures, and there are marked interindividual variations in the immunological response87.

Gene therapy Because malignant cells in the thecal sac are bathed in CSF, this anatomic region presents an interesting system in which to evaluate gene therapy. The poor penetration of gene therapy vectors into nodular accumulations of tumor cells is an obvious obstacle. At this time, no human clinical trials of gene

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therapy for LC exist, although several animal model systems have tested the applicability of gene therapy to LC. In a Fisher rat model system of LC, a retroviral vector-producer cell was used to evaluate the antitumor efﬁcacy of in situ transduction with the herpes simplex-thymidine kinase gene followed by ganciclovir therapy. The study reported signiﬁcant prolongation of survival in rats given injections of thymidine kinase vector-producer cells relative to controls. Histological examination of the rat spinal cord showed elimination of the inﬁltrative tumor in the leptomeninges but residual tumor mass present at the inoculation site, consistent with limited penetration of topical ganciclovir into the tumor 88. Another study demonstrated the possible use of geneticallymodiﬁed tumor cells to produce killing of additional tumor cells by infection from virally producing tumor cells and the bystander effect89. In a rat model system of Walker 256 LC, IT administration of herpes simplex virus-thymidine kinase (HSV-tk)-modiﬁed tumor cells was followed by systemic ganciclovir therapy. Up to 80% of ganciclovir-treated rats had long-term survival (120 days or more) compared with the control animals, which died from tumor growth 37 to 44 days after tumor cell implantation. This study also demonstrated the feasibility of repeated intrathecal administration of infected tumor cells89. Adenoviral vectors have been shown to survive in the CSF for a period of time sufﬁcient to allow leptomeningeal tumor transduction90. An animal model system using adeno-associated virus for LC treatment has also been developed91.

Systemic chemotherapy In a mouse model system of LC from melanoma, it has been shown that the tight junctions of the new vessels within the tumor masses are penetrable by horseradish peroxidase and adriamycin. The leakiness of the blood vessels increases with increased time of tumor presence and growth. This suggests that systemic chemotherapy may be able to play a role in the treatment of LC92. There is retrospective evidence that systemic chemotherapy with or without IT chemotherapy may increase the likelihood of longer patient survival times93–95. It is not generally considered possible to achieve therapeutic levels of most drugs in the CSF 96, although there is strong evidence that cytotoxic MTX levels (≥ 1 μM) can be reached after high-dose administration97. In a recent study that compared intravenous and IT high-dose MTX administration, the intravenous route was found to be more effective45. The difference in survival times for the two groups was remarkable (13.8 months versus 2.3 months, intravenous versus IT MTX administration, respectively). Other groups have suggested that the toxicity of intravenous systemic therapies directed toward LC is less than that associated with IT chemotherapy and that there is no loss of efﬁcacy44. The use of high-dose intravenous MTX administration in LC treatment may deserve further study. Oral temozolomide may be a candidate for the treatment of LC because of its relatively mild toxicity, broad range of activity against human tumors, and evidence that after systemic administration, CSF levels reach nearly 30% of plasma levels98 –100.

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Hormonal therapy There is some evidence that hormonal therapy in conjunction with IT therapy may result in better overall survival of LC patients94. There are also case reports of hormonally responsive LC from breast cancer primaries101.

Side-effects of therapy Major toxicities can result from placement of an Ommaya reservoir, delivery of IT chemotherapy, or radiation to the CNS102. Ommaya reservoirs can be improperly positioned or become infected. Infection of the Ommaya may necessitate its removal. There are rare case reports associating IT ara-C administration with neuropathy or myeloneuropathy103, 104. Treatment of patients with IT MTX can cause acute arachnoiditis, with nausea, vomiting, and mental status changes, and high CSF levels of it may cause seizures105. IT MTX administration can also cause mucositis and myelosuppression if it is not followed by systemic administration of folinic acid. Toxicity from IT Thiotepa administration is similar to that produced by IT MTX but may cause more hematologic toxicity50. Radiotherapy may worsen myelosuppression in heavily pretreated patients and may increase the likelihood of neurotoxicity from IT chemotherapy105. Necrotizing leukoencephalopathy associated with IT delivery of MTX, especially when MTX is administered after radiotherapy, is a feared complication in LC patients106. Leukoencephalopathy, manifested by dementia, seizures, progressive quadriparesis, and white matter changes observed by neuroimaging, may be more likely to occur in patients receiving IT chemotherapy than those treated with systemic chemotherapy44, 107.

Prognosis Treatment of LC arising from solid tumors will stabilize or improve neurological symptoms in about 45% of patients2. Without therapy, patients with LC have a very poor prognosis, with survival times in the three to six week range, with progressive neurological dysfunction often being the cause of death2, 4. A number of factors have been identiﬁed that may be predictive of longer survival or clinical response, although there is not complete agreement in the literature on the implications of all factors. Table 18.2 lists some patient- and treatment-related factors that may affect survival and response. Treatment that clears malignant cells from the CSF appears to correspond with an improved overall survival7, 37, 94. Glantz and colleagues found evidence that patients who responded to IT therapy had improvements in quality-of-life measures, providing support for the concept that effective treatment can provide meaningful beneﬁt to some patients with LC37. Table 18.3 provides the averages of the median survival times from a number of studies in which speciﬁc primary tumor histologies and outcomes for each group could be ascertained. There is wide variability in the outcomes in these studies. The recent studies by Glantz et al. have reported time to neurological progression

Leptomeningeal carcinomatosis: diagnosis and management 323 Table 18.2 Factors predictive of survival or response to chemotherapy.

Parameter

Impact on survival or response

Able to clear CSF of cells with IT chemotherapy No CSF block or CSF block cleared Controlled systemic disease History of intraparenchymal tumor KPS score ≥ 70 Longer duration of neurological symptoms Concomitant systemic + IT chemotherapy Treatment with IT chemotherapy Female sex Negative neuroimaging Longer pretreatment duration of CSF disease Spinal involvement Long delay from diagnosis to neurological symptoms Low CSF protein level Elevated CSF protein level Low CSF glucose level Cerebral involvement ECOG > 3 Cranial nerve deﬁcit Progressive systemic disease at study entry

+, +, + +, + + + + + + + + + + + + + +, −, 0, − −, 0 −, − − − −

References 7, 37, 94 38, 39 110 37 95 4 110 4 4 37 37 111 111 110 4, 7, 94, 111 94, 111 4, 111 50 50, 94 50

+, positive impact on survival or response; −, negative impact on survival or response; 0, no impact on survival or response; CSF, cerebrospinal ﬂuid; IT, intrathecal; KPS, Karnofsky Performance Scale; ECOG, electrocorticogram.

Table 18.3 Median survival time of patients with leptomeningeal carcinomatosis according to primary tumor histology. Primary tumor histology

Number of studies

Mean of studies in weeks, (range)

Breast cancer Lung cancer SCLC NSCLC Lymphoma

13 3 4 3 9

16.5 (5–38) 15 (8–22) 8.6 (4–15.5) 13 (9–20) 16 (8.8–32)

SCLC, small-cell lung cancer; NSCLC, non-small cell lung cancer.

References 2, 4, 7, 41, 50, 51, 59, 93–95, 110, 112–114 2, 4, 50 7, 8, 59, 93 9, 59, 93 41, 50, 56, 59, 114–118

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after the initiation of treatment37, 56. This measure may be a more useful tool for assessing treatment efﬁcacy in LC.

Conclusions/future At the present time, patients with LC require the expertise of neurosurgeons, radiation oncologists, medical oncologists and neuro-oncologists, but unfortunately the impact of treatment on patients’ outcomes has, up to this point, been unimpressive. Relatively few therapeutic agents have been tested in LC, and one goal for the future must be to test novel agents in this setting. Regimens that combine cytotoxic and noncytotoxic treatments targeting invasion, migration, and angiogenesis may be useful in the treatment of LC92, 108, 109. Future clinical trials will need to group patients with the same underlying tumor histologies for a better determination of the efﬁcacy of targeted therapies in speciﬁc disease states. To achieve meaningful outcomes from clinical trials, the cooperation of multiple cancer centers will be necessary. Ultimately, signiﬁcant improvement in outcomes for patients with LC will stem from a better understanding of molecular factors that promote metastasis, and the application of that understanding toward the development of novel treatments in the special situation of patients with this serious complication of metastasis.

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108 Friedberg MH, Glantz MJ, Klempner MS, et al.: Speciﬁc matrix metalloproteinase proﬁles in the cerebrospinal ﬂuid correlated with the presence of malignant astrocytomas, brain metastases, and carcinomatous meningitis. Cancer 1998; 82: 923 –930. 109 Mareel M, Leroy A, Bracke M: Cellular and molecular mechanisms of metastasis as applied to carcinomatous meningitis. J Neurooncol 1998; 38: 97–102. 110 Fizazi K, Asselain B, Vincent-Salomon A, et al.: Meningeal carcinomatosis in patients with breast carcinoma. Clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen. Cancer 1996; 77: 1315–1323. 111 Clamon G, Doebbeling B: Meningeal carcinomatosis from breast cancer: spinal cord vs. brain involvement. Breast Cancer Res Treat 1987; 9: 213 –217. 112 Yap HY, Yap BS, Rasmussen S, et al.: Treatment for meningeal carcinomatosis in breast cancer. Cancer 1982; 50: 219 –222. 113 Ongerboer de Visser BW, Somers R, Nooyen WH, et al.: Intraventricular methotrexate therapy of leptomeningeal metastasis from breast carcinoma. Neurology 1983; 33: 1565 – 1572. 114 Pfeffer MR, Wygoda M, Siegal T: Leptomeningeal metastasesatreatment results in 98 consecutive patients. Isr J Med Sci 1988; 24: 611– 618. 115 Young RC, Howser DM, Anderson T, et al.: Central nervous system complications of non-Hodgkin’s lymphoma. The potential role for prophylactic therapy. Am J Med 1979; 66: 435–443. 116 MacKintosh FR, Colby TV, Podolsky WJ, et al.: Central nervous system involvement in non-Hodgkin’s lymphoma: an analysis of 105 cases. Cancer 1982; 49: 586 –595. 117 Recht L, Straus DJ, Cirrincione C, et al.: Central nervous system metastases from nonHodgkin’s lymphoma: treatment and prophylaxis. Am J Med 1988; 84: 425 – 435. 118 Liang RH, Woo EK, Yu YL, et al.: Central nervous system involvement in non-Hodgkin’s lymphoma. Eur J Cancer Clin Oncol 1989; 25: 703 –710.

CHAPTER 19

Brain metastases from gynecologic cancers Maciej S Lesniak, Alessandro Olivi

Introduction The central nervous system (CNS) has traditionally been considered an uncommon site for metastatic disease from the female genital system. In most series, primary gynecological tumors involving the cervix, endometrium, or ovaries, contribute no more than 1–2% of all brain metastases in the United States each year1, 2. An exception to this is gestational trophoblastic disease, a term that describes a continuum of rare tumors that arise from the fetal chorion of the placenta. These tumors have a markedly different biological and clinical behavior than other gynecologic malignancies and present with intracranial metastases in up to 30% of patients3, 4. For the purpose of this discussion, they will be presented separately at the end of this chapter.

Gynecologic malignancies Cervical cancer In the United States, cervical cancer ranks eighth among cancers in women, with more than 12,000 new cases diagnosed each year5. As Pap screening has become more prevalent, however, the incidence of cervical cancer has signiﬁcantly decreased since the 1930s. Today, therapy for preinvasive disease is usually curative and can prevent the subsequent development of malignant disease. Cervical carcinoma represents the end spectrum of cervical intraepithelial neoplasia (CIN). CIN is a condition of disordered maturation of the squamous cells of the cervical epithelium, beginning as mild dysplasia (CIN I), which may gradually progress to high grade dysplasia (CIN II–III), carcinoma in situ, and invasive squamous or adenosquamous cancer. Fulminant invasive carcinoma is relatively rare before the age of 20 years, with the majority of patients presenting with the condition in their late forties and ﬁfties. The etiology of the epithelial changes that lead to the development of cervical cancer is most likely to be related to the human papillomavirus (HPV). Herpes simplex virus was formerly thought to be a causative agent, but this has never been proven, and more recent studies have documented a stronger 331

332

Chapter 19 Table 19.1 International Federation of Gynecology and Obstetrics (FIGO) staging of cervical carcinoma.

Stage 0 IA IB IIA IIB IIIA IIIB IVA IVB

Carcinoma in situ Tumor invasion to depth < 5 mm, width < 7 mm Tumor invasion to depth > 5 mm, width > 7 mm Carcinoma extends beyond the cervix, no obvious parametrial involvement Obvious parametrial involvement Extension to the pelvic wall Extension onto the pelvic wall Spread to adjacent organs Spread to distant organs

link between cervical carcinoma and HPV. Of the more than 50 different types of HPVs, types 6 and 11 have been frequently associated with cervical condylomata, whereas types 16, 18, 31, 33, and 35 have been associated with noninvasive and invasive cervical neoplasia6. This virus is usually transmitted sexually, and women who practice intercourse at an early age, have many sexual partners, or have partners who may have had many sexual partners, are at a higher risk of developing the disease. These risk factors, along with the relatively slow progression of the disease (10–20 years), may explain why cervical carcinoma is usually a disease of older women. The management of patients with CIN depends almost entirely on the stage of the disease. The majority of preinvasive lesions can be treated with a combination of cryosurgery, CO2 laser surgery, or loop electrocoagulation. Patients with carcinoma in situ beneﬁt the most from cervical conization or when appropriate, a hysterectomy. Invasive cervical tumors are further classiﬁed according to criteria issued by the International Federation of Gynecology and Obstetrics (FIGO) (Table 19.1). All invasive carcinomas are treated with surgery and/or radiation therapy. Chemotherapy has been notoriously ineffective in the treatment of patients with advanced or recurrent tumors, as most squamous cell carcinomas of the cervix are chemoresistant. The 5-year survival time for patients with stage I tumors is 91% versus 13% for patients with stage IV5. Metastatic propagation of cervical carcinoma usually occurs by local extension and lymphatic spreading. However, distant metastases do occur, suggesting a role for the hematogenous route. Whereas various autopsy studies report the incidence of extrapelvic metastases to be 15%–85%, brain metastases are relatively uncommon7, 8, 9. Behney and Brunschwig separately evaluated a total of 181 cases of cervical cancer and found no cerebral metastases10, 11. Holzaepfel subsequently documented a 1.5%–2.3% incidence, and Posner recently described a 5% incidence of brain metastases from cervical cancer 8, 12. In general, the time from initial diagnosis to presentation of the brain lesion

Brain metastases from gynecologic cancers 333

can be quite variable, ranging from the time of primary tumor diagnosis to 8 years, with a mean of 30 months13. Almost all of the patients who come to medical attention do so as a result of symptoms present with almost any metastatic brain tumor, including headaches (34%), hemiparesis (25.8%), mental status changes (22.7%), monoparesis (14.4%), and nausea/vomiting (9.2%)14. To date, only 67 cases have been reported in the English language literature regarding the treatment of patients with brain metastases from cervical cancer7–9, 12–38. In the majority of those cases, the patient’s radiological features were nondiagnostic, and the tumor histology was consistent with poorly differentiated squamous cell carcinoma (Figure 19.1). Patients with single

(A)

(B) Figure 19.1 Cervical carcinoma: A 62-year-old woman with a history of cervical cancer presented with left hemiparesis and MR imaging evidence of an enhancing frontoparietal lesion (A). The surgically resected lesion was histologically consistent with metastatic cervical cancer. The tumor cells are arranged in clumps and characteristically show no tendency toward keratinization. The nucleoli of individual cells are large, with a prominent nucleolus and abundant eosinophilic cytoplasm (B).

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lesions were treated with surgical resection followed by radiation therapy whereas patients with multiple intracranial metastases were treated with radiation alone. Although outcomes after surgical resection of solitary brain lesions have been quite favorable in a few cases, the overall survival after resection of brain metastases from cervical cancer has been rather poor 20, 27. With one exception, the longest documented survival time was nine months, with the majority of patients succumbing to the disease much sooner13. This poor prognosis in cases of systemic disease has renewed interests in adjuvant chemotherapy, and some recent studies suggest that cisplatin may be a promising agent, with a response rate of 20–30% in patients with metastatic cervical cancer39. Overall, cervical cancer continues to present a major challenge to the medical and surgical oncologist, and further progress in this research area will hopefully result in improved survival in the future.

Endometrial cancer Endometrial carcinoma is the most common gynecologic cancer, affecting approximately 36,000 women each year in the United States5. It is the fourth leading malignancy in the female population after breast, colorectal, and lung cancers. In spite of its relatively high incidence, the expected mortality rate is low, at 6,500 deaths, or less than 2% of cancer deaths in women. Early diagnosis is the major factor accounting for the low mortality rate as almost 80% of cases are diagnosed while the tumor is conﬁned to the uterus40. Endometrial cancer thus has the best prognosis of all female genital cancers. The median age for developing endometrial cancer is about 60 years. The most important risk factor for the development of this tumor appears to be the use of estrogens unopposed by progestins. In the 1970’s, the widespread use of estrogen replacement therapy (ERT) in postmenopausal women led to a sharp increase in endometrial cancer rates. Subsequently, it has been shown that the length of estrogen use and high dosage correlate with an increased risk of developing endometrial cancer41. On a biological level, these ﬁndings can be explained by the proliferative effects of estrogens, which when not counteracted by progestins, lead to endometrial hyperplasia and adenocarcinoma. Other risk factors that contribute to the development of endometrial cancer include obesity, nulliparity, late menopause, and irradiation of the pelvis. The International Federation of Gynecology and Obstetrics (FIGO) has recently modiﬁed the staging of uterine tumors (Table 19.2). In all cases, however, the treatment of patients with endometrial carcinoma is primarily surgical. If there is additional evidence of myometrial invasion, most patients receive adjuvant radiotherapy. For advanced disease, the treatment is individualized, and in addition to preoperative or postoperative radiation, patients may also require hormonal therapy, with or without chemotherapy. For most patients with metastases to the abdomen, lungs, or liver, treatment with highdose progestin or antiestrogens may be sufﬁcient. If the disease progresses in patients treated with progestins, chemotherapy may be of beneﬁt. In those cases, the anthracyclines such as doxorubicin appear to be the most active,

Brain metastases from gynecologic cancers 335 Table 19.2 International Federation of Gynecology and Obstetrics (FIGO) staging of endometrial carcinoma.

Stage 0 IA IB IC IIA IIB IIIA IIIB IVA IVB

Carcinoma in situ Tumor limited to the endometrium Invasion to < 1/2 of myometrium Invasion to > 1/2 of myometrium Endocervical glandular involvement only Cervical stromal invasion Tumor invades serosa and/or adnexa Vaginal metastases Spread to bladder and/or bowel mucosa Spread to distant organs

though the nature of the response is at best partial and is present in only about 35% of patients42, 43. The 5-year survival rate of patients with stage IV metastatic endometrial cancer is less than 30%5. Endometrial cancer, like cervical cancer, spreads by direct extension, lymphatic dissemination, and hematogenous dissemination. The most common route is by direct extension, though lymphatic propagation appears to occur in patients with signiﬁcant myometrial penetration by the tumor. Hematogenous dissemination is least common but is most likely to be responsible for the spread of the tumor to the liver, lungs, or brain. Disease that metastasizes to the brain is rare (< 1% of cases; Figure 19.2), and reports regarding the best management are limited44 – 49. However, the majority of patients with a solitary metastasis appear to beneﬁt from surgery followed by radiotherapy. This mode of therapy has been shown not only to improve neurologic function, but also to prolong survival, though the small number of affected patients and the variable and unpredictable potential of endometrial cancer make the conclusions tentative at best44, 45, 50. In the case of patients with multiple brain metastases, palliative radiation therapy is most effective in improving the quality of life without further contributing to the morbidity/mortality of the disease44. Uterine sarcomas are extremely rare and arise from the stromal components of the uterus, either the endometrial stroma or the mesenchymal and myometrial tissues. The most commonly encountered sarcomas are the leiomyosarcoma, endometrial stromal sarcoma, and the mixed Müllerian sarcoma. As a group, these tumors are usually advanced and metastatic at the time of presentation and are associated with an overall 5-year survival rate of less than 5%51. Rose et al., in the only published study to do so, analyzed the patterns of metastases in uterine sarcoma in 73 patients at autopsy52. Only six (8.2%) patients had evidence of intracranial metastasis, and further statistical analysis revealed a positive correlation between the presence of brain metastasis and lung metastasis. Although there are no published clinical data regarding the

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(A)

(B) Figure 19.2 Endometrial carcinoma. A 59-year-old woman with a history of endometrial cancer presented with a visual ﬁeld defect. Although the radiological features of enhancement and dural tail of the brain lesion suggested it was a meningioma (A), its histology was consistent with metastatic endometrial carcinoma. In general, these tumors consist of very abnormal and closelypacked glands arranged ‘back-to-back’. There is usually considerable mitotic activity in the tall columnar epithelial cells forming the glands, and some glands are full of cell debris (B).

management of these metastatic tumors, it is reasonable to assume that a combination of surgical resection followed by radiotherapy would be of similar beneﬁt to that observed in cases of endometrial adenocarcinoma.

Ovarian carcinoma Ovarian cancer is the ﬁfth most common cancer among women in the United States and the leading cause of death from gynecologic cancer. Each year, it affects about 23,000 women, and over 14,000 deaths are recorded from this disease5. The prognosis remains poor because most patients present with advanced disease. Not only are the ovaries difﬁcult to detect and examine but

Brain metastases from gynecologic cancers 337

the early disease has very few symptoms. As a result, little progress has been made in the management of patients with ovarian tumors. Most women who develop ovarian cancer are in their ﬁfth or sixth decades of life. Although the cause of this tumor is unknown, certain risk factors increase the incidence. For instance, having low parity, late age of menopause, a family history of gynecologic cancer, and being Caucasian have all been shown to increase the risk of ovarian tumors. In addition, Western countries, including the United States, have ovarian cancer rates three to seven times greater than Japan, although second generation Japanese immigrants to the United States have an incidence similar to that of American women53. This ﬁnding suggests that an environmental or dietary agent could play a role in the development of ovarian cancer, though studies to prove that point have not been successfully conducted. Unlike patients with cervical or endometrial cancer, patients with ovarian tumors can be evaluated with a tumor marker, CA-125. This marker, which unfortunately has an inadequate speciﬁcity in screening for ovarian cancer, has been found useful in testing patients for recurrence. Indeed, serial CA-125 levels show a strong positive correlation with tumor status and decline as tumor growth does in response to chemotherapy. For example, Sevelda et al. demonstrated that CA-125 levels obtained in patients three months after primary surgery for ovarian cancer were a strong independent prognostic factor for survival54. Likewise, Rustin et al. have shown a highly signiﬁcant relationship between progression-free survival and the change in CA-125 levels obtained prior to initiation of chemotherapy55. The CA-125 tumor marker is therefore very useful in indicating ovarian tumor responsiveness to chemotherapy, and in turn, predicting survival. A critical point for making decisions about speciﬁc treatment in ovarian carcinoma is at the time of staging (Table 19.3). Patients with an early stage ovarian cancer are classiﬁed as either low or high risk. Low-risk patients can be cured with surgery alone and have a survival rate of 95%. High-risk patients show ruptures of the ovarian capsule with extension of the tumor into the peritoneal cavity. These patients are generally treated with adjuvant chemotherapy. Most women who have ovarian cancer present with advanced disease and are treated with cytoreductive surgery followed by combination chemotherapy. In spite of these efforts, the 5-year survival rate for patients with advanced and metastatic disease remains at approximately 30%5. Epithelial carcinoma of the ovary consists of different histological subtypes, including serous, mucinous, endometrioid, clear cell, Brenner’s, and undifferentiated. Of these, the serous subtype is the most common, comprising up to 50% of all ovarian cancers56. Regardless of the underlying histology, all ovarian tumors metastasize primarily by direct extension, lymphatic spread, and occasionally, the hematogenous route. In spite of the propensity of the tumor to invade adjacent structures, involvement of the CNS is rare (Figure 19.3). Two autopsy series published in 1966 and 1976 assessed the frequencies of ovarian cancer metastases to the various organs. Combined data from these

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Table 19.3 International Federation of Gynecology and Obstetrics (FIGO) staging of ovarian carcinoma. Stage IA IB IC IIA IIB IIC IIIA IIIB IIIC IV

Tumor limited to one ovary, capsule intact, no ascites Tumor limited to both ovaries, capsule intact, no ascites Tumor limited to one or both ovaries with tumor on the surface of one or both ovaries, ruptured capsule, ascites, or positive peritoneal washings Extension to the uterus and/or tubes Extension to other pelvic tissues Tumor either IIA or IIB but with tumor on the surface of one or both ovaries, ruptured capsule, ascites, or positive peritoneal washings Tumor limited to true pelvis, negative nodes, but with microscopic seeding of abdominal peritoneal surfaces Tumor of one or both ovaries with implants on abdominal peritoneal surfaces, none exceeding 2 cm in diameter Abdominal implants > 2 cm in diameter and/or positive nodes Distant metastasis

studies showed that only one of 158 patients with ovarian carcinoma had brain metastasis57, 58. Although some authors have recently reported on a growing number of patients with CNS involvement of ovarian carcinoma, most published reports cite an incidence of around 1%59 – 63. One of the single largest case series involving cerebral metastases from ovarian carcinoma involved 14 patients followed at the University of Washington Cancer Center in Seattle, WA62. This cohort was identiﬁed from among 1,316 patients seen with ovarian carcinoma between 1980 and 1989, representing 1.1%. The clinical manifestations included motor weakness, seizures, headache, confusion, and speech disturbance. The median age of these patients at diagnosis was 52.5 years. The median interval from diagnosis of ovarian carcinoma to the diagnosis of CNS metastases was 14.5 months. Of the 14 patients, half had received prior chemotherapy consisting of cisplatin. Nine patients had single intracranial lesions, ﬁve of whom underwent surgical resection. Whereas the median survival time for the entire series was three months, the median survival was two months in patients receiving radiation therapy alone and 17 months in patients who received surgery and radiation. The presence of multiple cerebral metastases or evidence of extraperitoneal propagation elsewhere in the body was adversely associated with survival. The choice of treatment in patients with ovarian metastatic disease is based on their overall condition and the number of metastases. For patients with good systemic disease control and a single intracranial lesion, surgery appears to improve neurological outcome and median survival time64, 65. Moreover, Patchell et al. have shown that in patients with single cerebral metastases, including those arising from genitourinary primary lesions, the addition of surgery to whole-brain radiation therapy (WBRT) greatly improved outcome beyond that seen with WBRT alone66. Data from other studies on the man-

Brain metastases from gynecologic cancers 339

(A)

(B) Figure 19.3 Ovarian carcinoma. A 66-year-old woman with a history of ovarian carcinoma presented with a two-day history of worsening headaches, nausea, and vomiting. Her brain MR image shows a large enhancing cystic mass in the corpus callosum (A). This mass was metastatic ovarian carcinoma, which is characterized histologically by the presence of highly malignant epithelial cells that form a solid mass (B).

agement of single cerebral metastases stemming from gynecologic cancer also suggest a beneﬁt from surgery. For example, in a group of 44 patients that included eight different series of patients with ovarian metastases to the brain, surgical resection with adjuvant irradiation improved the overall median survival time from two to 10 months59, 60, 67–72. Consequently, it appears that most patients with ovarian carcinoma who develop a single cerebral lesion should undergo surgery not only because it provides immediate decompression leading to rapid neurological recovery but also because the removal of the tumor can further potentiate the effectiveness of radiotherapy. In patients with ovarian cancer, the role of radiation therapy or chemotherapy without surgery is less clear. Plaxe et al., for example, treated six patients

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with CNS metastases from ovarian carcinoma with WBRT and found that over 80% of the patients were symptomatically relieved when a course of 30 Gy to the whole brain was used63. This ﬁnding is supported by the study of the Radiation Therapy Oncology Group (RTOG), which demonstrated that 50% of patients with brain metastases were improved by WBRT alone73. However, unlike the RTOG study, Plaxe’s study reported no long-term survivors. In terms of chemotherapy, it is a well-established fact that the platinumcontaining drugs are the most important agents in the management of ovarian cancer74. Cisplatin and carboplatin have each been reported (in separate patients) to achieve complete remission of multiple cerebral and cerebellar metastases from ovarian carcinoma75, 76. Consequently, a combination of surgery, irradiation, and chemotherapy may offer the best treatment strategy in the management of patients with ovarian carcinoma metastatic to the brain.

Gestational trophoblastic disease Gestational trophoblastic neoplasia (GTN) represents a unique spectrum of disease. Currently, four main types are recognized on the basis of histopathological, cytogenetic, and clinical ﬁndings. They are complete hydatidiform mole, partial hydatidiform mole, gestational choriocarcinoma, and placental site trophoblastic tumor. The classiﬁcation of GTN as a mole versus a gestational choriocarcinoma or a placental site trophoblastic tumor is of clinical value, as the former are usually benign whereas the latter are invasive and malignant. Nevertheless, all of them share several important characteristics as follows: 1 they arise in fetal chorion 2 they produce human chorionic gonadotropin (hCG), and 3 they respond extremely well to chemotherapy. About 3,000 hydatidiform moles are diagnosed annually in the United States and in the majority of cases they follow a benign course. The small number of patients with metastatic disease can be cured with chemotherapy, making gestational trophoblastic malignancies potentially curable tumors of the female genital system. Complete and partial hydatidiform moles represent two distinct forms of an abnormal pregnancy (Figure 19.4)77–82. The majority of hydatidiform moles are complete moles and have a 46 XX karyotype, with both X chromosomes being paternal in origin. This phenomenon is believed to occur as a result of fertilization of an egg without chromosomes by a haploid sperm (23 X) which then duplicates its genome to restore the diploid chromosomal component (46 XX). As seen clinically, in patients with complete hydatidiform moles the uterus is large, and the hCG levels are high for the duration of pregnancy. As viewed by ultrasonography, there are abundant grape-like structures in the uterus representing the hydropic villi, with no evidence of a viable fetus. This is in contrast to partial hydatidiform moles where one usually ﬁnds a triploid chromosomal constitution (69 XXX or 69 XXY), with both paternal and maternal chromosomes being present. The extent of development of hydropic villi is

Brain metastases from gynecologic cancers 341 (A)

(B)

Figure 19.4 Cytogenetic makeup of hydatidiform mole. (A) Chromosomal origin of a complete mole. A single sperm fertilizes an “empty egg.” Reduplication of its haploid (23 X) chromosome set gives a completely homozygous diploid genome of 46 XX. (B) Chromosomal origin of the triploid, partial mole. A normal egg with a 23 X haploid set is fertilized by two sperms that can carry either sex chromosome to give a total of 69 chromosomes with a sex chromosome conﬁguration of XXY, XXX, or XYY. (Reprinted with permission from Szulman AE: Syndromes of hydatidiform moles: partial vs. complete. J Reprod Med 1984; 29: 789–79080.)

variable, and usually they are more difﬁcult to diagnose clinically, owing to the relatively normal uterine size. As such, partial hydatidiform moles are more likely to be diagnosed as an incomplete abortion rather than a molar pregnancy. However, with all other factors being equal, women carrying complete hydatidiform moles are more likely to develop persistent disease or malignant sequelae than those with partial hydatidiform moles. Consequently, patients

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with either clinical entity require regular physical exams, chest X-rays, and weekly hCG assays, until serum levels return to normal. Gestational choriocarcinomas and placental site trophoblastic tumors (PSTT) represent two malignant forms of gestational trophoblastic disease (GTD). Both can follow any type of pregnancy, including molar, aborted, ectopic, or even one ending in term delivery; yet, whereas the choriocarcinoma is composed of syncytiotrophoblasts and cytotrophoblastic cells, PSTT is composed of only one cell type, the intermediate trophoblast. Of the two, the choriocarcinoma is by far the more malignant and is associated with hemorrhage, necrosis, and vascular invasion. The reported 5-year survival rate for patients treated by hysterectomy for nonmetastatic choriocarcinoma has been reported as 41% versus 5% for those having metastatic choriocarcinoma83. The addition of chemotherapy increases the 5-year survival rate to 100% in the group with nonmetastatic disease and 80% in the group having metastases84. A fundamental question regarding the need for adjuvant chemotherapy occurs in the setting of nonmetastatic choriocarcinoma. Although most investigators agree that treatment with chemotherapy is indicated even in women who have choriocarcinoma limited to the uterus, the debate arises in the case of patients who are being followed after evacuation of a hydatidiform mole and have a persistently elevated hCG level. Based on the natural history of molar pregnancy and its relationship to serum hCG levels, current recommendations are to start chemotherapy when elevated hCG levels persist for two months after evacuation of a mole (Figure 19.5)85. In this situation, early identiﬁcation of patients requiring chemotherapy leads to complete cure of this form of GTD. Central nervous system involvement from metastatic GTD is not uncommon, with a reported incidence of 8–30%86 – 88. Brain metastases should be suspected and investigated in all patients with metastatic choriocarcinoma, as asymptomatic brain metastases may be present in 4 to 20% of patients3, 89. Direct morbidity and mortality from intracranial GTD results from increased intracranial pressure and mass effect, especially hemorrhage, infarction, or seizures (Figure 19.6). In fact, hemorrhage into the highly vascular metastatic lesions is responsible for the majority of deaths and may occur before effective chemotherapy can be delivered86. Early diagnosis is the key to successful treatment, and multiple reports have documented improved survival in patients whose brain metastases are discovered at ﬁrst presentation. An hCG serum: cerebrospinal ﬂuid (CSF) ratio of less than 60:1 is a strong indicator of occult metastases in the CNS of patients with GTD90. For this reason, most studies recommend that determination of hCG in serum and CSF be carried out in all patients with identiﬁable metastases in any extracranial site and in any patient with neurological symptoms. Routine brain imaging studies are likely to be of equal beneﬁt in early detection of metastatic disease. Factors inﬂuencing survival in choriocarcinoma patients with brain metastases are the time of diagnosis, number of intracranial metastases, volume of the extracranial tumor, and the type of treatment. Patients whose diagnosis is delayed have survival rates approaching 20%, regardless of subsequent

Brain metastases from gynecologic cancers 343 1,000,000

100,000

SERUM βb-hCG mIU/ml

10,000

1000

100

10 5

NORMAL

0 PRE-EVACUATION

4

8

12

WEEKS POST EVACUATION

Figure 19.5 Normal regression curve of serum level of b-hCG in women after evacuation of a hydatidiform mole. (Reprinted with permission from Morrow CP, Kletzky OA, Di Saia PJ, et al.: Clinical and laboratory correlates of molar pregnancy and trophoblastic disease. Am J Obstet Gynecol 1977; 424: 424–430 91.)

therapy4. Moreover, 50% of patients presenting with a single intracranial lesion have been shown to survive, as opposed to 37% of patients with multiple lesions4. This survival rate mimics that of patients with multiple extracranial lesions, where involvement of multiple organs reduces the survival rate to 23%4. In light of these ﬁndings, early and aggressive multiagent chemotherapy with WBRT is recommended for all patients with metastatic disease. The selection of initial chemotherapy for women being treated for GTD is based on their risk category as determined by the World Health Organization (WHO) staging system (Table 19.4). Patients in the low-risk category are most commonly treated with methotrexate (with folinic acid rescue) and dactinomycin, given in a 5-day intermittent course71, 92, 93. All patients in this category are curable. Patients in the medium-risk category are treated with multiagent chemotherapy, including methotrexate, dactinomycin, and cyclophosphamide, along with folinic acid rescue94, 95. Another combination involves using

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(A)

(B) Figure 19.6 Choriocarcinoma. This postmortem exam (A) of the cerebellum shows the prominence of multiple hemorrhagic lesions scattered throughout both hemispheres. On histological examination, the lesion was very hemorrhagic (B). It consisted of small cells with clear cytoplasm and well-deﬁned cytoplasmic borders (cytotrophoblasts), as well as sheets of multinucleated cytoplasm (syncytiotrophoblasts), characteristic of choriocarcinoma.

methotrexate, folinic acid rescue, 6-mercaptopurine, dactinomycin, vincristine, cyclophosphamide, and hydroxycarbamide92. Virtually all of the patients in this category can be cured. Finally, patients in the high-risk category are treated with etoposide, methotrexate, and dactinomycin (alternating with vincristine and cyclophosphamide)92. The treatment can be successful in up to 80% of the patients84. Of the patients who die from metastatic GTD, the majority do so early in their treatment. Indeed, over one-half of the deaths caused by brain metastases from choriocarcinoma have been shown to occur within 15 days of diagnosis3. These early deaths are due to increased intracranial pressure from the tumor or hemorrhage. For this reason, early WBRT has been recommended, along

Brain metastases from gynecologic cancers 345 Table 19.4 World Health Organization scoring system for women being treated for gestational trophoblastic disease based on prognostic factors. Score Prognostic factor

1

2

Age (yrs) Antecedent pregnancy Interval (months) hCG (IU/L) ABO blood type groups (female × male)

≤ 39 HM 4 103

> 39 Abortion 4–6 103–104 O×A A×O 3–5 cm Spleen Kidney 1–4

Largest tumor Site of metastases No. of metastases Prior chemotherapy (Number of drugs)

3

Term 7–12 104–105 B AB 5 cm GI tract Liver 4–8 1

4

12 105

Brain 8 2+

hCG, human chorionic gonadotropin; HM, hydatidiform mole; GI, gastrointestinal; IU/L, international units/liter of serum. Total score for a patient determines risk category. It is derived by adding the individual scores in each prognostic category. Low risk, ≤ 4, medium risk, 5–7; and high risk ≥ 8. From WHO Scientiﬁc Group on Gestational Trophoblastic Disease. Technical Report Series No. 692. Geneva: World Health Organization, 1983: 51.

with multiagent chemotherapy. In at least one recent study aimed at further elucidating the role of radiotherapy, whereas 44% of those who received chemotherapy alone died, none of the patients who received irradiation plus chemotherapy died of CNS involvement 87. This ﬁnding is further supported by Hammond et al. who, after observing early demise in two patients treated with chemotherapy alone, added WBRT to the treatment of their patients and encountered no further deaths in their series96. These results suggest that early irradiation of the brain is as important as early chemotherapy in managing the patient with a large intracranial mass who is at risk of death from brain hemorrhage or herniation. The role of a craniotomy in the management of patients with brain metastases from GTD is limited to a small subset who have a progressively deteriorating neurological condition. Surgical intervention has no place in the diagnosis of GTD, as radiographic evidence of a lesion in conjunction with elevated serum and/or CSF hCG level is diagnostic. Surgical intervention is usually reserved for patients who develop an acute increase in intracranial pressure resulting from hemorrhage into a brain metastasis. Such a hemorrhage may occur at any time, even in patients who show a good response to chemotherapy97. In addition, a craniotomy for cure is occasionally indicated in patients with isolated brain metastases that are refractory to primary therapy or in those who have developed brain metastases during therapy98. It is important to note, however, that patients who are refractory to primary therapy or

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who develop brain metastases during therapy have the lowest cure rates. As a result, in those cases a decision to pursue a craniotomy must be weighed against the risks of surgery and systemic tumor burden. Patients who present with intracranial metastases from gestational trophoblastic tumors should receive multiagent chemotherapy combined with radiation therapy. Patients with acute presentations involving hemorrhage or edema due to tumor volume may be suitable for surgical resection. Combined, these early and aggressive therapies provide the best opportunities for achieving cure and allowing the patients a chance to return back to normal life.

Radiosurgery A review of the literature regarding the treatment of brain metastases from gynecologic tumors with radiosurgery is limited to isolated case reports. In 1997, Kawana and colleagues described a patient with multiple brain metastases from ovarian cancer who was successfully treated with Gamma Knife radiosurgery99. The patient was a 47-year-old woman diagnosed with a serous adenocarcinoma of the ovaries, FIGO stage IV, associated with systemic metastases. Multiple brain metastases occurred 36 months after the initial diagnosis. She underwent surgical resection of two accessible lesions and then Gamma Knife radiotherapy for another unresectable lesion after receiving 30 Gy of cranial irradiation. This treatment produced a complete remission of the multiple brain metastases for 21 months with the patient experiencing good quality of life. In a 1999 study of 32 women who had ovarian cancer metastatic to the brain that was treated with WBRT, nine women (29%) experienced a complete response as assessed radiographically, compared with two of the ﬁve patients (40%) treated with stereotactic radiosurgery100. The 2-year survival rate was 60% among those treated with radiosurgery and 15% among those who received WBRT. Based on this small cohort, the study concluded that radiosurgery may be of clinical beneﬁt to a select group of patients with brain metastases resulting from ovarian cancer. Clearly, whether radiosurgery is as effective as surgical resection and/or WBRT is subject to future research. It is only by means of prospective randomized trials that anecdotal observations such as those presented here will ﬁnd true scientiﬁc support.

Conclusions Brain metastases from gynecologic cancers are rare, and limited experience is available regarding their treatment. In the majority of cases, cervical, endometrial, and ovarian tumors metastatic to the brain are so rare that they form only a handful of case reports in the literature. The treatment of these tumors is therefore based on the general principles and practice involving most metastatic intracranial tumors. For single lesion metastatic disease, surgical resection followed by WBRT appears to be superior to other treatment

Brain metastases from gynecologic cancers 347

modalities. In the case of multiple intracranial lesions, radiotherapy plays the dominant role. The results with radiosurgery are promising, though in need of more studies that compare the efﬁcacy of radiosurgery with standard therapy. Chemotherapy adds little to the treatment of cervical and endometrial tumors and is an adjuvant in the therapy of ovarian cancer. Gestation trophoblastic tumors pose a special set of challenges to both the primary care gynecologist and the neurosurgeon. These tumors can arise in the setting of almost any pregnancy and metastasize to the brain in up to 30% of cases. Metastatic gestational tumors can pose further diagnostic problems, because the rise in the level of serum hCG, the tumor marker, does not always correlate with the presence of radiologically observable metastatic disease. In those patients, treatment is started early and just as in patients having documented metastatic disease, consists of irradiation and multiagent chemotherapy. Neurosurgical intervention is limited to patients who experience rapid neurological deterioration, often associated with a sudden increase in intracranial pressure, either due to tumor edema or intracranial hemorrhage. Early recognition and treatment of GTD offers the best patient prognosis, because up to 80% of GTD patients with advanced metastatic disease can achieve cure. This fact alone makes GTD one of the most curable of cancers that affect the female genital system. As new advances continue to be made in the diagnosis, management, and treatment of patients with gynecologic tumors, neurosurgeons are likely to see an increasing number of patients with metastatic disease. In this setting, a knowledge of the patient and the cancer should help to pave the way in eradicating the disease and promoting long-term cure.

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11 Brunschwig A, Pierce V: Necropsy ﬁndings in patients with carcinoma of the cervix. Am J Obstet Gynecol 1948; 56: 1134 –1137. 12 Posner JB, Chernik NL: Intracranial metastasis from systemic cancer. Adv Neurol 1978; 19: 579–592. 13 Robinson JB, Morris M: Cervical carcinoma metastatic to the brain. Gynecol Oncol 1997; 66: 324–326. 14 Kishi K, Nomura K, Miki Y, et al.: Metastatic brain tumor: A clinical and pathologic analysis of 101 cases with biopsy. Arch Pathol Lab Med 1982; 106: 133 –135. 15 Lefkowitz D, Asconape J, Biller J: Intracranial metastases from carcinoma of the cervix. South Med J 1983; 76: 519 –521. 16 Gill TJ, Dammin GJ: A case of epidermoid carcinoma of the cervix uteri with cerebral metastasis. J Pathol Bacteriol 1959; 78: 569 –571. 17 Andrew JD: Cerebral metastases from cervical carcinoma. J Obstet Gynecol Br Emp 1953; 60: 545–548. 18 Buchsbaum HJ, Rice AC: Cerebral metastasis in cervical carcinoma. Am J Obstet Gynecol 1972; 114: 276–278. 19 Friedman M, Nissenbaum M, Lakier R, et al.: Brain metastases in early cancer of the uterine cervix. South Afr Med J 1983; 24: 498 – 499. 20 Kumar L, Tanwar RK, Singh SP: Intracranial metastases from carcinoma cervix and review of literature. Gynecol Oncol 1992; 46: 391–392. 21 Nielsen SL, Posner JB: Brain metastasis localized to an area of infarction. J Neurooncol 1983; 1: 191–195. 22 Seidel R, Steinfeld A: Carcinoid of the cervix. Natural history and implications for therapy. Gynecol Oncol 1988; 30: 114 –119. 23 Habib A, Kaneko M, Cohen CJ, et al.: Carcinoid of the uterine cervix: a case report with light and electron microscopic studies. Cancer 1979; 43: 535 –538. 24 Silva EG, Kott MM, Ordonez NG: Endocrine carcinoma intermediate cell type of the uterine cervix. Cancer 1984; 54: 1705 –1713. 25 Kodousek R, Gazarek F, Dusek J, et al.: [Malignant apudoma (argyrophilie carcinoma) of the uterine cervix in a 24-year-old woman in pregnancy]. Cesk Patol 1976; 12: 37– 44. 26 Saphner T, Gallion HH, Van Nagell JR, et al.: Neurologic complications of cervical cancer. A review of 2261 cases. Cancer 1989; 64: 1147–1151. 27 Vieth RG, Odom GI: Intracranial metastases. J Neurosurg 1965; 23: 375–383. 28 Harnett WL: A statistical report on 955 cases of cancer of the cervix uteri and 321 cases of cancer of the corpus uteri. Br J Cancer 1949; 3: 433 – 473. 29 Peeples WJ, Inalsingh CH, Hazra TA, et al.: The occurrence of metastasis outside the abdomen and retroperitoneal space in invasive carcinoma of the cervix. Gynecol Oncol 1976; 4: 307–310. 30 Chason JL, Walker FB, Landers JW: Metastatic carcinoma in the central nervous system and dorsal root ganglia. Cancer 1963; 16: 781–787. 31 Badib AO, Kurohara SS, Webster JH, et al.: Metastasis to organs in carcinoma of the uterine cervix. Cancer 1968; 21: 434 – 439. 32 Sotto LSJ, Graham JB, Pickren JW: Postmortem ﬁndings in cancer of the cervix: an analysis of 108 autopsies in the past ﬁve years. Am J Obstet Gynecol 1960; 80: 791–794. 33 Haar F, Patterson RH: Surgery for metastatic intracranial neoplasm. Cancer 1972; 30: 1241–1245. 34 Stortebecker TP: Metastatic tumors of the brain from a neurosurgical point of view: a follow-up study of 158 cases. J Neurosurg 1954; 11: 84 –111.

Brain metastases from gynecologic cancers 349 35 Morris JM, Meigs JV: Carcinoma of the cervix: Statistical evaluation of 1938 cases and results of treatment. Surg Gynecol Obstet 1950; 90: 135 –150. 36 De Alvarez RR: The sites of metastasis in carcinoma of the cervix. West J Surg Obstet Gynecol 1953; 61: 623 – 627. 37 Hunter KMF, Rewcastle NB: Metastatic neoplasms of the brainstem. Can Med Assoc J 1968; 98: 1–7. 38 Drescher CW, Hopkins MP, Roberts JA: Comparison of the pattern of metastatic spread of squamous cell cancer and adenocarcinoma of the uterine cervix. Gynecol Oncol 1989; 33: 340–343. 39 Bonomi P, Blessing JA, Stehman FB, et al.: Randomized trial of three cisplatin dose schedules in squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 1985; 3: 1079 –1085. 40 Silverberg E, Boring CC, Squires TS: Cancer statistics, 1990. CA Cancer J Clin 1990; 40: 9–26. 41 Hulka BS: Replacement estrogens and risk of gynecologic cancers and breast cancer. Cancer 1987; 60: 1960 –1964. 42 Deppe G: Chemotherapeutic treatment of endometrial carcinoma. Clin Obstet Gynecol 1982; 25: 93–99. 43 Fung MF, Krepart GV, Lotocki RJ, et al.: Treatment of recurrent metastatic adenocarcinoma of the endometrium with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate. Obstet Gynecol 1991; 78: 1033 –1038. 44 Ogawa K, Toita T, Kahinohana Y, et al.: Palliative radiation therapy for brain metastases from endometrial carcinoma: report of two cases. Jpn J Clin Oncol 1999; 29: 498 –503. 45 Salvati M, Cervoni L, Raguso, M: Therapeutic considerations in solitary cerebral metastases from uterine carcinoma. Minerva Ginecol 1998; 50: 445 – 447. 46 Martinez-Manas RM, Brell M, Rumia J, et al.: Brain metastases in endometrial carcinoma. Gynecol Oncol 1998; 70: 282–284. 47 Ruelle A, Zuccarello M, Andrioli G: Brain metastasis from endometrial carcinoma. Report of two cases. Neurosurg Rev 1994; 17: 83 – 87. 48 Wronski M, Zakowski M, Arbit E, et al.: Endometrial cancer metastasis to brain: report of two cases and a review of the literature. Surg Neurol 1993; 39: 355 –359. 49 Sawada M, Inagaki M, Ozaki M, et al.: Long-term survival after brain metastasis from endometrial cancer. Jpn J Clin Oncol 1990; 20: 312–315. 50 Cormio G, Lissoni A, Losa G, et al.: Brain metastases from endometrial carcinoma. Gynecol Oncol 1996; 61: 40– 43. 51 Morrow CP, Townsend DE: Tumors of the vagina. In: Morrow CP, Townsend DE (eds): Synopsis of Gynecologic Oncology. Third edn. New York, NY, John Wiley & Sons, Inc, 1987, pp. 211–219. 52 Rose PG, Piver S, Tsukada Y, et al.: Patterns of metastasis in uterine sarcoma: an autopsy study. Cancer 1989; 63: 935 –938. 53 Herrinton LJ, Stanford JL, Schwartz SM, et al.: Ovarian cancer incidence among Asian migrants to the United States and their descendants. J Natl Cancer Inst 1994; 86: 1336–1339. 54 Sevelda P, Schemper M, Spona J: CA-125 as an independant prognostic factor for survival in patients with epithelial ovarian cancer. Am J Obstet Gynecol 1989; 161: 1213 –1216. 55 Rustin GJS, Gennings JN, Nelstrop AE, et al.: Use of CA-125 to predict survival of patients with ovarian carcinoma. J Clin Oncol 1989; 7: 1667–1671. 56 Longacre TA, Kempson RL, Hendrickson MR: Well-differentiated serous neoplasms of the ovary. Pathology (Phila) 1993; 1: 255 –306.

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57 Julian CG, Goss J, Blanchard K, et al.: Biologic behavior of primary ovarian malignancy. Obstet Gynecol 1974; 44: 873 – 884. 58 Bergman F: Carcinoma of the ovary: a clinicopathological study of 86 autopsied cases with special reference to mode of spread. Acta Obstet Gynecol Scand 1966; 45: 211–231. 59 Larson DM, Copeland LJ, Moser RP, et al.: Central nervous system metastases in epithelial ovarian carcinoma. Obstet Gynecol 1986; 68: 746 –750. 60 Mayer RJ, Berkowitz RS, Grifﬁths CT: Central nervous system involvement by ovarian carcinoma. Cancer 1978; 41: 776 –783. 61 Hoffman JS, Pena YM: Central nervous system lesions and advanced ovarian cancer. Gynecol Oncol 1988; 30: 87–97. 62 LeRoux PD, Berger MS, Elliott P, et al.: Cerebral metastases from ovarian carcinoma. Cancer 1991; 67: 2194 –2199. 63 Plaxe SC, Dottino PR, Lipsztein R, et al.: Clinical features and treatment outcome of patients with epithelial carcinoma of the ovary metastatic to the central nervous system. Obstet Gynecol 1990; 75: 278 –281. 64 Winston KR, Walsh JW, Fisher EG: Results of operative treatment of intracranial metastatic tumors. Cancer 1980; 45: 2639 –2645. 65 Galicich JH, Sundaresan N, Thaler HT: Surgical treatment of single brain metastasis: evaluation of results by computerized tomography scanning. J Neurosurg 1980; 53: 63–67. 66 Patchell R, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 67 Barker GH, Orledge J, Wiltshaw E: Involvement of the central nervous system in patients with ovarian carcinoma. Br J Obstet Gynaecol 1981; 88: 690 – 694. 68 Ziegler J, Gliedman P, Fass D, et al.: Brain metastasis from ovarian cancer. J Neurooncol 1987; 5: 211–215. 69 Dauplat J, Nieberg RK, Hacker NF: Central nervous system metastasis in epithelial ovarian carcinoma. Cancer 1987; 60: 2559 –2562. 70 Deutsch M, Beck D, Manor D, et al.: Metastatic tumor following negative second look operation in ovarian carcinoma. Gynecol Oncol 1987; 27: 116 –120. 71 Ross WM, Carmichael VA, Shelly WE: Advanced carcinoma of the ovary with central nervous system relapse. Gynecol Oncol 1988; 30: 398 – 406. 72 Stein M, Steiner M, Klein B, et al.: Involvement of the central nervous system by ovarian carcinoma. Cancer 1986; 58: 2066 –2069. 73 Borgelt B, Gelber R, Kramer S: The palliation of brain metastasis: ﬁnal results of the ﬁrst two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980; 6: 1–9. 74 Niloff JM: Ovarian malignancy. Curr Opin Obstet Gynecol 1991; 3: 66 –72. 75 Aiba T, Koyama M, Watanabe T, et al.: Brain metastasis of ovarian cancer treated by chemotherapy including cis-platinum: a case report. No Shinkei Geka 1989; 17: 159 –161. 76 Cormio G, Gabriele A, Maneo A, et al.: Complete remission of brain metastases from ovarian carcinoma with carboplatin. Eur J Obstet Gynecol Reprod Biol 1998; 78: 91–93. 77 Vassilakos P, Kajii T: Hydatidiform mole: two entities. Lancet 1976; 1: 259. 78 Vassilakos P, Riotton G, Kajii T: Hydatidiform mole: two entities: a morphologic and cytogenetic study with some clinical considerations. Am J Obstet Gynecol 1977; 127: 167–170. 79 Kajii T, Ohama K: Androgenetic origin of hydatidiform mole. Nature 1977; 268: 633 – 634. 80 Szulman AE: Syndromes of hydatidiform moles: partial vs. complete. J Reprod Med 1984; 29: 789–790.

Brain metastases from gynecologic cancers 351 81 Szulman AE, Surti U: The syndromes of hydatidiform mole: 1. cytogenetic and morphologic correlations. Am J Obstet Gynecol 1978; 131: 655– 671. 82 Szulman AE, Surti U: The syndromes of hydatidiform mole: 2. morphological evaluation of the complete and partial mole. Am J Obstet Gynecol 1978; 132: 20 –27. 83 Park WW, Lees JC: Choriocarcinoma: a general review, with analysis of 516 cases. Arch Pathol 1950; 49: 73. 84 Newlands ES, Bagshawe KD, Begent RHJ, et al.: Results with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumors, 1979–1989. Br J Obstet Gynaecol 1991: 98: 550 –557. 85 Delfs E: Chorionic gonadotropic determinations in patients with hydatidiform mole and choriocarcinoma. Ann NY Acad Sci 1957; 80: 125 –139. 86 Weed JC Jr, Hunter VJ: Diagnosis and management of brain metastasis from gestational trophoblastic disease. Oncology 1991; 5: 48 –50. 87 Yordan EL, Schlaerth J, Gaddis O, et al.: Radiation therapy in the management of gestational choriocarcinoma metastatic to the central nervous system. Obstet Gynecol 1987; 69: 627–630. 88 Jones WB, Wagner-Reiss KM, Lewis JL: Intracerebral choriocarcinoma. Gynecol Oncol 1990; 38: 234–243. 89 Hilgers RD: Improving the outcome of high-risk gestational trophoblastic neoplasia. Contemp Obstet Gynecol 1987; 29: 73 –92. 90 Bagshawe KD, Harland J: Immunodiagnosis and monitoring of gonadotropinproducing metastases in the central nervous system. Cancer 1976; 38: 112–118. 91 Morrow CP, Kletzky OA, DiSaia PJ, et al.: Clinical and laboratory correlates of molar pregnancy and trophoblastic disease. Am J Obstet Gynecol 1977; 424: 424 – 430. 92 World Health Organization Scientiﬁc Group on Gestational Trophoblastic Diseases. Technical report series: no.692. Geneva: The World Health Organization, 1983. 93 Ross GT, Stohlabach LL, Hertz R: Actinomycin D in the treatment of methotrexateresistant trophoblastic disease in women. Cancer Res 1962; 22: 1015 –1017. 94 Li MC, Whitmore WF, Golbey R, et al.: Effects of combined drug therapy on metastatic cancer of the testis. JAMA 1960; 174: 1291–1299. 95 Li MC: Management of choriocarcinoma and related tumors of uterus and testis. Med Clin North Am 1961; 45: 661– 676. 96 Hammond CB, Borchert LG, Tyrey LG, et al.: Treatment of metastatic trophoblastic disease: good and poor prognosis. Am J Obstet Gynecol 1973; 115: 451– 457. 97 Kobayashi T, Kida Y, Yoshida J, et al.: Brain metastasis of choriocarcinoma. Surg Neurol 1982; 17: 395–403. 99 Rustin GJ, Newlands ES, Begent RH, et al.: Weekly alternating etoposide, methotrexate, and actinomycin/vincristine and cyclophosphamide chemotherapy for the treatment of CNS metastases of choriocarcinoma. J Clin Oncol 1989; 7: 900 –903. 99 Kawana K, Yoshikawa H, Yokota H, et al.: Successful treatment of brain metastases from ovarian cancer using gamma-knife radiosurgery. Gynecol Oncol 1997; 65: 357–359. 100 Corn BW, Mehta MP, Buatti JM, et al.: Stereotactic irradiation: potential new treatment method for brain metastases resulting from ovarian cancer. Am J Clin Oncol 1999; 22: 143–146.

CHAPTER 20

Brain metastases from genitourinary cancer: germ cell, testicular, prostate and bladder cancer Philip V Theodosopoulos, James L Rubenstein, Michael W McDermott

Introduction Cancers of the genitourinary system are frequent malignancies and affect a large portion of the United States’ population. Testicular cancer is the most common cancer in men 15 to 35 years old, with an incidence of 3:100,000 men. Prostate cancer is second only to lung cancer as a cause of cancer deaths in men and is the most common cancer in them. Bladder cancer is the least common malignancy among the malignancies of the genitourinary tract, accounting for 4% of the new cancers diagnosed annually in the United States, producing nearly 12,000 deaths annually1, 2.

Pathology Most testicular cancers are derived from germ cell elements. A common histological scheme distinguishes pure seminomas from nonseminomatous germ cell tumors, which include embryonal carcinoma, teratoma, choriocarcinoma, yolk sac tumors, Leydig cell tumors, and gonadoblastoma. The vast majority of prostate cancers are adenocarcinomas (98%), although 2% are classiﬁed as transitional cell carcinomas, squamous cell carcinomas, papillary carcinomas, and ductal carcinomas. Among bladder cancers, approximately 95% are transitional cell carcinomas, 3% are squamous cell carcinomas, and the remainder are adenocarcinomas1.

Presentation Genitourinary cancer metastases to the brain are rare. Germinal testicular cancer most commonly metastasizes to the brain, with an incidence ranging from 2 to 15% in clinical series3, 4 and up to 40% in post-mortem autopsy studies5. Furthermore, the development of isolated relapse of testicular cancer in the brain, although rare, has been well described in the literature6, 7. The reported rate of brain metastases from urothelial cancer ranges from 1–12%8–10. Yet, 352

Brain metastases from genitourinary cancer 353

recent improvements in systemic therapy have allowed for increased survival and an apparent increase in the diagnosis of brain metastases in patients with advanced bladder cancer9, 11–14. Finally, the incidence of prostatic cancer metastases to the brain is the lowest among genitourinary tumors and ranges from 0.2% in clinical studies to 1% in autopsy studies15. The majority of brain metastases from genitourinary tumors are asymptomatic. When they become symptomatic, presentations include symptoms and signs of increased intracranial pressure, including headaches and papilledema, as well as symptoms and signs of cortical compression and irritation, such as seizures and focal neurological ﬁndings.

Clinical staging Testicular cancer After the diagnosis of testicular cancer, which is usually made by inguinal orchiectomy, the extent of disease is determined both by radiographic imaging studies, using computerized tomography (CT) of the chest, abdomen, and pelvis, as well as by serum levels of beta-human chorionic gonadotropin (betaHCG), alpha-feto proteins (AFP), and lactate dehydrogenase (LDH). Although 90% of seminomas are marker negative, 10% will be associated with an elevated beta-HCG level alone. Elevation of AFP strongly suggests the presence of a nonseminomatous germ cell tumor, a type known to be marker negative in only 15% of cases. The presence of choriocarcinoma mandates imaging studies of the brain as part of the staging evaluation. Bone scans are also useful but not mandatory in routine staging of patients with germ cell tumors.

Prostate cancer Most patients with localized cancer based upon clinical evaluation will not require a work-up for metastatic disease unless the patient’s serum prostatespeciﬁc antigen level (PSA) or the Gleason grade of the tumor is high. The Gleason system is the most widely used grading system, which classiﬁes prostatic adenocarcinoma on the basis of the degree of glandular differentiation. Bone scans are extremely useful in the evaluation of the axial or appendicular skeleton when the patient’s serum PSA is greater than 10 ng/ml or with Tumor-Node-Metastasis (TNM) stage T3 disease or higher. Imaging studies of the chest are necessary because 6% of patients with metastatic carcinoma of the prostate have lung metastases at presentation16. CT or magnetic resonance (MR) imaging is recommended for patients with a high probability of dissemination outside the pelvis, which includes patients with a serum PSA level above 20, or those with a tumor having a Gleason grade of 7 or greater (Table 20.1) (Figure 20.1).

Bladder cancer Staging is critical in the initial management of bladder cancers. The presence or absence of distal metastases can be documented by a physical examination, a

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Chapter 20 Table 20.1 Gleason grading of prostate cancer. Numeric score

Degree of differentiation

2–4 5–6 7 8–10

Well differentiated Moderately differentiated Moderately–poorly differentiated Poorly differentiated

Figure 20.1 Contrast-enhanced T1-weighted magnetic resonance (MR) image showing a lesion adjacent to the left occipital horn. This is presumed to be one of several prostate brain metastases treated with radiosurgery that showed a complete response on follow-up imaging studies.

CT scan of the chest, abdomen, and pelvis, and a radionuclide bone scan. The utility of bone scan is increased if the patient has bone pain or an elevated alkaline phosphatase level.

Imaging Brain metastases generally occur supratentorially, along the gray matter to white matter interface15, 17. This holds true for testicular and bladder cancer metastases (Figures 20.2 and 20.3). There is also an isolated report of a testicular germ cell tumor causing a pineal metastasis18. Prostate cancer, however, frequently tends to involve the meninges. In a review of ﬁfty-seven patients with brain metastases from prostate cancer, 67% involved the meninges, whereas 25% involved the cerebrum, and 8% involved the cerebellum15. There currently exists no generally accepted standard of brain imaging for patients with metastatic genitourinary malignancies. A study by Mathews et al.17 suggests that brain imaging is indicated in the presence of focal neurological ﬁndings or seizures but not in asymptomatic individuals. Focal neurological ﬁndings predicted the presence of brain metastases in 15 of 17 patients, whereas seizures were predictive in three of six patients. No brain metastases were identiﬁed among the 25 asymptomatic patients who were imaged.

Brain metastases from genitourinary cancer 355

Figure 20.2 Embryonal and mature teratoma brain metastasis at the gray-white matter junction in a young man treated with radiosurgery.

(A)

(B)

Figure 20.3 (A) T1-weighted contrast-enhanced magnetic resonance (MR) image of nonseminomatous brain metastasis at the gray-white matter junction after treatment with radiosurgery. (B) The precontrast study showed subacute blood collection anterior to solid mass, which is best seen as an area of increased signal on this T2-weighted image.

A retrospective study of 133 patients with advanced urothelial cancer identiﬁed 14 patients with brain metastases, all of which were diagnosed during a partial or complete response to treatment. Eight of these patients also had lung metastases concurrently. The authors of this study concluded that evaluation of the central nervous system should be performed at routine follow up in patients with metastatic bladder cancer who have complete

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response to treatment and before resection of residual disease, especially in patients with lung lesions.

Laboratory markers The presence of elevated serum AFP (> 500 ng/mL) and beta-HCG (> 1000 IU/L) is clearly associated with a worse prognosis in patients with testicular germ cell tumors19–24. Although elevated markers are universally associated with advanced disease, no direct connection exists between serum AFP or beta-HCG elevation and the development of brain metastases. Serum PSA is a sensitive indicator of prostate cancer recurrence after radical prostatectomy. Patients with PSA elevations are closely evaluated for the presence of locally recurrent or distant metastatic disease, including rare brain metastases. Yet, distant prostatic tumor metastases, including those in the brain, can occur without PSA elevation25. Abnormally high levels of LDH have been shown to be predictive of distant metastases of transitional cell carcinoma of the urinary tract. Although not directly related to the presence of brain metastases, it is an indicator of advanced disease, which in turn is associated with the development of brain metastases9.

Treatment Most intensive chemotherapy regimens, including autologous bone marrow transplantation, have been tried with success with germ cell tumors. Nonseminomatous germ cell tumors exhibit a more aggressive biology than seminomatous germ cell tumors. Pure choriocarcinomas are typically most aggressive and exhibit early dissemination to the lungs, brain, and viscera. Brain metastases arising from choriocarcinoma have a high risk of spontaneous hemorrhage. The majority of the literature on the treatment of genitourinary brain metastases deals with the results of whole-brain irradiation with or without surgery. No study deals speciﬁcally with radiosurgery, a technique used frequently now in the treatment of brain metastases from renal cell carcinoma. At our institution, less than 1% of the brain metastases treated have been from genitourinary cancers, and some of the MR images from these patients are shown in this chapter. Attempts have been made by several authors to deﬁne the role and timing of radiosurgery for brain metastases, but to date only one prospective randomized trial has been reported. Kondziolka et al. randomized patients with 2–4 brain metastases to treatment with whole-brain radiation therapy (WBRT) alone or WBRT plus radiosurgery26. The study was stopped early because of an interim analysis showing that combined treatment produced signiﬁcantly better local tumor control (p = 0.0005) and delayed the time to any failure of local control in the brain (p = 0.002). Overall patient survival times between the two treatment groups were not signiﬁcantly different (7.5 months

Brain metastases from genitourinary cancer 357

without radiosurgery and 11 months with it; p = 0.22). Sneed et al. retrospectively evaluated the role of salvage therapy when WBRT was initially withheld27. The overall survival times in the radiosurgery alone and radiosurgery plus WBRT groups were not statistically different (11.3 and 11.1 months, respectively; p = 0.80). When allowing for ﬁrst successful salvage treatment of new brain disease with radiosurgery and/or surgery and/or WBRT, the authors found no difference in subsequent freedom from tumor progression in the brain. Clearly, the role of radiosurgery for the treatment of brain metastases continues to evolve, and other prospective trials are already underway to help answer the questions that remain regarding its use.

Testicular tumors The introduction of cisplatin-based combination chemotherapy regimens increased the long-term cure rates of patients with testicular cancer from 20% to 80%. Even in the setting of advanced metastatic disease, the overall survival rate of patients 3 years after treatment is 75%–85%19, 22. The combination of bleomycin, etoposide, and cisplatin remains the preferred regimen for poor-prognosis testicular germ cell tumors23. More intensive chemotherapy regimens have been tried with varied success23, 28. The treatment of brain metastases from germ cell tumors consists of the combination of cisplatinbased chemotherapy and WBRT. Although the presence of brain metastases is a uniform predictor of poor prognosis20, 22, 24, 29, occasional long-term survival has been reported30. Among the patients who develop brain metastases from germ cell tumors, those who have brain metastases at the time of initial diagnosis survive best, followed by those who develop brain metastases after initial complete remission and those who develop brain metastases during treatment31, 32 (Table 20.2). In a few series, cytoreductive surgery of brain metastases from germ cell tumors has been shown to be associated with long-term survival, although its role has not been assessed in a prospective fashion30, 33.

Bladder cancer The treatment of advanced urothelial carcinoma of the bladder is also based on cisplatin combination chemotherapeutic regimens. A regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) has produced more than 30% complete responses and more than a year of median overall patient survival time10, 34. A randomized comparison of cisplatin alone versus M-VAC demonstrated a clear survival beneﬁt for the combination regimen34. Predictors for survival from the same group of patients included performance status, histology, and the presence of metastases to liver or bone35. The treatment of brain metastases from bladder cancer includes a combination of surgical debulking and radiotherapy12, 14. In a study of 28 patients with transitional cell cancer of the bladder who had brain metastases, Rosenstein et al. found an advantage of surgical resection and WBRT compared with WBRT alone, reporting mean survival times of 19 and 6 months, respectively. This

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Table 20.2 Results of treatment for brain metastases from genitourinary cancer. Overall survival time from date of diagnosis

Study

Patients

Primary tumor

Treatment

Logothetis et al. 198229

12

Germ cell tumor

WBRT, CIS

30 months, single metastasis; 13.7 months, multiple metastases

Raghavan et al. 198730

4

NSGCT

WBRT, CIS, surgery

Two long-term survivors, 78 and 31 months

Rustin et al. 198639

10

NSGCT

CIS, IT methotrexate

8 of 10 alive at mean follow up, 32 months

Spears et al. 199232

24

NSGCT

WBRT with or without CIS

*(1) 56 months (2) 3/4 alive at (81, 94, 174 months after diagnosis) (3) 10 months

Bokemeyer et al. 199731

44

Germ cell tumor

WBRT, CIS, with or without surgery

(1) 15 months (2) 93 months (3) 3 months

Kabalin et al. 198813

4

Transitional cell cancer of the bladder

WBRT with or without surgery

< 4 months

Rosenstein et al. 199314

28

Transitional cell cancer of the bladder

WBRT with or without surgery

4 months

Dhote et al. 199812

8

Transitional cell cancer of the bladder

WBRT with or without surgery

3 months

Prostate cancer

WBRT, surgery, androgen deprivation

4 months**

Lynes et al. 198615

Review of reported cases

NSGCT, nonseminomatous germ cell tumor; WBRT, whole-brain radiation therapy; CIS, cisplatin-based combination chemotherapy regimen; IT, intrathecal. *For survival in patients with germ cell tumors: (1) patients with metastases to the brain at diagnosis. (2) metastases to brain after initial complete response to treatment. (3) metastases to brain diagnosed during treatment. **Median survival not reported in all cases.

comparison was biased by patient selection for surgical treatment, which included only patients with solitary metastases. Yet, even when only patients with solitary lesions were reviewed, surgical treatment was associated with improved survival14.

Prostate cancer Although prostate cancer brain metastases are rare, their diagnosis portends a very poor prognosis. In the scant literature of case reports and small case series, the majority of patients succumb to their disease within months after their diagnosis. Based on limited data, it appears that surgical debulking

Brain metastases from genitourinary cancer 359

combined with WBRT and androgen therapy might prolong survival and should be recommended in patients who, aside from their brain metastases, may be saved15, 36 –38.

Conclusions Brain metastases from genitourinary tumors are rare. Similarly to other cancers that metastasize to the brain, treatment of systemic and central nervous system disease can proceed in isolation. Staging, treatment, and control of systemic disease has a huge impact on the survival of patients with brain metastases from the same tumor. With improved criteria for selecting patients for treatment and with the improving methods for treating brain metastases, the prospect for better outcomes seems bright.

References 1 DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, J.B. Lippincott Co., 1993. 2 Parker SL, Tong T, Bolden S, et al.: Cancer statistics, 1997. CA Cancer J Clin 1997; 47: 5 –27. 3 Kaye SB, Bagshawe KD, McElwain TJ, et al.: Brain metastases in malignant teratoma: a review of four years’ experience and an assessment of the role of tumour markers. Br J Cancer 1979; 39: 217–223. 4 Williams SD, Einhorn LH: Brain metastases in disseminated germinal neoplasms: incidence and clinical course. Cancer 1979; 44: 1514 –1516. 5 Schold SC, Vurgrin D, Golbey RB, Posner JB: Central nervous system metastases from germ cell carcinoma of testis. Sem Oncol 1979; 6: 102–108. 6 Perry JJ, Jelinek JS: Isolated central nervous system relapse of testicular cancer. Med Pediat Oncol 1992; 20: 68 –70. 7 Raina V, Singh SP, Kamble N, et al.: Brain metastasis as the site of relapse in germ cell tumor of testis. Cancer 1993; 72: 2182–2185. 8 Sengeløv L, Kamby C, von der Maase H: Pattern of metastases in relation to characteristics of primary tumor and treatment in patients with disseminated urothelial carcinoma. J Urol 1996; 155: 111–114. 9 Sengeløv L, von der Maase H, Kamby C, et al.: Assessment of patients with metastatic transitional cell carcinoma of the urinary tract. J Urol 1999; 162: 343 –346. 10 Sternberg CN, Yagoda A, Scher HI, et al.: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efﬁcacy and patterns of response and relapse. Cancer 1989; 64: 2448 –2458. 11 Bloch JL, Nieh PT, Walzak MP: Brain metastases from transitional cell carcinoma. J Urol 1987; 137: 97–99. 12 Dhote R, Beuzeboc P, Thiounn N, et al.: High incidence of brain metastases in patients treated with an M-VAC regimen for advanced bladder cancer. Eur Urol 1998; 33: 392–395. 13 Kabalin JN, Freiha FS, Torti FM: Brain metastases from transitional cell carcinoma of the bladder. J Urol 1988; 140: 820 – 824. 14 Rosenstein M, Wallner K, Scher H, et al.: Treatment of brain metastases from bladder cancer. J Urol 1993; 149: 480 – 483. 15 Lynes WL, Bostwick DG, Freiha FS et al.: Parenchymal brain metastases from adenocarcinoma of prostate. Urology 1986; 28: 280 –287.

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16 Lindell MM, Doubleday LC,von Eschenbach AC, et al.: Mediastinal metastasis from prostatic carcinoma. J Urol 1982; 128: 331–334. 17 Mathews VP, Broome DR, Smith RR, et al.: Neuroimaging of disseminated germ cell neoplasms. AJR Am J Roentgenol 1990; 154: 1299 –1304. 18 Delahunt B, Teoh HH, Balakrishnan V, et al.: Testicular germ cell tumor with pineal metastases. Neurosurgery 1990; 26: 688 – 691. 19 Prognostic factors in advanced non-seminomatous germ-cell testicular tumours: results of a multicentre study. Report from the Medical Research Council Working Party on Testicular Tumours. Lancet 1985; 1: 8 –11. 20 International Germ Cell Consensus Classiﬁcation: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997; 15: 594 – 603. 21 Aass N, Klepp O, Cavallin-Stahl E, et al.: Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience. J Clin Oncol 1991; 9: 818–826. 22 Gerl A, Clemm C, Schmeller N, et al.: Advances in the management of metastatic nonseminomatous germ cell tumours during the cisplatin era: a single-institution experience. Br J Cancer 1996; 74: 1280 –1285. 23 Kaye SB, Mead GM, Fossa S, et al.: Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: a Randomized Medical Research Council/European Organization for Research and Treatment of Cancer study. J Clin Oncol 1998; 16: 692–701. 24 Mead GM, Stenning SP, Parkinson MC, et al.: The Second Medical Research Council study of prognostic factors in nonseminomatous germ cell tumors. Medical Research Council Testicular Tumour Working Party. J Clin Oncol 1992; 10: 85 –94. 25 Leibman BD, Dillioglugil O, Wheeler TM, et al.: Distant metastasis after radical prostatectomy in patients without an elevated serum prostate speciﬁc antigen level. Cancer 1995; 76: 2530–2534. 26 Kondziolka D, Patel A, Lunsford LD, et al.: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999; 45: 427– 434. 27 Sneed PK, Lamborn KR, Forstner JM, et al.: Radiosurgery for brain metastases: is whole brain irradiation necessary? Int J Radiat Oncol Biol Phys 1999; 43: 549 –558. 28 Lewis CR, Fossà SD, Mead G, et al.: BOP/VIPaa new platinum-intensive chemotherapy regimen for poor prognosis germ cell tumours. Ann Oncol 1991; 2: 203 –211. 29 Logothetis CJ, Samuels ML, Trindade A: The management of brain metastases in germ cell tumors. Cancer 1982; 49: 12–18. 30 Raghavan D, Mackintosh JF, Fox RM, et al.: Improved survival after brain metastases in non-seminomatous germ cell tumours with combined modality treatment. Br J Urol 1987; 60: 364–367. 31 Bokemeyer C, Nowak P, Haupt A, et al.: Treatment of brain metastases in patients with testicular cancer. J Clin Oncol 1997; 15: 1449 –1454. 32 Spears WT, Morphis JG 2nd, Lester SG, et al.: Brain metastases and testicular tumors: longterm survival. Int J Radiat Oncol Biol Phys 1992; 22: 17–22. 33 Kulkarni RP, Reynolds KW, Newlands ES, et al.: Cytoreductive surgery in disseminated non-seminomatous germ cell tumours of testis. Br J Surg 1991; 78: 226 –229. 34 Loehrer PJ Sr, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992; 10: 1066 –1073.

Brain metastases from genitourinary cancer 361 35 Saxman SB, Propert KJ, Einhorn LH, et al.: Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1997; 15: 2564 –2569. 36 Baumann MA, Holoye PY, Choi H: Adenocarcinoma of prostate presenting as brain metastasis. Cancer 1984; 54: 1723 –1725. 37 Castaldo JE, Bernat JL, Meier FA, et al.: Intracranial metastases due to prostatic carcinoma. Cancer 1983; 52: 1739 –1747. 38 Rao KG: Carcinoma of prostate presenting as intracranial tumor with multiple cranial nerve palsies. Urology 1982; 19: 433 – 435. 39 Rustin GJ, Newlands ES, Bagshawe KD, et al.: Successful management of metastatic and primary germ cell tumors in the brain. Cancer 1986; 57: 2108 –2113.

CHAPTER 21

Brain metastasis from upper gastrointestinal tract cancers: esophageal, gastric, hepatic, gallbladder, and pancreatic Jeffrey S Weinberg, Renato Lenzi, Ziya L Gokaslan

Cancers of the upper gastrointestinal tract (those originating in the esophagus, stomach, gallbladder, liver, or pancreas) are common, accounting for a signiﬁcant number of hospitalizations and deaths each year. These tumors rarely present with brain metastases; however, the presence of such metastases implies a more advanced stage of disease and usually a worse prognosis. A search of the institutional database of The University of Texas M. D. Anderson Cancer Center (M. D. Anderson) between 1950 and July 2000 identiﬁed 9,897 patients with brain metastases. Of these, 264 patients (2.7%) had metastases from upper gastrointestinal tract primary sites. This chapter provides a brief introduction of the presentation and management of the most common upper gastrointestinal tract cancers and discusses the neurosurgical implications of brain metastasis from each of these sites.

Esophageal cancer Esophageal cancer is uncommon in the United States, with an overall incidence of 4.0/100,0001. Approximately 12,300 new cases are diagnosed per year2. However, incidence rates range widely depending on the geographic region, indicating that environmental or nutritional inﬂuences play a role in the development of esophageal cancer. Most tumors present in the middle-third of the esophagus (50%), whereas 35% and 15% present in the lower- and upperthirds, respectively3. The two major types of tumors are squamous cell carcinoma, which presents mostly in the middle-third, and adenocarcinoma, which presents in the lower portion of the esophagus. There has been a notable increase in the incidence of adenocarcinoma, while that of squamous cell carcinoma has remained unchanged4. Esophageal cancer is very difﬁcult to treat, as patients exhibit symptoms only late in the course of the disease, making the chances for cure very small. Multiple risk factors confer an increased susceptibility toward the development of squamous cell esophageal cancer. Alcohol consumption and cigarette 362

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smoking are implicated5 as are achalasia (an impairment or abolition of smooth muscle relaxation, resulting in a loss of normal peristaltic mechanisms and an increase in abnormal contractions)6, oral intake of caustic agents such as lye7, esophageal diverticula8, and esophageal webs (in Plummer-Vinson syndrome)9. Esophageal squamous cell cancer has been identiﬁed as a second primary tumor in patients originally presenting with head and neck tumors9, 10. Conclusive evidence exists implicating Barrett’s esophagus (metaplastic transformation due to chronic gastroesophageal reﬂux) in the development of adenocarcinoma. In fact, surgical treatment for Barrett’s esophagus does not reduce one’s risk of developing adenocarcinoma11. Caucasians and males have a higher incidence of adenocarcinoma than African-Americans and females; the opposite association exists for squamous cell cancer12. Obese people are more likely to have gastroesophageal reﬂux disease and subsequently are at risk for development of adenocarcinoma of the esophagus13. Poor nutrition, with vitamin A and riboﬂavin deﬁciencies, may predispose to squamous cell cancer3, whereas a diet rich in fruits, vegetables, ﬁber, and antioxidants such as vitamin C correlate with a decreased risk of developing adenocarcinoma14. When the primary tumor has progressed to involve approximately 75% of the circumference of the esophagus at the level of the lesion, patients will complain of dysphagia and will suffer progressive weight loss3. Many will also complain of epigastric discomfort and frequent regurgitation. Hematemesis and melena may develop. Larger lesions put local structures at risk for involvement. Thus, in rare cases, patients may present with a superior vena cava syndrome, hemorrhage secondary to aortic erosion, or hemoptysis secondary to a tracheo-esophageal ﬁstula. Physical examination may identify prominent lymphadenopathy in the supraclavicular and cervical lymph nodes. In such cases, lymph node biopsy may ascertain the histopathological diagnosis15. Diagnostic work up is usually initiated with a barium swallow. This may be nondiagnostic, prompting evaluation with other studies. Direct visualization using esophagoscopy and lesion biopsy will usually provide conclusive evidence for a diagnosis. Direct visualization may reveal other intraluminal metastases, which implies a worse prognosis. Classiﬁcation and staging are performed using the TNM system. The local venous plexi and abundant lymphatic drainage provide a route for distant metastasis to the liver, lung, pleura, stomach, peritoneum, kidney, adrenal gland, bone, and brain. Computed tomography (CT) of the chest, thorax, and abdomen may identify local and distant metastases. The depth of tumor invasion and length of the involved esophagus, which are inversely correlated with prognosis, are better assessed by endoscopic ultrasound than CT scanning16. For localized disease, esophagectomy is the treatment of choice. Several surgical techniques have been developed in the attempt to improve outcomes. Transhiatal and standard transthoracic esophagectomy are the most commonly used. En bloc esophagectomy and three-ﬁeld lymphadenectomy seek to maximize locoregional control. Overall survival at ﬁve years for patients of stages I through III treated with transhiatal esophagectomy is 23%17. Although

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(B)

Figure 21.1 The patient, a 66-year-old man, presented 3.5 months after esophagectomy for primary esophageal adenocarcinoma. He was not treated with adjuvant therapy. Prior to admission, he presented with progressive headaches, gait ataxia, and slurred speech. Magnetic resonance (MR) imaging of the brain revealed multiple lesions. (A) Preoperative axial, T1 MR image, after the administration of gadolinium. A large, heterogeneously enhancing right cerebellar lesion is visible with obvious mass effect and almost complete obstruction of the fourth ventricle. He underwent resection of the posterior fossa lesion, followed by whole-brain irradiation. Pathological examination revealed adenocarcinoma, consistent with the esophageal primary lesion. (B) Postoperative contrast-enhanced T1 MR image reveals a gross-total resection. His symptoms resolved.

preoperative chemoradiation can yield a pathologic response in the tumor in as many as 25% of patients, it is associated with signiﬁcant morbidity and mortality and it remains an experimental modality18. Recent efforts have focused on the development of less toxic perioperative regimens. A drug combination of infusional 5-ﬂuorouracil and cisplatin plus radiation followed by esophagectomy and paclitaxel/cisplatin has been shown to be effective in inducing pathologic complete remissions and downstaging, with a median survival in excess of 30 months19. Means of providing palliation in patients with diffuse disease and severe dysphagia include esophagectomy, intraluminal brachytherapy, dilation, intubation, and laser treatment. Esophagectomy provides for complete resolution of dysphagia but has the highest rates of morbidity and mortality. With laser treatment, greater than 80% of patients experience resolution of their symptoms19. Few isolated case reports and case series describe the management of esophageal cancer brain metastases, and only limited conclusions can be drawn (Figure 21.1). One of the earliest of these reports was published in 1978 by Irie et al., who described resection of a large dural-based esophageal squamous cell carcinoma metastasis diagnosed 17 years after treatment of the primary disease20. The patient survived for eight months after surgery and died secondary to generalized sepsis. Chalif et al. presented the case of a 62-year-old man who underwent tumor resection and subsequent irradiation

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of a metastatic esophageal squamous cell cancer 15 months after treatment of the primary tumor21. Survival was not described. In a similar case, a 44-yearold man was treated by surgical resection and irradiation of a squamous cell metastasis22. He survived until 19 months later, when he died of two new brain metastases. Odaimi and Ajani discussed a 48-year-old man who developed multiple brain metastases secondary to poorly differentiated esophageal carcinoma23. Surgery was deferred, but he did improve in response to steroids and whole-brain irradiation. Finally, a 58-year-old woman presented seven months after diagnosis of squamous cell esophageal carcinoma with ﬂat affect and aphasia24. She had a left temporal lobe lesion, a presumed metastasis, that was treated with radiation and steroids, alleviating her symptoms. Survival was not discussed. The largest series from the pre-magnetic resonance (MR) imaging era examined the usefulness of CT scanning as a screening tool for brain metastases in patients with newly diagnosed esophageal cancer25. In this report, only patients without any evidence of distant metastatic disease were candidates for esophagectomy, indicating that CT veriﬁcation of metastasis in the brain would exclude patients from surgical treatment of the primary tumor. Seven hundred and twenty-two patients with primary esophageal cancer were followed, and 15 developed brain metastases (incidence = 2%). Twelve of the cancers were adenocarcinomas, two were squamous cell carcinomas, and one was a poorly differentiated carcinoma. The brain lesions were diagnosed at a mean of 9.5 months after diagnosis of the primary tumor in all but two patients who presented initially with neurological symptoms. Risk of brain metastases was statistically correlated with the size of the primary, and a trend existed for adenocarcinoma to metastasize more frequently than squamous cell carcinoma (in contrast to the aforementioned cases, which were metastatic squamous cell carcinomas). All 240 prospectively identiﬁed patients who were candidates for esophagectomy underwent CT of the head. No metastases were detected; however, over time, six of these patients developed brain metastases. The 15 patients who presented with or developed brain metastases underwent treatment for the metastatic disease. Data analysis indicates that the mean survival time of the ﬁve patients who underwent surgical excision of the brain lesions was 10.2 months. This increases to 12.7 months (range 5–17 months) if the one patient who died of medical complications 1 day postoperatively is excluded. Patients treated with radiation, chemotherapy, or both survived for an average of 6.4 months. Thus, in this small series, it appears that surgery for esophageal brain metastases almost doubles the mean survival time. Because only 0.9% had brain metastases detected by CT scan at time of presentation, this is not a cost-effective screening exam.

Gastric cancer The number of newly diagnosed patients with gastric cancer (GCa) has increased in the last 15 years, reaching as high an incidence as 93.3:100,000 males in Japan1. In the United States, there is a higher incidence of this disease

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in males than in females, and it is higher in black males than in white males. There has been an increase in proximal gastric cancers, and these have a worse prognosis than more distally located malignancies26. Risk factors for the development of GCa include cigarette smoking and alcohol use27; low dietary antioxidants28; high dietary intake of salty foods, processed meat, and vegetables29; prior gastric surgery30; and Helicobacter pylori infection27. Typically, patients present with only mild abdominal discomfort, weight loss, hematemesis, and anorexia. Dysphagia may occur when lesions are located at the gastroesophageal junction. Metastatic disease may present as an ovarian mass, peritoneal carcinomatosis, metastatic liver disease, or lymphadenopathy of the periumbilical or subclavian nodes. The diagnostic work-up includes upper GI endoscopy, a barium study of the GI tract, and a CT scan. The CT scan may also delineate the extent of intra-abdominal and intrathoracic metastatic foci. Newer methods, such as endoscopic ultrasound, provide information regarding the depth of tumor invasion and the presence of metastatic lesions. Whether or not surgical resection for cure should be undertaken depends on the data gained from these examinations. GCa is staged using the TNM grading scheme. Because of the extensive lymphatic and vascular supply to the stomach, patients with GCa usually present at a late stage. Invasion may occur via local extension into the peritoneum and omentum; via lymphatic spread to noncontiguous sites in the stomach, the esophagus, and duodenum, or via the bloodstream to distant sites, such as the liver, lungs, and brain. The only curative treatment for GCa is surgical resection, an option only for localized and early stage disease. Increased stage of disease and increased level of lymph node involvement are inversely correlated with survival. Even after total gastrectomy, recurrence is the norm, typically due to unresected residual disease31. With small noninvasive tumors, 5-year survival rates with curative resection can reach 90%32. Postoperative combined radiation and chemotherapy has recently been shown to improve disease-free survival and overall survival, and is now considered the standard of care for high-risk patients who undergo resection for locally advanced cancer of the stomach and gastroesophageal junction and display no gross or microscopic residual disease33. Given the poor prognosis of patients with gastric carcinoma, only rare case reports exist describing the neurological manifestations, treatment, and outcome of patients with brain metastases from a gastric primary. Earlier diagnoses are being made with increased frequency, with screening programs established in regions that have a high incidence of gastric adenocarcinoma. Presumably, with earlier diagnosis, curative treatment will become a more frequent goal. In addition, the incidence of metastatic brain lesions may rise because of the cancer’s earlier detection and the patients’ longer survival. In fact, a Medline search on gastric cancer and brain metastases reveals a notable increase in the number of case reports and small series in the 1990s compared with prior years.

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The incidence of brain metastases from gastric carcinoma is under 1%34, 35. Patients usually present with neurological manifestations during the course of their disease, but in rare cases, symptoms due to the brain metastasis may be the initial symptom of the systemic malignancy34, 36. Gastric metastases are most frequently located in the supratentorial region but may also occur in the parasellar region37, pineal region38, infratentorial region34, or the dura35, 39 and may be multiple at presentation34. In a retrospective review of 13 patients with gastric cancer metastatic to the brain, Kim noted that neither chemotherapy nor brain irradiation altered the clinical course or outcome of these patients35. Kasakura et al.40 and York et al.34 further conﬁrmed this. In their review of three of their own patients and eight others reported in the literature, Kasakura et al. noted an improved outcome for patients who underwent resection of their brain metastatic lesions from gastric cancer40. In the largest series to date, York et al. described the clinical outcome of 24 patients with gastric cancer metastases to the brain34. For the 19 patients diagnosed antemortem, the median survival time was 2.4 months. However, by separating the patients into three treatment categories (steroids alone, whole-brain radiation and steroids, and surgery plus whole-brain radiation and steroids), a signiﬁcant difference in survival was noted. Median survival times for the ﬁrst two groups were 7 and 9 weeks, respectively, whereas the third group reached 1 year (median, 54 weeks). Thus, we practice aggressive surgical intervention in patients whose medical condition does not preclude general anesthesia and craniotomy (Figure 21.2). (A)

(B)

Figure 21.2 The patient, a 45-year-old right-handed man, presented three weeks after diagnosis of gastric cancer with a left upper-extremity monoparesis; MR imaging revealed a posterior right frontal brain lesion. He was treated with whole-brain irradiation and chemotherapy for the metastatic tumor prior to resection of the primary lesion. Five months later, brain-imaging studies demonstrated an increase in the size of the lesion. (A) Contrast-enhanced coronal MR image demonstrates a deep right posterior frontal lesion with mass effect on the right frontal horn of the right lateral ventricle. The patient underwent uncomplicated craniotomy and excision of the lesion. (B) Contrast-enhanced coronal MR image demonstrates complete resection of the lesion.

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Liver cancer Hepatocellular carcinoma (HCC) is endemic to regions of China and Thailand, reaching an annual incidence of 90/100,000, with a male-to-female ratio of approximately 4:1. HCC had an incidence of 3.3/100,000 in 1990–1991 in the United States1, and an estimated 15,300 new cases were expected to be diagnosed in the year 20002. Any type of hepatitis and cirrhosis has the potential to lead to HCC. Aﬂatoxin b1, commonly found in inappropriately stored grains from hot and humid locations, confers an increased susceptibility to the development of HCC41. Other causative agents include vinyl chloride, anabolic steroids, estrogens, phenobarbital, and other hepatocarcinogenic pollutants42, 43. However, in many countries, the largest risk stems from chronic hepatitis secondary to viral hepatitis B (HBV), hepatitis C (HCV), and alcohol-induced cirrhosis44. The fact that primary biliary cirrhosis confers a higher risk for cholangiocarcinoma than do hepatitis and HCC43 indicates that the actual cause of the cirrhosis may be the offending agent, rather than the cirrhotic process itself. Hemochromatosis, alpha1-antitrypsin disease, and other congenital hepatic metabolic diseases are also associated with the development of HCC43. The most common presenting symptom is abdominal pain, followed by such constitutional symptoms as weight loss, weakness, and anorexia, with jaundice occurring in 7% of patients43. In late-stage disease, hematemesis, respiratory complaints, and bone pain secondary to esophageal varices, ascites, and diffuse metastatic disease may be present. Last, paraneoplastic syndromes due to erythrocytosis45, hypoglycemia and hypertension46, peripheral neuropathy47, acute porphyria48, and hypercholesterolemia49 have been reported in HCC patients. The work-up for the patient with suspected HCC includes an adequate history to assess risk factors for hepatitis. A thorough physical exam may reveal hepatosplenomegaly, ascites, fever, and signs of chronic liver disease, including jaundice, palmar erythema, testicular atrophy, and gynecomastia. Radiographic studies should include abdominal CT scans, both with and without contrast, and may include CT portography and CT arteriography. Serum levels of alpha-fetoprotein (AFP) should be measured, and a hepatitis panel, routine liver function tests, and coagulation studies (PT/PTT) should be performed as well. Abdominal ultrasound may be used for initial screening and is very useful for monitoring. Measurement of serum soluble interleukin-2 receptor levels may be more reliable for long-term monitoring than measurement of serum AFP50. Recently, MRI has shown promise in deﬁning the anatomy of these liver tumors51. Treatment of HCC is based on the observed stage of the disease. TNM grading is used to assess staging. Chest, abdomen, and pelvic CT scans may frequently reveal lymphadenopathy, ascites, and pulmonary metastatic lesions. In the case of diffuse disease, a core biopsy may be performed. In unresectable disease, adverse prognostic factors include the presence of an estrogen receptor variant52, a tumor of Child’s grade B or C, a tumor size of > 5 cm in

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greatest diameter, and a portal vein thrombosis secondary to tumor invasion53. The presence of the latter is a contraindication to resection and may be assessed by ultrasound-guided percutaneous portal vein biopsy in the presence of vascular thrombosis54. Options for treatment for early stage (I and II) disease include tumor resection and liver transplantation. Recent data support the aggressive use of liver transplantation because this treats the cirrhotic liver as well as the cancer and can lead to a 5-year disease-free survival rate of 60% versus 31% for patients undergoing resection alone55. Recurrences due to incompletely resected lesions, true recurrences, and new primaries can occur and may be amenable to re-resection or transplantation. In rare cases, liver transplantation may be used for palliation. Other treatment methods include percutaneous injection of alcohol and liver embolization. Systemic chemotherapy has not had an appreciable effect on survival. However, locoregional chemotherapy for advanced disease may be beneﬁcial56. Radiation therapy, the usefulness of which is limited by the possibility of radiation-induced hepatitis, also is of little beneﬁt for HCC treatment. Intracranial metastases, including intraparenchymal and skull lesions, from HCC are rare, occurring in 0.6%57 to 2.9%58 of patients with primary HCC. There are many case reports and few series, most of which have appeared in the Chinese and Japanese literature. Occasionally, acute neurological complaints may be the ﬁrst presenting symptom of a patient with HCC; this pattern was described in seven of 19 patients in one series57. Frequently, the neurological symptoms are due to acute hemorrhage into the brain lesion59 or to an acute epidural or subdural hematoma from a hemorrhagic lesion60. In the series of Kim et al.57, all eight patients had a normal coagulation proﬁle. The authors postulated that hemorrhage occurs because of the lesions’ vascularity and large sinusoidal blood vessels. Mental status changes not due to hepatic encephalopathy and in the presence of normal ammonia levels are frequently present. The patient may also complain of progressive headaches; focal neurological deﬁcits may develop because local eloquent structures are compressed. When HCC metastases are located at the skull base, patients frequently present with cranial nerve palsies. It is postulated that HCC spreads by a hematogenous route to gain access to the intracranial compartment. Patients with intraparenchymal metastatic disease frequently have lung metastases, whereas those with skull lesions rarely do. Yen et al. postulate that if the lesion gains access to the pulmonary system, cells may travel to an intraparenchymal location.61 Skull lesions are associated with bony metastases and may spread via Batson’s venous plexus61, 62. The radiographic appearance of skull HCC metastases has been well documented. In their review of six patients with nine HCC skull metastases, Murakami et al. described the lesions’ radiographic and angiographic appearance63. The CT appearance of a skull HCC metastatic lesion is one of an osteolytic, expansile, diffusely enhancing lesion. On MRI, the lesion is isoto hypointense on T1-weighted images and hypointense on T2-weighted

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images. Flow voids may be readily apparent on the T2-weighted images, and the lesion may homogeneously enhance with the administration of intravenous contrast. When viewed by cerebral angiography, the lesions have a typical blush and are frequently supplied by the external carotid artery. Because these lesions have a tendency to be located at the skull base, the differential diagnosis includes primary bone tumors such as chondrosarcoma and chordoma, as well as locally invasive tumors from the sinuses or nasal pharynx. Meningiomas, which may cause hyperostosis, are also included in the differential diagnosis. Intraparenchymal lesions are frequently located in the parietal area, in the watershed zone between the territories of the middle and posterior cerebral arteries; they are less frequently located in the posterior fossa. A single metastatic HCC lesion has been reported in the parasellar region37. Yen et al.61 described 18 patients with intraparenchymal metastatic HCC; 16 lesions were located in the supratentorial compartment. The lesions were hyperdense on non-contrast CT scans and were either homogenously enhanced or demonstrated ring-enhancement on contrast imaging; a large percentage of them were associated with perilesional edema. The MR imaging characteristics of these metastases were not discussed. Many lesions may be associated with acute hemorrhage. Therefore, when a patient presents with an acute intraparenchymal hematoma secondary to a metastatic lesion, HCC should be included in the differential diagnosis, along with metastatic renal cell carcinoma, choriocarcinoma, lung cancer, and melanoma61. The treatment of patients with intracranial metastatic HCC has not been well described because of the paucity of cases. In the few series that are available, it appears that for patients with stable systemic disease in which the intracranial lesion is the only evidence of metastatic disease or who have acute neurologic deterioration and impending herniation, surgical intervention is warranted. Prior to surgical intervention, one must conﬁrm that the patient is not coagulopathic secondary to liver failure. Once the coagulation proﬁle is normalized, surgery may be performed. In the series of 33 patients described by Yen et al.61, 22 patients were treated with steroids, nine underwent radiotherapy, and two were treated with craniotomy and removal of the lesions. The median survival time for the entire group was 20 days from the time of diagnosis. Positive predictive factors for survival were a lactate dehydrogenase (LDH) level of < 316 and surgery or radiotherapy. Mean aggregate survival time for the groups treated with surgery and radiation was 94 days versus 15 days for the cohort treated only with steroids. Hepatoblastoma is a childhood liver tumor that frequently metastasizes to the lung. Survival is correlated with aggressive surgical resection of the primary tumor and the metastatic foci64. In an isolated case report, a 17-year-old girl presented with a solitary cerebral metastasis after prior aggressive treatment that included liver transplantation and pulmonary metastasis resection. After undergoing three craniotomies for recurrent disease at the same location plus adjuvant radiation and chemotherapy, she was disease free 4.5 years after her

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last treatment. This case report supports aggressive treatment in young children with metastatic hepatoblastoma65.

Gallbladder cancer As with other upper gastrointestinal tract tumors, cancers of the gallbladder are usually not detected until late in the course of disease. Carcinoma of the gallbladder (GBC) is a highly malignant lesion usually occurring in older women (the female-to-male ratio is approximately 3:1). As in esophageal cancer, GBC demonstrates a wide variety of incidences related to geography. In the United States, 6,900 new cases were expected in the year 20002. In Peru, the incidence reaches as high as 12.9/100,000 for females; in India, the incidence is as low as 0.4/100,000 for males66. It has been postulated that any condition that theoretically leads to the reﬂux of pancreatic juice or to bile stasis can lead to the development of GBC. Concomitant cholelithiasis or cholecystitis is frequently detected when GBC is diagnosed. Choledochal cysts and an anomalous junction between the pancreatic and biliary ducts are correlated with the development of GBC. Gallbladder polyps, obesity, and estrogens (the latter two are also associated with gallstones) may lead to the formation of GBC67, 68. Cholangiocarcinoma is a tumor of any part of the biliary system; the most common location is in the perihilar region. There is no notable gender predilection with this disease. Biliary stasis, infection by the liver ﬂuke Clonorchis sinensis, sclerosing cholangitis, hepatolithiasis, and ulcerative colitis have a clear relationship with the incidence of cholangiocarcinoma67. Most patients with GBC present with abdominal pain, nausea, vomiting, and anorexia; jaundice is seldom reported. This is in contrast to patients with cholangiocarcinoma, who frequently present initially with jaundice and later develop weight loss and abdominal pain. Many times, patients undergo a cholecystectomy for symptomatic cholecystitis or cholelithiasis, and pathological examination of the surgical specimen reveals GBC. The work-up includes a laboratory evaluation of the complete blood cell count, electrolyte levels, and liver function. Radiographic studies include a right upper quadrant ultrasound and CT scan. However, ultrasound is less able than CT to identify lymph node involvement, common bile duct inﬁltration, and peritoneal dissemination69. The chest, lungs, and abdomen should also be imaged to identify metastatic foci and lymphadenopathy suggestive of tumor extension. Magnetic resonance (MR) cholangiography has recently been used to more accurately deﬁne areas of vascular invasion70. In most cases of GBC and cholangiocarcinoma, the lesion is unresectable and a diagnostic biopsy is performed. Surgical intervention is warranted in the rare instances that imaging ﬁndings suggest that a curative resection can be achieved. Separate TNM grading systems are used to grade GBC and cholangiocarcinoma. The presence of poorly differentiated tumors, bilobar tumors, locally invasive tumors, metastatic disease, cirrhosis, portal hypertension, and sepsis imply a poor prognosis. For patients incidentally diagnosed with GBC after

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uncomplicated cholecystectomy, ﬁve-year survival can reach 92%71. Patients who present with early stage disease undergo a cholecystectomy or extended resection that includes the surrounding liver parenchyma; in these circumstances, the ﬁve-year survival approaches 100% and 78% for patients with stage I and II disease, respectively72. Even patients with stage IV disease who undergo radical resection and adjuvant therapy have a ﬁve-year survival rate of 9.8%73. However, most patients present with unresectable lesions, and only palliative maneuvers can be performed. The main goal of palliation is to prevent the onset of acute cholecystitis, which can be accomplished using biliary stents. Radiation and celiac ganglion block are successful treatments for pain. Chemotherapeutic regimens using single or multiple agents and radiotherapy have not yet been proved to alter survival. Early stage cholangiocarcinoma is treated with hepatic resection. When curative resection is attempted, the three-year survival rate approaches 35.6% for patients with intrahepatic lesions74 and 58% for patients with perihilar lesions75. For patients with unresectable lesions, median survival time is 6.7 months76. Liver transplantation is rarely used for patients with cholangiocarcinoma because of their overall poor prognosis77. As in the case of patients with GBC, the addition of chemotherapy or radiation to surgical treatment has conferred no documented statistical improvement in survival. Gallbladder malignancies commonly metastasize to the bones and lungs but rarely to the brain. In Sons and Borchard’s review of 65 patients with extrahepatic biliary duct carcinoma who underwent autopsy78, 75.4% had evidence of systemic metastases. Most frequently, the distant lesions were found in a noncontiguous location in the liver, lungs, or skeletal system. In only 3.1% of cases were brain metastases noted78. In a separate study, Donohue et al. reviewed the records of 111 patients with GBC who were treated surgically79. Their data are in agreement with that of Sons and Borchard78, with 4% of patients having evidence of a central nervous system metastasis. It is therefore very difﬁcult to draw conclusions regarding the radiographic imaging characteristics and speciﬁc treatment protocols for patients with brain lesions from metastatic biliary disease. In a single case report, a rare bile duct tumor (an adenoendocrine carcinoma) was diagnosed in a 68-year-old man. Six years after resection of the primary lesion and three years after resection of a liver metastatic focus, he presented with a right homonymous hemianopsia and cerebellar ataxia. He subsequently underwent resection of a left occipital lobe lesion and a vermian lesion without complication. Eight months later, follow-up imaging demonstrated two new lesions80. Recently, at M. D. Anderson, a 54-year-old man with a history of GBC presented with acute neurological deterioration due to a right cerebellar parenchymal hemorrhage (Figure 21.3). Once his coagulopathy was corrected, he underwent right frontal ventriculostomy and suboccipital craniotomy and evacuation of the hematoma. Analysis of the pathological specimen conﬁrmed the presence of neoplastic cells consistent with metastatic gallbladder cancer. Postoperative

Brain metastasis from upper gastrointestinal tract cancers 373 (A)

(B)

(C)

(D) Figure 21.3 A 54-year-old man with gallbladder cancer. See text for clinical history. (A) Noncontrast axial CT scan demonstrates a large right intracerebellar parenchymal hemorrhage causing obvious mass effect and almost complete obliteration of the fourth ventricle. (B) Postoperative noncontrast axial CT scan demonstrates compete resection of the lesion and decreased mass effect. (C), (D) Contrast-enhanced axial CT scan demonstrates multiple small intra-axial lesions consistent with diffuse metastatic disease.

imaging conﬁrmed gross total resection of the hematoma and tumor but identiﬁed multiple metastases in the supratentorial location. In the case of a brain metastasis from GBC or any brain lesion, regardless of its histology, surgical intervention may be warranted for acute deterioration secondary to hydrocephalus, hemorrhage, mass effect, or impending herniation or may be warranted if the brain represents the only site of metastatic disease. However, one must always be mindful of the extent of disease. Because most patients with biliary duct cancers present at an advanced stage, prognosis is poor, and surgical intervention for a brain lesion may be deemed a heroic measure.

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Pancreatic cancer Pancreatic cancer is the ﬁfth leading cause of cancer death in the United States. The incidence of adenocarcinoma of the pancreas reaches its peak in the seventh decade of life, and the disease is rare before the age of 50. In the year 2000, 28,300 new cases were anticipated in the United States. This incidence is equivalent to the 28,200 deaths expected2. Multiple risk factors have been proposed for this cancer and include cigarette smoking81, a high-fat diet82, diabetes mellitus83, and chronic pancreatitis84. Of these, cigarette smoking has been established to be linked to the development of ductal pancreatic adenocarcinoma. Because of the regional anatomy, carcinomas of the pancreas can produce different symptoms depending upon which part of the pancreas is involved. Patients with tumors located in the head of the pancreas may present relatively early on with jaundice from obstruction of the biliary duct and steatorrhea due to pancreatic duct obstruction. Additional signs and symptoms include weight loss, abdominal discomfort, back pain, and glucose intolerance85. Malignant pancreatic carcinomas are most frequently derived from cells of the pancreatic ducts (80%). The work-up for patients presumed to have pancreatic carcinoma includes an abdominal CT scan. Recent data from M. D. Anderson have demonstrated that CT imaging is superior to laparoscopy and ultrasound at determining a tumor’s resectability and can prevent subjecting the patient to an unnecessary laparotomy86. A TNM grading scheme exists for this disease but is difﬁcult to use because lymph node involvement and subclinical metastatic foci (usually hepatic) are frequently undiagnosed until surgical exploration is performed. Metastatic foci are found most frequently in the liver and abdominal lymph nodes but may also be found in the stomach, small intestine, spleen, peritoneum, and lungs87. Patients’ serum levels of antigen CA 19-9 are usually measured pre- and postoperatively; persistent elevations in CA 19-9 are inversely correlated with survival88. Early stage lesions, as determined by CT imaging, should be resected. Almost all of these tumors are located in the head of the pancreas. Even when gross total resection of these tumors is performed and clean margins are obtained, metastases to the liver are frequently responsible for tumor recurrence, and median survival time of patients approaches only 19 months89. With the addition of local chemotherapy to extended pancreatectomy, the ﬁveyear survival rate for these patients improves to 39% because of a decrease in liver metastasis90. However, among patients with unresectable nonmetastatic disease, the three-year survival rate is less than 20%91. When metastases that were inapparent on preoperative imaging studies are identiﬁed during surgical resection of the primary tumor, palliative biliary and gastric outlet bypass may be performed. In patients with known advanced disease, stenting may be used for palliation. In clinical practice, brain metastases are extremely rare in patients with adenocarcinoma of the pancreas (Figure 21.4). In an autopsy study of 128 patients

Brain metastasis from upper gastrointestinal tract cancers 375 (A)

(B)

Figure 21.4 The patient, a 69-year-old woman who presented with vague abdominal pain, was found to have a mass in the body of her pancreas. She underwent preoperative chemoradiotherapy and then lesion resection. Approximately two years later, she presented with a right hemiparesis, expressive aphasia, and writing difﬁculty. An axial T2-weighted MR image (A) and a coronal contrast T1-weighted image (B) demonstrated a lesion in the posterior left frontal region adjacent to the motor strip. She had no other evidence of metastatic disease. The lesion was resected without effecting change in her neurological condition.

with adenocarcinoma of the pancreas diagnosed at autopsy, four of 38 patients (or 10.5%) who had a detailed neuropathologic examination had metastatic brain lesions87. No attempt has been made to draw conclusions regarding optimal management or prognosis, given the paucity of cases. Brain metastases have been described in cancer of the endocrine pancreas, a condition with an incidence of 1:100,00092. In a rare case, an 85-year-old woman presented initially with neurological symptoms due to multiple cystic brain metastases. No treatment was instituted because of the patient’s age. An autopsy was performed four years later when she died of pneumonia and a hemorrhagic gastric ulcer. Postmortem examination identiﬁed an islet cell pancreatic tumor. The brain lesions were of similar histological appearance93. In a rare case of an endocrine pancreatic somatostatinoma, a patient presented on two separate occasions with brain metastases that occurred 10 years after diagnosis of the primary tumor. After undergoing resections of both metastatic lesions, he was alive 12.3 years later94.

Conclusions Metastatic tumors from cancers originating in upper gastrointestinal sites represent a small proportion of diagnosed brain metastases. Usually, their presence implies poor prognosis and diffuse metastatic disease. However, when the brain is the only site of metastatic disease or when the patient has

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experienced an acute neurological decline or impending brain herniation, surgical intervention may be warranted.

References 1 Ries L, Eisner M, Kosary C, et al.: SEER Cancer Statistics Review, 1973–1997. Bethesda, MD, National Cancer Institute, 2000. 2 American Cancer Society: Estimated new cancer cases and deaths by sex for all sites, United States, 2000. (http://www3.cancer.org/cancerinfo/sitecenter.asp?ct=1&ctid= 8&scp=8.3.10.40038&scs=4&scss=3&scdoc=41170&pnt=2&language=english, accessed November 4, 2000). 3 Roth J, Putnam J Jr, Rich T, et al.: Cancer of the esophagus. In: DeVita V Jr, Hellman S, Rosenberg S (eds): Cancer. Principles and Practice of Oncology. Vol 2. New York, LippincottRaven, 1997, pp. 980 –1021. 4 Firoozi B, Vega KJ, Holland BK, et al.: Epidemiologic pattern of esophageal cancer at an inner-city university hospital. J Assoc Acad Minor Phys 1999; 10: 44 – 47. 5 Kabat GC, Ng SK, Wynder EL: Tobacco, alcohol intake, and diet in relation to adenocarcinoma of the esophagus and gastric cardia. Cancer Causes Control 1993; 4: 123 –132. 6 Sandler RS, Nyren O, Ekbom A, et al.: The risk of esophageal cancer in patients with achalasia. A population-based study. JAMA 1995; 274: 1359 –1362. 7 Ribeiro U Jr, Posner MC, Safatle-Ribeiro AV, et al.: Risk factors for squamous cell carcinoma of the oesophagus. Br J Surg 1996; 83: 1174 –1185. 8 Avisar E, Luketich JD: Adenocarcinoma in a mid-esophageal diverticulum. Ann Thorac Surg 2000; 69: 288–289. 9 Lightdale CJ, Winawer SJ: Screening diagnosis and staging of esophageal cancer. Semin Oncol 1984; 11: 101–112. 10 Schwartz LH, Ozsahin M, Zhang GN, et al.: Synchronous and metachronous head and neck carcinomas. Cancer 1994; 74: 1933 –1938. 11 McDonald ML, Trastek VF, Allen MS, et al.: Barrett’s esophagus: does an antireﬂux procedure reduce the need for endoscopic surveillance? J Thorac Cardiovasc Surg 1996; 111: 1135–1138. 12 Brown LM: The role of race/ethnicity in the epidemiology of esophageal cancer. J Assoc Acad Minor Phys 2000; 11: 32–37. 13 Lagergren J, Bergstrom R, Lindgren A, et al.: Symptomatic gastroesophageal reﬂux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999; 340: 825– 831. 14 Bosetti C, La Vecchia C, Talamini R, et al.: Food groups and risk of squamous cell esophageal cancer in northern Italy. Int J Cancer 2000; 87: 289 –294. 15 van Overhagen H, Lameris JS, Zonderland HM, et al.: Ultrasound and ultrasound-guided ﬁne needle aspiration biopsy of supraclavicular lymph nodes in patients with esophageal carcinoma. Cancer 1991; 67: 585 –587. 16 Lee RB, Miller JI: Esophagectomy for cancer. Surg Clin North Am 1997; 77: 1169 –1196. 17 Orringer M, Marshall B, Iannettoni M: Transhiatal esophagectomy: clinical experience and reﬁnements. Ann Surg 1999; 230: 392– 400. 18 Ajani JA: Current status of new drugs and multidisciplinary approaches in patients with carcinoma of the esophagus. Chest 1998; 113: 112S–119S. 19 Carazzone A, Bonavina L, Segalin A, et al.: Endoscopic palliation of oesophageal cancer: results of a prospective comparison of Nd: YAG laser and ethanol injection. Eur J Surg 1999; 165: 351–356.

Brain metastasis from upper gastrointestinal tract cancers 377 20 Irie K, Austin E, Morgenstern L: Solitary meningocerebral metastasis from squamous cell carcinoma of the esophagus: a case report. Cancer 1978; 42: 2461–2465. 21 Chalif D, Epstein N, Flamm ES, et al.: Intracerebral metastasis of esophageal carcinoma: case report. Neurosurgery 1981; 9: 311–313. 22 Vaquero J, Abreu L, Cabezudo JM: Esophageal carcinoma metastatic to the brain. Am J Gastroenterol 1982; 77: 541–542. 23 Odaimi M, Ajani JA: Brain metastases and elevated alpha-fetoprotein level in a patient with esophageal carcinoma. South Med J 1986; 79: 1304 –1306. 24 Averbuch SD, Blinder MA: Brain metastasis from esophageal carcinoma. CA Cancer J Clin 1983; 33: 164–166. 25 Gabrielsen TO, Eldevik OP, Orringer MB, et al.: Esophageal carcinoma metastatic to the brain: clinical value and cost-effectiveness of routine enhanced head CT before esophagectomy. AJNR Am J Neuroradiol 1995; 16: 1915 –1921. 26 Ohno S, Tomisaki S, Oiwa H, et al.: Clinicopathologic characteristics and outcome of adenocarcinoma of the human gastric cardia in comparison with carcinoma of other regions of the stomach. J Am Coll Surg 1995; 180: 577–582. 27 Zaridze D, Borisova E, Maximovitch D, et al.: Alcohol consumption, smoking and risk of gastric cancer: case-control study from Moscow, Russia. Cancer Causes Control 2000; 11: 363–371. 28 Ekstrom AM, Seraﬁni M, Nyren O, et al.: Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-based casecontrol study in Sweden. Int J Cancer 2000; 87: 133 –140. 29 Ward MH, Lopez-Carrillo L: Dietary factors and the risk of gastric cancer in Mexico City. Am J Epidemiol 1999; 149: 925 –932. 30 von Holstein CS: Long-term prognosis after partial gastrectomy for gastroduodenal ulcer. World J Surg 2000; 24: 307–314. 31 Shiraishi N, Inomata M, Osawa N, et al.: Early and late recurrence after gastrectomy for gastric carcinoma. Univariate and multivariate analyses. Cancer 2000; 89: 255 –261. 32 Maruyama K, Okabayashi K, Kinoshita T: Progress in gastric cancer surgery in Japan and its limits of radicality. World J Surg 1987; 11: 418 – 425. 33 Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725 –730. 34 York JE, Stringer J, Ajani JA, et al.: Gastric cancer and metastasis to the brain. Ann Surg Oncol 1999; 6: 771–776. 35 Kim M: Intracranial involvement by metastatic advanced gastric carcinoma. J Neurooncol 1999; 43: 59–62. 36 Nomura T, Yoshikawa T, Kato H, et al.: Early gastric cancer manifested as brain metastasis: report of a case. Surg Today 1997; 27: 334 –336. 37 Bitoh S, Hasegawa H, Ohtsuki H, et al.: Parasellar metastases: four autopsied cases. Surg Neurol 1985; 23: 41– 48. 38 Yanamoto H, Kakita K, Fukuma S: Pineal metastasisaa case report and a review of literature. No Shinkei Geka 1987; 15: 1329 –1334. 39 Kovachev D, Ruseva V: Carcinoid of the stomach with metastases into the dura mater. Vutreshni Bolesti 1976; 15: 98 –103. 40 Kasakura Y, Fujii M, Mochizuki F, et al.: Clinicopathological study of brain metastasis in gastric cancer patients. Surg Today 2000; 30: 485 – 490. 41 Akriviadis EA, Llovet JM, Efremidis SC, et al.: Hepatocellular carcinoma. Br J Surg 1998; 85: 1319–1331.

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42 Ulmer SC: Hepatocellular carcinoma. A concise guide to its status and management. Postgrad Med 2000; 107: 117–124. 43 Carr B, Flickinger J, Lotze M: Cancer of the liver. In DeVita V Jr, Hellman S, Rosenberg S (eds): Cancer. Principles and Practice of Oncology. Vol 2. New York, Lippincott-Raven, 1997, pp. 1087–1114. 44 Kubicka S, Rudolph KL, Hanke M, et al.: Hepatocellular carcinoma in Germany: a retrospective epidemiological study from a low-endemic area. Liver 2000; 20: 312–318. 45 Giovanardi P, Sacchetti C, Cameroni P, et al.: Erythrocytosis in patients with hepatocarcinoma in alcoholic cirrhosis: ectopic production of erythropoietin? Recenti Prog Med 1998; 89: 250–252. 46 Arai H, Saitoh S, Matsumoto T, et al.: Hypertension as a paraneoplastic syndrome in hepatocellular carcinoma. J Gastroenterol 1999; 34: 530 –534. 47 Hatzis GS, Delladetsima I, Koufos C: Hepatocellular carcinoma presenting with paraneoplastic neurologic syndrome in a hepatitis B surface antigen-positive patient. J Clin Gastroenterol 1998; 26: 144 –147. 48 Huang WS, Liao LY, Wang CS, et al.: Hepatocellular carcinoma presenting with acquired porphyria: a case report and review of the literature. Changeng Yi Xue Za Zhi 1999; 22: 111–116. 49 Hwang SJ, Lee SD, Chang CF, et al.: Hypercholesterolaemia in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 1992; 7: 491– 496. 50 Izzo F, Cremona F, Delrio P, et al.: Soluble interleukin-2 receptor levels in hepatocellular cancer: a more sensitive marker than alfa fetoprotein. Ann Surg Oncol 1999; 6: 178 –185. 51 Macdonald GA, Peduto AJ: Magnetic resonance imaging (MRI) and diseases of the liver and biliary tract. Part 1. Basic principles, MRI in the assessment of diffuse and focal hepatic disease. J Gastroenterol Hepatol 2000; 15: 980 –991. 52 Villa E, Moles A, Ferretti I, et al.: Natural history of inoperable hepatocellular carcinoma: estrogen receptors’ status in the tumor is the strongest prognostic factor for survival. Hepatology 2000; 32: 233 –238. 53 Shimada M, Yamashita Y, Hamatsu T, et al.: Surgical indications for advanced hepatocellular carcinoma. Hepatogastroenterology 2000; 47: 1095 –1099. 54 Dodd GDD, Carr BI: Percutaneous biopsy of portal vein thrombus: a new staging technique for hepatocellular carcinoma. AJR Am J Roentgenol 1993; 161: 229 –233. 55 Figueras J, Jaurrieta E, Valls C, et al.: Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy. J Am Coll Surg 2000; 190: 580–587. 56 Marcos-Alvarez A, Jenkins RL, Washburn WK, et al.: Multimodality treatment of hepatocellular carcinoma in a hepatobiliary specialty center. Arch Surg 1996; 131: 292–298. 57 Kim M, Na DL, Park SH, et al.: Nervous system involvement by metastatic hepatocellular carcinoma. J Neurooncol 1998; 36: 85 –90. 58 Lai CR, Liu HC: Hepatocellular carcinoma in Taiwan: clinicopathological study of 440 cases from a consecutive 6000 autopsies. Chung Hua I Hsueh Tsa Chih (Taipei) 1993; 51: 249–256. 59 Shuangshoti S, Yenrudi S. Massive cerebral hemorrhage from metastatic hepatocellular carcinoma. J Med Assoc Thai 1991; 74: 531–538. 60 Endo M, Hamano M, Watanabe K, et al.: Combined chronic subdural and acute epidural hematoma secondary to metastatic hepatocellular cancer: case report. No Shinkei Geka 1999; 27: 331–334. 61 Yen FS, Wu JC, Lai CR, et al.: Clinical and radiological pictures of hepatocellular carcinoma with intracranial metastasis. J Gastroenterol Hepatol 1995; 10: 413 – 418.

Brain metastasis from upper gastrointestinal tract cancers 379 62 del Regato JA: Pathways of metastatic spread of malignant tumors. Semin Oncol 1977; 4: 33–38. 63 Murakami R, Korogi Y, Sakamoto Y, et al.: Skull metastasis from hepatocellular carcinoma. CT, MR and angiographic ﬁndings. Acta Radiologica 1995; 36: 597– 602. 64 Dower NA, Smith LJ, Lees G, et al.: Experience with aggressive therapy in three children with unresectable malignant liver tumors. Med Pediatr Oncol 2000; 34: 132–135. 65 Robertson PL, Muraszko KM, Axtell RA: Hepatoblastoma metastatic to brain: prolonged survival after multiple surgical resections of a solitary brain lesion. J Pediatr Hematol Oncol 1997; 19: 168–171. 66 Parkin D, Muir C, Whelan S, et al.: Cancer Incidence in Five Continents. Lyon, France, IARC Scientiﬁc Publication No. 120. World Health Organization, International Agency for Research on Cancer, 1992. 67 Pitt H, Grochow L, Abrams R: Cancer of the biliary tree. In: DeVita V Jr, Hellman S, Rosenberg S (eds): Cancer. Principles and Practice of Oncology. Vol 2. New York, LippincottRaven, 1997, pp. 1114 –1128. 68 Moerman CJ, Bueno-de-Mesquita HB: The epidemiology of gallbladder cancer: lifestyle related risk factors and limited surgical possibilities for prevention. Hepatogastroenterology 1999; 46: 1533–1539. 69 Pandey M, Sood BP, Shukla RC, et al.: Carcinoma of the gallbladder: role of sonography in diagnosis and staging. J Clin Ultrasound 2000; 28: 227–232. 70 Reinhold C, Bret PM: Current status of MR cholangiopancreatography. AJR Am J Roentgenol 1996; 166: 1285 –1295. 71 Suzuki K, Kimura T, Ogawa H: Long-term prognosis of gallbladder cancer diagnosed after laparoscopic cholecystectomy. Surg Endosc 2000; 14: 712–716. 72 Todoroki T, Kawamoto T, Takahashi H, et al.: Treatment of gallbladder cancer by radical resection. Br J Surg 1999; 86: 622– 627. 73 Todoroki T, Takahashi H, Koike N, et al.: Outcomes of aggressive treatment of stage IV gallbladder cancer and predictors of survival. Hepatogastroenterology 1999; 46: 2114 – 2121. 74 Kim HJ, Yun SS, Jung KH, et al.: Intrahepatic cholangiocarcinoma in Korea. J Hepatobiliary Pancreat Surg 1999; 6: 142–148. 75 Tabata M, Kawarada Y, Yokoi H, et al.: Surgical treatment for hilar cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2000; 7: 148 –154. 76 Roayaie S, Guarrera JV, Ye MQ, et al.: Aggressive surgical treatment of intrahepatic cholangiocarcinoma: predictors of outcomes. J Am Coll Surg 1998; 187: 365 –372. 77 Meyer CG, Penn I, James L: Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000; 69: 1633 –1637. 78 Sons HU, Borchard F: Carcinoma of the extrahepatic bile ducts: a postmortem study of 65 cases and review of the literature. J Surg Oncol 1987; 34: 6 –12. 79 Donohue JH, Nagorney DM, Grant CS, et al.: Carcinoma of the gallbladder. Does radical resection improve outcome? Arch Surg 1990; 125: 237–241. 80 Tanaka M, Shibui S, Nomura K, et al.: Brain metastases from adenoendocrine carcinoma of the common bile duct: a case report. Jpn J Clin Oncol 1999; 29: 252–255. 81 Villeneuve PJ, Johnson KC, Hanley AJ, et al.: Alcohol, tobacco and coffee consumption and the risk of pancreatic cancer: results from the Canadian Enhanced Surveillance System case-control project. Canadian Cancer Registries Epidemiology Research Group. Eur J Cancer Prev 2000; 9: 49–58. 82 Andren-Sandberg A, Hoem D, Backman PL: Other risk factors for pancreatic cancer: hormonal aspects. Ann Oncol 1999; 10 (Suppl 4): 131–135.

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83 Gapstur SM, Gann PH, Lowe W, et al.: Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 2000; 283: 2552–2558. 84 Talamini G, Bassi C, Falconi M, et al.: Early detection of pancreatic cancer following the diagnosis of chronic pancreatitis. Digestion 1999; 60: 554 –561. 85 DiMagno EP: Pancreatic cancer: clinical presentation, pitfalls and early clues. Ann Oncol 1999; 10 (Suppl 4): 140–142. 86 Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al.: Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 1994; 167: 104 –111. 87 Lee YT, Tatter D: Carcinoma of the pancreas and periampullary structures. Pattern of metastasis at autopsy. Arch Pathol Lab Med 1984; 108: 584 –587. 88 Halm U, Schumann T, Schiefke I, et al.: Decrease of CA 19-9 during chemotherapy with gemcitabine predicts survival time in patients with advanced pancreatic cancer. Br J Cancer 2000; 82: 1013 –1016. 89 Staley CA, Lee JE, Cleary KR, et al.: Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head. Am J Surg 1996; 171: 118 –124. 90 Ishikawa O, Ohhigashi H, Sasaki Y, et al.: Extended pancreatectomy and liver perfusion chemotherapy for resectable adenocarcinoma of the pancreas. Digestion 1999; 60 (Suppl 1): 135–138. 91 Paulino AC, Latona C: Unresectable adenocarcinoma of the pancreas: patterns of failure and treatment results. Cancer Invest 2000; 18: 309 –313. 92 Schein P, Kahn R, Gorden P, et al.: Streptozotocin for malignant insulinomas and carcinoid tumor. Report of eight cases and review of the literature. Arch Intern Med 1973; 132: 555 – 561. 93 Sabo RA, Kalyan-Raman UP: Multiple intracerebral metastases from an islet cell carcinoma of the pancreas: case report. Neurosurgery 1995; 37: 326 –328. 94 Abe T, Oshida K, Matsumoto K, et al.: Brain metastasis from malignant pancreatic somatostatinoma. Case report. J Neurosurg 1996; 85: 681– 684.

CHAPTER 22

Brain metastases from thyroid carcinoma and other endocrine malignancies Rena Vassilopoulou-Sellin

Introduction Malignancies of the endocrine system constitute a small minority of all carcinomas and have an even smaller impact on cancer mortality1. The biology of most endocrine malignancies allows prolonged survival in most cases. However, some patients have aggressively growing tumors with widespread metastases that include the central nervous system (CNS) that seriously curtail their survival. For example, thyroid cancer is generally considered an indolent disease with minimal associated mortality; within this group, however, the subset of anaplastic thyroid cancer represents a most aggressive malignancy with relentless progression and a ﬁve-year survival rate of only 3.6%2.

Differentiated thyroid cancer General discussion In most cases, thyroid malignancies arise within the follicular epithelium and are classiﬁed as papillary or follicular carcinomas. There are fewer than 20,000 new cases each year, almost always sporadic and affecting women more frequently than men. Although they constitute almost 90% of all endocrine malignancies, they account for only about half of the deaths related to endocrine malignancies3. The disease is usually regional, and life expectancy is nearly normal in most cases. The biological behavior of thyroid cancer tends to be more aggressive in older patients. In papillary thyroid cancer, the pattern of metastatic dissemination commonly begins with regional lymph node involvement, followed by lung metastases and less frequently, skeletal metastases; CNS metastases are exceedingly uncommon but may occur in patients with extensive disease elsewhere. In follicular thyroid cancer, hematogenous dissemination is more common. Thus, skeletal and pulmonary metastases are more prominent; involvement in the CNS usually takes the form of skull-based metastases4. Treatment includes surgery for disease in the neck, radioactive iodine for thyroid remnant or radioiodine-avid metastases, and radiotherapy for radioiodine-unresponsive disease5 –9. 381

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Metastases affecting the central nervous system In his classic series of 774 patients with thyroid cancer published in 1939, Pemberton described skull metastases in 4% to 9% of the cases but did not discuss their response to treatment or their impact on mortality10. A few years later, Seidlin et al. described a patient with a malignant thyroid tumor metastatic to multiple sites, including the skull; in this patient, clinical and radiological responses to radioactive iodine therapy were documented for the ﬁrst time11. Since then, information regarding CNS metastases has appeared in case reports or small descriptive series12–17. In larger series, brain metastases are mentioned either as extremely rare events18 or as affecting up to 10% of patients19, 20. McConahey et al. from the Mayo Clinic described brain metastases in 15% of their patients but noted that in none of these patients was CNS metastasis the cause of death21. CNS metastases are frequently asymptomatic ﬁndings of diagnostic imaging or autopsy examination. However, neurological abnormalities may bring CNS metastases to clinical attention in patients with known thyroid cancer22; in one case report, metastasis to the pituitary gland was recognized when the thyroid-stimulation hormone level of a patient with thyroid cancer failed to rise after thyroxine withdrawal23. CNS involvement usually is discovered later in patients with known metastatic thyroid cancer, but brain metastases also have been reported at initial presentation24, 25. In one case report, unilateral exophthalmos due to an orbital mass was the primary manifestation of the disease26. Treatment options depend on the presence of related symptoms, the location of CNS lesions, and their afﬁnity for radioactive iodine. When CNS lesions are radioiodine avid, durable radiological and symptomatic improvement may follow radioactive iodine therapy27–31. In some patients, acute swelling of the metastatic lesions occurs shortly after administration of radioactive iodine and may precipitate neurological deterioration; such patients require careful monitoring. Premedication with pharmacological doses of glucocorticoids may prevent this complication, and thus this is frequently given empirically. Radiotherapy, with or without concomitant chemotherapy32, 33 and surgery34, has also been mentioned as a treatment option for CNS metastases. Most authors comment that the development of CNS metastases carries a very poor prognosis34, 35 and may be considered the cause of death in 2% to 4% of patients who die of thyroid cancer36–38. Given the overall good prognosis of thyroid cancer and the rarity of CNS metastases, it is also important to consider that a CNS lesion in a successfully treated patient may, in fact, represent a different disease39.

Differentiated thyroid cancer in children and adolescents Differentiated thyroid cancer affects mostly women during their mid-life. However, a minority of patients are children and adolescents. In this age group, the regional extent of the disease may be quite extensive, and pulmonary metastases are found more frequently at the time of the initial presentation40, 41;

Brain metastases from thyroid carcinoma and other endocrine malignancies 383

skeletal involvement is very uncommon and CNS metastases, distinctly rare. Overall, these young patients live for many decades despite the extent of their disease. The therapeutic principles of surgery and radioactive iodine are similar to those used in the treatment of adults, but radiotherapy is generally avoided. Metastases to the choroid plexus42, parietal lobe of the brain43, and brainstem44 have been reported as isolated instances in selected series. Many other large series, however, do not mention any cases of CNS metastases39, 45– 48. CNS metastases, although possible, must be considered exceedingly rare in children and adolescents with differentiated thyroid cancer.

Histological variants Variants of papillary thyroid cancer exist in a small number of patients49 whose disease exhibits aggressive clinical behavior; these include the tall-cell, columnar, insular, and diffuse sclerosing variants. In addition, Hürthle cell cancer is considered a type of follicular thyroid cancer. In general, these variants of differentiated thyroid cancer carry a worse prognosis and show a curtailed patient survival pattern. In addition, anaplastic transformation may occur in differentiated thyroid cancer, resulting in one of the most aggressive malignancies. Available reports on these diseases describe the increased frequency of distant metastases, but generally, details regarding CNS involvement are sparse at best.

Medullary thyroid cancer Medullary thyroid cancer reﬂects the malignant proliferation of parafollicular “c-cells” in the thyroid gland. It comprises fewer than 10% of all thyroid cancers and has many features of a neuroendocrine malignancy (such as the capability to present with paraneoplastic Cushing’s syndrome or acromegaly)50. Whereas most patients have sporadic disease, medullary thyroid cancer may be an inherited familial disease or a component of multiple endocrine neoplasia type 2a (with parathyroid hyperplasia and pheochromocytoma) or type 2b (with pheochromocytoma and neuromas). In its inherited form, medullary thyroid cancer is associated with germline mutations of the RET proto-oncogene51. Metastases from medullary thyroid cancer tend to involve regional lymph nodes, lungs, bones, and liver. Although metastatic involvement of the skeleton may present as skull lesions, parenchymal CNS lesions, including those of the brain and retina, are mentioned as isolated case examples in most reviews52–54. Conventional diagnostic imaging techniques generally help identify such lesions, although octreotide scanning can also be helpful55.

Carcinoid tumors Carcinoid tumors are uncommon neuroendocrine neoplasms that usually arise in the gastrointestinal tract or lung56. They generally exhibit a very low

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malignant potential and require limited, curative resection of the primary disease. Occasionally, however, carcinoid tumors behave as lethal neoplasms with progressive metastases and patients have a shortened survival. The most common metastatic sites are peritoneum and liver; other soft-tissue or skeletal involvement is unusual. CNS involvement due to skull metastases has been reported, but rarely57. There are isolated case reports of patients presenting with neurological symptoms from CNS metastases58 and from carcinoid carcinomatous meningitis59. Valli et al. reported eight patients with thymic carcinoid tumors; among the ﬁve patients presenting with stage 3 disease, brain mestastases developed in three within 3 years60. Brain metastases have also been reported in patients with atypical carcinoid tumors of the larynx61, 62. In other series, however, CNS metastases are distinctly not mentioned63, 64. From a therapeutic standpoint, radiotherapy appears to be an effective approach. Chakravarthy et al. reported a median survival time of 33 months for patients with brain metastases65, and Schupak et al. presented information on eight patients with brain metastases that became clinically and radiologically stable after radiotherapy66. CNS metastases, therefore, should be viewed as unlikely but not impossible complications in patients with carcinoid tumors.

Adrenocortical cancer Next to anaplastic thyroid cancer, adrenocortical carcinoma is considered the most lethal of endocrine neoplasms. It tends to be a sporadic disease with no signiﬁcant gender predilection; approximately half of the patients have some evidence of steroid hormone hypersecretion, although this characteristic does not affect their clinical outcome. The diagnosis of adrenocortical carcinoma may be unduly delayed because the patients usually remain asymptomatic until the primary tumors become very large or symptomatic metastases develop. In the current era, incidental discovery of adrenal masses has become more frequent, and surveillance for recurrent or metastatic disease has improved. Clinical outcome beneﬁts will, it is hoped, follow soon. Distant metastases from adrenocortical carcinoma usually involve the lungs, liver, and bones. Although CNS metastases have been described in patients as young as nine years old67, they are generally either limited to a few isolated cases in some series68, 69 or not listed among the metastatic sites in others70, 71. At The University of Texas M. D. Anderson Cancer Center, brain metastases have been documented in 4.5% of patients with adrenocortical carcinoma72; this apparently increased frequency may reﬂect referral patterns to the cancer center. Symptom palliation with radiotherapy is frequently applied in the management of such patients.

Malignant tumors of chromafﬁn tissue origin The neoplastic transformation of neural crest-derived tissues represents another type of endocrine neoplasm. When the tumors arise within the adrenal

Brain metastases from thyroid carcinoma and other endocrine malignancies 385

medulla, they generally are named “pheochromocytomas;” when they arise elsewhere in the paraganglionic system, they are referred to as “paragangliomas.” Malignant behavior has been described for both variants. Although discussion of these malignant tumors often combines the features of these two entities, important clinical differences exist between them73. Patients with malignant pheochromocytoma may present with skull-based metastases74, although intracranial CNS involvement has also been described75. Patients with paragangliomas of the head and neck region have been reported to rarely manifest involvement of the CNS by direct extension from a large, invasive primary tumor76 –79. In our review of 50 patients with malignant pheochromocytoma or malignant abdominal paraganglioma73, we identify none with CNS metastases. In the rare cases of CNS metastases from such tumors, therapy must be individualized and may involve palliative radiotherapy or resection (especially in patients with a limited number of slowly growing lesions).

Other endocrine malignancies Parathyroid carcinoma represents a very rare endocrine malignancy; lifethreatening hypercalcemia usually dominates the therapeutic priorities in the patients. Reviews of clinical experience in this disease usually describe rather small numbers of patients. We have encountered a case report of a patient with parathyroid carcinoma and a metastasis in the occipital lobe of the brain80; her symptoms of hemianopsia resolved after surgical resection. In other published series of patients with parathyroid cancer, however, CNS metastases are not described81– 83. Malignant tumors arising in the thymus gland are considered endocrine in nature by some authors, primarily because they are at times associated with endocrine paraneoplastic syndromes; they usually present a challenge in regional disease control84. Finally, pituitary tumors may be considered in the context of the present review. They are almost always benign lesions clearly demarcated from the surrounding tissues. Aggressive, invasive pituitary tumors have been described that encroach into the CNS by direct extension. Truly malignant pituitary tumors exhibiting repeated regional recurrence or distant propagation have been reported but are extremely rare85, 86.

Conclusion Endocrine malignancies are uncommon and tend to follow a relatively indolent clinical course. Thus, CNS involvement with metastatic disease is described infrequently, and therapeutic strategies generally are tailored to provide needed palliation in the individual cases. Differentiated thyroid cancer is the exception in this area; skull-based metastases are relatively more common, and speciﬁcally targeted therapy with radioactive iodine often is possible. In

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recent years, improved diagnostic techniques have allowed for early detection of many malignancies, including endocrine cancers; this advance should lead toward a decrease in symptomatic CNS metastases. These same diagnostic improvements, however, allow the detection of subclinical, asymptomatic lesions in different organ systems, including the CNS. The appropriate guidelines for the detection and treatment of CNS involvement from endocrine malignancies should continue to be reﬁned through prospective analysis of the clinical experience.

References 1 Norton JA, Levin B, Jensen RT: Cancer of the endocrine system. In: De Vita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology: 4th edn. Philadelphia, J. B. Lippincott Co, 1993, pp. 1333–1436. 2 Nel CJC, van Heerden JA, Goellner JR, et al.: Anaplastic carcinoma of the thyroid: a clinicopathologic study of 82 cases. Mayo Clin Proc 1985; 60: 51–58. 3 Silverberg E, Boring CC, Squires TS: Cancer statistics. CA Cancer J Clin 2000; 40: 9 –26. 4 Vassilopoulou-Sellin R, Delpassand ES: Follicular thyroid cancer: clinical outcome and impact of radioiodine therapy in patients with distant metastases. Int J Oncol 1996; 8: 969–976. 5 DeGroot LJ, Kaplan EL, McCormick M, et al.: Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990; 71: 414 – 424. 6 Vassilopoulou-Sellin R: Management of papillary thyroid cancer. Oncology 1995; 9: 145–152. 7 Feld S: AACE Clinical practice guidelines for the management of thyroid carcinoma. Endocr Practice 1997; 3: 61–71. 8 Schlumberger MJ: Papillary and follicular thyroid carcinoma. N Engl J Med 1998; 338: 297–306. 9 Mazaferri EL: Recombinant human thyrotropin symposium: an overview of the management of papillary and follicular thyroid carcinoma. Thyroid 1999; 9: 421– 427. 10 Pemberton JJ: Malignant lesions of the thyroid gland. Gynecology and Obstetrics. An International Magazine 1939; 69: 417– 430. 11 Seidlin SM, Marinelli LD, Oshry E: Radioactive iodine therapy: effect on functioning metastases of adenocarcinoma of thyroid. JAMA 1946; 132: 838 – 847. 12 Hay ID: Brain metastases from papillary thyroid carcinoma. Arch Intern Med 1987; 147: 607, 611. 13 Salvati M, Cervoni L, Celli P: Solitary brain metastases from thyroid carcinoma: study of 6 cases. Tumori 1995; 81: 142–143. 14 Jyothirmayi R, Edison J, Nayar PP, et al.: Case report: brain metastases from papillary carcinoma thyroid. Br J Radiol 1995; 68: 767–769. 15 Honma Y, Kawakita K, Nagao S: Intramedullary spinal cord and brain metastases from thyroid carcinoma detected 11 years after initial diagnosisacase report. Neurol Med Chir (Tokyo) 1996; 36: 593 –597. 16 Hjiyiannakis P, Jefferies S, Harmer CL: Brain metastases in patients with differentiated thyroid carcinoma. Clin Oncol (R Coll Radiol) 1996; 8: 327–330. 17 Isoda H, Takahashi M, Arai T, et al.: Multiple haemorrhagic brain metastases from papillary thyroid cancer. Neuroradiology 1997; 39: 198–202.

Brain metastases from thyroid carcinoma and other endocrine malignancies 387 18 Vassilopoulou-Sellin R, Schultz P, Hynie T: Clinical outcome of patients with papillary thyroid carcinoma who have recurrence after initial radioactive iodine therapy. Cancer 1996; 78: 493–501. 19 Dinneen F, Valimaki MJ, Bergstralh EJ, et al.: Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades. J Clin Endocrinol Metab 1995; 80: 2041–2046. 20 Hoe J, Stenwig AE, Kullmann G, et al.: Distant metastases in papillary thyroid cancer. a review of 91 patients. Cancer 1998; 61: 1– 6. 21 McConahey WM, Hay ID, Woolner LB, et al.: Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic ﬁndings, therapy, and outcome. Mayo Clin Proc 1986; 61: 978 –996. 22 Pacak K, Sweeney DC, Wartofsky L, et al.: Solitary cerebellar metastasis from papillary thyroid carcinoma: a case report. Thyroid 1998; 8: 327–335. 23 Masiukiewicz US, Nakchband IA, Stewart AF, et al.: Papillary thyroid carcinoma metastatic to the pituitary gland. Thyroid 1999; 9: 1023 –1027. 24 Samuel AM, Shah DH: Brain metastases in well-differentiated carcinoma of the thyroid. Tumori 1997; 83: 608 – 610. 25 Altimari-Romero RA, Montenegro FL, Michaluart JP, et al.: Brain metastases from papillary thyroid carcinoma: A case report and review of the literature. Rev Hosp Clin Fac Med Sao Paulo 1997; 52: 263 –266. 26 Caumerie CH, De Potter P, Godfraind C, et al.: Orbital metastasis as primary manifestation of thyroid carcinoma. Thyroid 2000; 10: 189 –192. 27 Parker LN, Wu SY, Kim DD, et al.: Recurrence of papillary thyroid carcinoma presenting as a focal neurologic deﬁcit. Arch Intern Med 1986; 146: 1987–1988. 28 Miyamoto S, Kasagi K, Endo K, et al.: Results of radioiodine therapy in 47 patients with distant metastases of differentiated thyroid carcinoma. Nippon Igaku Hoshasen Gakkai Zasshi 1991; 51: 810 – 821. 29 Orsolon P, Bagni B, Cattaruzzi E, et al.: A brain metastasis, with no uptake of 99mTcECD, secondary to Hurthle cell carcinoma of the thyroid. Minerva Endocrinol 1995; 20: 233–236. 30 Freeman, JL, Gershon A, Liavaag P-G, et al.: Papillary thyroid carcinoma metastasizing to the sphenoid-ethmoid sinuses and skull base. Thyroid 1996; 6: 59 – 61. 31 Pelikan DMV, Lion HL, Hermans J, et al.: The role of radioactive iodine in the treatment of advanced differentiated thyroid carcinoma. Clin Endocrinol 1997; 47: 713 –720. 32 Hidalgo V, Dy C, Fernandez Hidalgo O, et al.: Simultaneous radiotherapy and cisplatinum for the treatment of brain metastases. A pilot study. Am J Clin Oncol 1987; 10: 205–209. 33 Biswal BM, Bal CS, Sandhu MS, et al.: Management of intracranial metastases of differentiated carcinoma of thyroid. J Neurooncol 1994; 22: 77– 81. 34 Chiu, AC, Delpassand ES, Sherman SI: Prognosis and treatment of brain metastases in thyroid carcinoma. J Clin Endocrinol Metab 1997; 82: 3637–3642. 35 Venkatesh S, Leavens ME, Samaan NA: Brain metastases in patients with well-differentiated thyroid carcinoma: study of 11 cases. Eur J Surg Oncol 1990; 16: 448 – 450. 36 Silliphant WM, Klinck GH, Levitin MS: Thyroid carcinoma and death. Cancer 1964; 17: 513–525. 37 Samaan NA, Schultz PN, Hickey RC, et al.: The results of various modalities of treatment of well differentiated thyroid carcinoma: a retrospective review of 1599 patients. J Clin Endocrinol Metab 1992; 75: 714 –720.

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38 Kitamura Y, Shimizu K, Nagahama M, et al.: Immediate causes of death in thyroid carcinoma: clinicopathological analysis of 16 fatal cases. J Clin Endocrinol Metab 1999; 84: 4043–4049. 39 DeAngelis LM: Primary central nervous system lymphoma as a secondary malignancy. Cancer 1991; 67: 1431–1435. 40 Vassilopoulou-Sellin R, Klein MJ, Smith TH, et al.: Pulmonary metastases in children and young adults with differentiated thyroid cancer. Cancer 1993; 71: 1348 –1352. 41 Vassilopoulou-Sellin R: Childhood thyroid cancer outcome and mortality. M. D. Anderson Oncology Case Reports 1998; 13: 1–10. 42 Duffy BJ, Fitzgerald PJ: Cancer of the thyroid in children: a report of 28 cases. J Clin Endocrinol 1950; 10: 1296 –1308. 43 Hassoun AAK, Hay ID, Goellner JR, et al.: Insular thyroid carcinoma in adolescents. Cancer 1997; 79: 1044 –1048. 44 La Quaglia MP, Black T, Holcomb GW, et al.: Differentiated thyroid cancer: clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases. A report from the Surgical Discipline Committee of Children’s Cancer Group. J Pediatr Surg 2000; 35: 955 – 960. 45 Buckwalter JA, Gurll NJ, Thomas CG: Cancer of the thyroid in youth. World J Surg 1981; 5: 15–25. 46 Goepfert H, Dichtel WJ, Samaan NA: Thyroid cancer in children and teenagers. Arch Otolaryngol 1984; 110: 72–75. 47 Schlumberger J, De Vathaire F, Travagli JP, et al.: Differentiated thyroid carcinoma in childhood: long-term follow-up of 72 patients. J Clin Endocrinol Metab 1987; 65: 1088–1094. 48 Harness JK, Thompson NW, McLeod MK, et al.: Differentiated thyroid carcinoma in children and adolescents. World J Surg 1992; 16: 547–554. 49 Mazzaferri EL: Undifferentiated thyroid carcinoma and unusual thyroid malignancies. In: Mazzaferri EL, Samaan NA (eds): Endocrine Tumors. Oxford, Blackwell Scientiﬁc Publishers, 1993, pp. 378–400. 50 Samaan NA, Ordonez NG, Hickey RC: Medullary thyroid carcinoma. In: Mazzaferri EL, Samaan NA (eds): Endocrine Tumors. Oxford, Blackwell Scientiﬁc Publishers, 1993, pp. 334–347. 51 Decker RA, Peacock ML: Update on the proﬁle of multiple endocrine neoplasia type 2a RET mutations. Cancer 1997; 80: 557–568. 52 Saad MF, Ordonez NG, Rashid RK, et al.: A study of the clinical features and prognostic factors in 161 patients. Medicine 1984; 63: 319 –342. 53 Schlumberger M, Abdelmoumene N, Delisle MJ, et al.: Treatment of advanced medullary thyroid cancer with an alternating combination of 5 FUastreptozocin and 5 FUdacarbazine. The Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer 1995; 71: 363–365. 54 Mizukami Y, Nonomura A, Michigishi T, et al.: Medullary thryoid carcinoma experience at Kanazawa University Hospital. J Surg Oncol 1996; 61: 27–33. 55 Pitale SU, Melian E, Thomas C, et al.: Brain metastases from medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2A. Thyroid 1999; 9: 1123 –1125. 56 Rothmund M: World progress in surgerya carcinoid tumors. World J Surg 1996; 20: 125–202. 57 Kvols LK, Brown ML, O’Connor MK, et al.: Evaluation of a radiolabeled somatostatin analog (I-123 octreotide) in the detection and localization of carcinoid and islet cell tumors. Radiology 1993; 187: 129 –133.

Brain metastases from thyroid carcinoma and other endocrine malignancies 389 58 Greene KA, Anson JA, Martinez JA, et al.: Multicystic metastatic carcinoid to brain: case report. J Neurooncol 1993; 17: 15 –20. 59 Nagaourney RA, Hedaya R, Linnoila M, et al.: Carcinoid carcinomatous meningitis. Ann Intern Med 1985; 102: 779 –782. 60 Valli M, Fabris GA, Dewar A, et al.: Atypical carcinoid tumour of the thymus: a study of eight cases. Histopathology 1994; 24: 371–375. 61 Wolf GT, Lloyd RV, McClatchey KD, et al.: Carcinoid (neuroendocrine carcinoma) of the larynx. Ann Otol Rhinol Laryngol 1987; 96: 315 –321. 62 Woodruff JM, Senie RT: Atypical carcinoid tumor of the larynx. ORL 1991; 53: 194 –209. 63 Pearson CM, Fitzgerald PJ: Carcinoid tumorsaA re-emphasis of their malignant nature. Cancer 1949; 2: 1005 –1026. 64 Taal BG, Hoefnagel CA, Valdes Olmos RA, et al.: Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors. J Clin Oncol 1996; 14: 1829 –1838. 65 Chakravarthy A, Abrams RA: Radiation therapy in the management of patients with malignant carcinoid tumors. Cancer 1995; 75: 1386 –1390. 66 Schupak KD, Wallner KE: The role of radiation therapy in the treatment of locally unresectable or metastatic carcinoid tumors. Int J Radiat Oncol Biol Phys 1991; 20: 489 – 495. 67 Piniella AM, Siatkowski RM: Adrenal cortical carcinoma metastatic to the brain in a child. J Neuroophthalmol 2000; 20: 35 –37. 68 Pommier RF, Brennan MF: An eleven-year experience with adrenocortical carcinoma. Surgery 1991; 112: 963 –971. 69 Soreide AJ, Brabrand K, Thoresen SO: Adrenal cortical carcinoma in Norway, 1970–1984. World J Surg 1992; 16: 663 – 668. 70 Brennan MF: Adrenocortical carcinoma. CA Cancer J Clin 1987; 37: 347–365. 71 Flack MR, Pyle RG, Mullen NM, et al.: Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metab 1993; 76: 1019 –1024. 72 Venkatesh S, Hickey RC, Sellin RV, et al.: Adrenal cortical carcinoma. Cancer 1989; 64: 765–769. 73 Vassilopoulou-Sellin R: Clinical outcome of 50 patients with malignant abdominal paragangliomas and malignant pheochromocytomas. Endocr Relat Cancer 1998; 5: 59 – 68. 74 Grabel JC, Gottesman RI, Moore F, et al.: Pheochromocytoma presenting as a skull metastasis with massive extracranial and intracranial extension. Neurosurgery 1990; 27: 134–136. 75 Yu L, Fleckman AM, Manjeet C, et al.: Radiation therapy of metastatic pheochromocytoma: case report and review of the literature. Am J Clin Oncol 1996; 19: 389 –393. 76 Nelson MD, Kendall BE: Intracranial catecholamine-secreting paragangliomas. Neuroradiology 1987; 29: 277–282. 77 Otokida K, Ohira A, Kamimura A, et al.: Cervical catecholamine-secreting paraganglioma in the pterygopalatine fossa. Tohoku J Exp Med 1987; 153: 347–354. 78 Felten D, Catala M, Kujas M, et al.: Intracerebral extension of cervical paraganglioma. Rev Neurol 1994; 150: 796 –798. 79 Noble ER, Smoker WR, Ghatak NR: Atypical skull base paragangliomas. AJNR Am J Neuroradiol 1997; 18: 986 –990. 80 Yamamoto T, Matsumura A, Fujita K, et al.: Cerebral metastasis of parathyroid carcinoma. Neurol Med Chir 1996; 36: 96 –98. 81 Sandelin K, Auer H, Bondeson L, et al.: Prognostic factors in parathyroid cancer: a review of 95 cases. World J Surg 1992; 16: 724 –731. 82 Sandelin K, Tullgren O, Farnebo LO: Clinical course of metastatic parathyroid cancer. World J Surg 1994; 18: 594 –599.

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83 Favia G, Lumachi F, Polistina F, et al.: Parathyroid carcinoma: sixteen new cases and suggestions for correct management. World J Surg 1998; 22: 1225 –1230. 84 Thomas CR, Wright CD, Loehrer PJ: Thymoma: state of the art. J Clin Oncol 1999; 17: 2280–2289. 85 Doniach I: Pituitary carcinoma. In: Sheaves R, Jenkins PJ, Wass JAH, (eds): Clinical Endocrine Oncology. Oxford, Blackwell Scientiﬁc Publishers, 1997, pp. 225–227. 86 Kaltsas GA, Mukherjee JJ, Plowman PN, et al.: The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors. J Clin Endocrinol Metab 1998; 83: 4233–4238.

CHAPTER 23

Brain metastasis from sarcomas Andrew E Sloan, Michael Kraut

Epidemiology The sarcomas are a rare group of tumors that arise from mesenchymal tissue rather than the germ cell layer where carcinomas, which are far more common, originate. Sarcomas are diverse in both cellular origin and behavior, and comprise 0.7% of all cancers, with an incidence of 2/100,000 population per year1, 2. Sarcomas are generally classiﬁed as originating either from soft tissue or from bone and commonly arise in the limbs or retroperitoneal organs. There are multiple subtypes of tumor within each category, ranging from benign to malignant. Each of these has distinct histological and epidemiological characteristics, staging, treatment, and prognoses. These have recently been extensively reviewed3, 4. A detailed description of the various primary tumors is beyond the scope of this chapter, but the most common examples within each category are illustrated in Table 23.1. In the United States, there are about 10,400 sarcomas diagnosed yearly, 7,800 derived from soft-tissues and 2,600 of skeletal origin3, 4. There are two peaks in incidence. Soft-tissue sarcomas occur primarily in adults, with age group peaks ranging from 18 to 25 years in alveolar soft-part sarcoma, from 30 to 39 years for ﬁbrosarcomas, and from 60 to 69 years for liposarcomas3. In contrast, osteosarcoma and Ewing’s sarcoma, the two most common sarcomas of bone, peak in incidence in children and adolescents and comprise two of the three most common types of brain metastases seen in children4, 5. Metastatic disease typically occurs in the later stages of sarcoma. The most common organs affected are the lungs and bones3. Brain metastases from sarcomas are particularly rare and account for less than 3% of all brain metastases at autopsy6. The incidence of brain metastasis is 1 to 14% in most types of soft-tissue sarcomas6 –12 with the exception of alveolar soft-part sarcoma in which the incidence may be as high as 21 to 29%7, 13, 14. It is thought that brain metastasis probably occurs in the later stages of all metastatic sarcomas6. Parenchymal brain metastases from sarcomas of bone are even more rare overall4. However, the high incidence of these neoplasms in children makes them the most frequent source of brain tumors in patients less than 21 years old2, 15, 16. Chordomas and chondrosarcomas more frequently invade brain parenchyma from the skullbase after transgressing dural boundaries, but this is local invasion rather than distant metastasis. These tumors are

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Table 23.1 Classiﬁcation of sarcomas with common examples. Tissue of origin

Histological type

Benign

Malignant

Fibrous Fibrohistiocytic

Nodular fasciitis Fibrous histiocytoma

Lipomatous Smooth muscle Skeletal muscle Blood and lymph nodes

Lipoma Leiomyoma Rhabdomyoma Hemangioma

Perivascular

Glomus tumor

Synovial Mesothelial Neural Paraganglionic Cartilagenous Pluripotential Miscellaneous

Tenosynovial giant cell Adenomatoid tumor Morton’s neuroma Paraganglioma Chondroma Mesenchymoma Amyloid

Fibrosarcoma Malignant ﬁbrous histiocytoma Liposarcoma Leiomyosarcoma Rhabdomyosarcoma Angiosarcoma & lymphangiosarcoma Malignant hemangiopericytoma Synovial sarcoma Mesothelioma Malignant schwanoma Malignant paraganglioma Chondrosarcoma Malignant mesenchymoma Alveolar soft-part sarcomas

Hematopoietic Chondrogenic Osteogenic Fibrogenic Notochordal Vascular Unknown origin

— Chondroma Osteoma Fibroma — Hemangioma Giant cell tumor

Reticulum cell sarcoma Chondrosarcoma Osteosarcoma Fibrosarcoma Chordoma Hemangiopericytoma Ewing’s tumor

SOFT TISSUE

BONE

more commonly addressed by chapters in textbooks on surgery of the skullbase and will not be considered further in this chapter. Whereas only about 10% of sarcoma patients present with symptomatic brain metastases, the incidence at autopsy is somewhat higher, suggesting that brain metastasis occurs more frequently in the later stages of disease2, 7. Just over 300 patients with sarcomatous metastases to the brain parenchyma have been reported in the literature, and the vast majority have been described in case reports or small case series17–20. The incidence of brain metastases in males is slightly higher than in females in the largest series (52 to 60%), and the mean interval between the diagnosis of the primary disease and the diagnosis of brain metastasis is 27 months, with a range of 0 to 180 months17–20. Sarcomas primarily metastasize via the hematogenous route, and lung metastases have preceded or been detected simultaneously with brain metastases in most cases6, 17–20. The number of brain metastases detected has increased in recent decades. This is partly because of improved imaging techniques, but prolonged survival due to improved multi-modality treatment has also been hypothesized to play a role in this increase3, 6 – 8, 21.

Brain metastasis from sarcomas 393

Diagnosis Clinical presentation There is no common pattern of presentation of brain metastasis from sarcoma. However, although the epidemiology, incidence, and timing of brain metastases varies according to the tissue of origin, the clinical presentation of brain metastases from sarcomas in adults is similar to those of metastases from carcinomas. Metastatic sarcomas are most typically single lesions that present with symptoms of increased intracranial pressure (ICP) or focal irritation and/or destruction of neural tissues. Leptomenigeal metastasis from sarcoma has seldom been reported and occurs predominantly in children with embryonal rhabdomyosarcoma7, 22 and Ewing’s sarcoma2, 23. Brain metastases are rarely the presenting symptom of sarcoma and most commonly follow pulmonary involvement2, 6, 7, 17–20, 24. Focal irritation or damage to surrounding brain from brain metastases often produces signs and symptoms with localizing value such as focal motor and/or sensory deﬁcits, visual ﬁeld cuts, seizures, and ataxia. In contrast, symptoms caused by increased ICP rarely have localizing value and are caused by tumor mass, edema, or obstruction of cerebrospinal ﬂuid (CSF) ﬂow. Patients typically present with symptoms of headache, nausea, vomiting, confusion, and altered level of consciousness. The onset is usually chronic but may be acute, particularly in the case of intratumoral hemorrhage, which is common6, 25, 26.

Radiologic appearance Radiologically, sarcomatous brain metastases are typically single rather than multiple, as is seen in the case of most metastatic carcinomas17–20. They usually show gadolinium contrast enhancement on radiographic images and may be either cystic or solid in appearance6, 27, 28. Often they are large, with signiﬁcant mass effect (Figure 23.1). Similar to other types of brain metastases, they are typically surrounded by considerable edema. Metastatic sarcomas can not be distinguished from metastatic carcinomas radiologically. However, in patients with known sarcoma, radiological evidence of brain metastases should suggest the diagnosis of brain metastasis from the sarcoma primary, regardless of whether single or multiple lesions are seen. Biopsy or resection provides the most accurate way to make the diagnosis.

Pathology Although their histology is characteristic of the tumor of origin, sarcomatous brain metastases share many characteristics grossly. They are typically spherical, well-circumscribed, and found at the gray-white matter junction. Single metastases are most typical, but the incidence of multiple metastases ranges from 13 to 40% in most large series17–20. The consistency of sarcomatous metastases is generally ﬁrm, though some are cystic and many have necrotic or

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Figure 23.1 T1 weighted magnetic resonance image demonstrates a large right frontoparietal mass in a 40-year-old African-American man who presented with a rapidly progressive left-sided hemiparesis 22 months after treatment for a pulmonary metastasis from alveolar soft-part sarcoma. The primary tumor was located in the periscapular region, and had been treated with local excision and chemotherapy 89 months earlier81.

hemorrhagic centers. No preferred topographic location within the brain has been described for these lesions. However, there is anecdotal evidence that sarcomas metastasize to the brainstem more frequently than do carcinomas24, 29. It is believed that most sarcomas metastasize to the brain via a hematogenous route. In contrast to soft-tissue sarcomas, sarcomas of bone (Ewing’s sarcoma in particular) often metastasize both via the hematogenous route and by local extension from a lesion of the skull or meninges. Leptomeningeal disease has also been reported in children with Ewing’s sarcoma and with embryonal rhabdomyosarcoma2, 7, 22. Brain metastases usually occur late in the course of the disease6, but as many as 12 to 18% of patients presented with “solitary” lesions prior to the diagnosis of systemic disease6, 7.

Management and clinical decision-making There have been no published randomized trials of treatment for sarcomatous metastasis to the brain parenchyma. Furthermore, the rarity of this disease makes it unlikely that such a randomized trial could be accomplished. Most published papers are case studies and retrospective case series considering several types of sarcomas together. Selection bias may be involved in treatment decisions in such studies, and thus any conclusions must be made with these limitations in mind. In the sections that follow, the literature regarding treatment of the most common subtypes of sarcomas of the soft tissues (rhabdomyosarcoma, malignant ﬁbrous hystiocytoma, leiomyosarcoma, and alveolar soft-tissue sarcoma) and bone (Ewing’s sarcoma, osteosarcoma) will be reviewed. This will be followed by a summary of the efﬁcacy of the various treatment modalities for these diseases, as well as conclusions and recommendations for treatment and future studies.

Brain metastasis from sarcomas 395

Management of speciﬁc tumors Because of the wide variety of primary sarcomas, each with differing clinical characteristics, management of the sarcomas that most commonly metastasize to the brain will be considered individually below.

Soft-tissue sarcomas Malignant ﬁbrous histiocytoma (MFH) Malignant ﬁbrous histiocytoma (MFH) is the most common soft-tissue sarcoma of late adult life3. Nearly 75% of these lesions arise in the extremities, whereas 25% arise in the trunk or retroperitoneal region30. Although the incidence of brain metastases in the two largest studies of MFH is only 1 to 2%30, 31, it accounts for 12 to 25% of sarcomatous brain metastases in most large series due to the frequency of the primary disease, and more than 50 cases have been reported in the literature2, 8, 18 –20. Primary MFH of the brain is even more rare, but has also been reported32, 33. The prognosis of patients who have primary and metastatic disease is dependent largely on whether the primary tumors were in locations considered superﬁcial or deep, which is deﬁned as invasive of muscle30. About 90% of primaries that resulted in brain metastases were deeply located, with six reported exceptions that were located superﬁcially8, 18, 20, 30, 32. Nearly all brain metastases were preceded by known lung metastasis2, 17, 19, 32. The outcome for patients with sarcomatous brain metastases treated with conservative management alone (steroids with or without anticonvulsants) is poor, with median survival times ranging from 1 to 3 months reported for 7 patients7, 8, 20, 34 (Table 23.2). Patients treated surgically fared better. Postoperative survival times of four and 16 months were reported by Ogose et al.20 Notably, the patient who survived only four months committed suicide; his neurological status and extent of disease were unknown. Addition of postoperative whole-brain radiotherapy (WBRT; 30 Gy) led to similar survival times of 6 to 19 months in six of eight patients in three large surgical series17–19. The two outliers were a patient with multiple metastases who succumbed to neurological progression 2.3 months postoperatively17 and one who survived for 65 months postoperatively18. Addition of chemotherapy to the treatment regimen did not appear to add efﬁcacy, and the single patient so-treated survived for only seven months postoperatively32.

Rhabdomyosarcoma Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood, comprising 5 to 15% of all solid malignancies in patients less than 15 years old and 4 to 8% of all malignancies in this age group26. In patients aged 15 to 19, it comprises 2% of all cancers35. It is often curable, with approximately 60% of patients surviving for ﬁve years36. The prognosis of patients with rhabdomyosarcoma is related to site of origin of the tumor, tumor burden, extent of disease, and tumor histology36. Brain metastases are rare in this disease. The most

Table 23.2 Survival with various modalities for the treatment of metastatic sarcomas of the brain.

Neoplasm

Conservative treatment

WBRT

Chemotherapy

Surgery

WBRT + chemotherapy

Surgery + WBRT

Surgery + chemotherapy

Surgery + WBRT + chemotherapy

MFH

1–3 (7)

—

—

4–16 (2)

—

9–10 (12) range, 0.5–65 mos.

7 (1)

—

Rhabdomyosarcoma

≤ 3 (11) range, 0.1–20 mos.

< 1 (1)

2–4 (2)

5 (1)

7 (1)

4 (6) (2–64)

—

3, 5.5 (2)

Leiomyosarcoma

3.5–4.3 (3)

—

—

1, 1.3 (2)

—

13 (11) range, 2.7–30 mos.

22, 51 (2)

6, 30 (2)

ASPS

4 (2)

—

—

24 (2)

—

23–25 (6) range, 12–73 mos.

—

18 (1)

Osteosarcoma

2 (2)

4 (3) range, 2–8 mos.

6 (4) range, 1.5–108 mos.

16 (5) range, 3–39 mos.

4 (1)

5.4–7.5 (8) range, 5–67 mos.

5, 15 (2)

—

Ewing’s sarcoma

< 1 (4) range, 1–6 mos.

2–3 (6) range, 2–8 mos.

1, 6 (2)

19.5 (3) range, 12–30 mos.

6 (5) range, 2–21 mos.

10–15 (4) range, 1–22 mos.

5 (1)

15–16 (8) range, 1–112 mos.

For each neoplasm, median survival time of patients in months is given in the top row of each treatment column, followed by the number of patients treated, in parenthesis. WBRT, whole-brain radiotherapy; MFH, malignant ﬁbrous histiocytoma; ASPS, alveolar soft-part sarcoma.

Brain metastasis from sarcomas 397

comprehensive intergroup study published noted a complete absence of brain metastases at the time of diagnosis37. However, the central nervous system (CNS) was the most common site of recurrent metastasis37. One study suggests that brain metastases are more frequent in rhabdomyosarcomas of renal origin, with three of eight patients in the series (57%) developing brain metastases, whereas none of the six patients with tumors of extrarenal origin experienced brain metastases38. Rhabdomyosarcomas of extrarenal origin have been reported to metastasize to the brain by others, however39. The largest published case series, from Memorial Sloan-Kettering, estimates the total number of reported cases at about 3018. The natural history of untreated brain metastases from rhabdomyosarcoma is dismal (Table 23.2). In 11 patients treated conservatively, survival time was three months or less7, 8, 21, 24, 38, 40. The single exception was a patient who survived for 20 months8. Survival time was no better in a single patient who was treated with WBRT alone and survived for less than a single month20. Chemotherapy alone produced survival times of two and four months, respectively, in two patients20, 38, whereas craniotomy alone resulted in a postoperative survival time of ﬁve months in a single patient26. Combined craniotomy and adjuvant WBRT (30 Gy) produced a survival time similar to that observed for either modality alone in most cases, with ﬁve of six patients in the series of Wronski et al. succumbing within 2 to 6 months18. A single patient survived for 64 months postoperatively, though the 164-month delay between the primary diagnosis and the development of brain metastases suggests that this prolonged survival may have been inﬂuenced more by tumor biology than treatment efﬁcacy18. A single patient treated with combined WBRT (30 Gy) and chemotherapy (vincristine, cyclophosphamide, adriamycin, and actinomycin) survived for 17 months after diagnosis of brain metastasis38. Combined modality treatment with postoperative WBRT in addition to adjuvant chemotherapy did not appear to improve efﬁcacy, as survival times in two patients were only three and 5.5 months, respectively, postoperatively38, 41.

Leiomyosarcoma Sarcomas of the uterus are uncommon and typically occur in women who are at least 50 years old, though they have been reported in patients who are in their mid 20s. Leiomyosarcomas are the second most common of the uterine sarcomas, with an incidence of 0.64/100,000 individuals42. Their most common sites of metastasis are the peritoneal cavity (59%), lungs (52%), and pelvic lymph nodes (41%)11. Brain metastases are rare, with symptomatic metastases reported in < 1% of the 139 patients seen with this disease at the Royal Marsden Hospital 1961–7011. Rose et al. reported a somewhat higher incidence of 5.8% at autopsy11. Brain metastases are usually single and supratentorially located, though multiple metastases17, 19, 43, as well as infratentorial metastases, have been reported42, 43. They are also typically a late manifestation of this disease and typically occur later than one year after initial diagnosis and nearly always after lung metastasis8, 11, 44. Ziyal et al. reviewed nine cases in the

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literature in addition to his own case report44. Additional cases reported by others bring the total number published to at least thirty-ﬁve2, 7, 18, 19, 21, 43, 45. The outcome of patients with brain metastasis from leiomyosarcoma is poor, with median survival times of 3.5 to 4.3 months or less after conservative management in three cases6 – 8 (Table 23.2). Reports of rapid local recurrence also suggest locally invasive behavior44, 46. The results of chemotherapy and radiation therapy alone for these metastases are ambiguous. Surgery alone did not improve results in two patients in the series by Bindal et al., with postoperative survival times of only one and 1.3 months, respectively17. Surgery combined with adjuvant radiotherapy resulted in improved outcome in 12 patients. Ziyal et al. reported a postoperative survival time of 4.5 months despite resection with adjuvant WBRT (50 Gy) and re-resection of recurrent lesions44. Survival times of 2.7, 15, and 30 months, respectively, were reported for a series of three patients treated using surgical resection with and without WBRT (unable to assess treatment of individual patients) at Memorial SloanKettering18, whereas the median survival time after surgery and WBRT (30 Gy) was ﬁve months (range 3–14 months) in the series of ﬁve patients of Salvati et al.19, and two patients treated with both modalities survived for 14 and 16 months, respectively, in the series of Bindal et al.17. It should be noted that the latter two patients died of systemic, rather than intracranial, progression17. The best outcomes have been obtained in two patients who were treated with surgical resection of brain metastases followed by adjuvant chemotherapy. Gercovich et al. reported a single patient who was alive without evidence of disease 22 months after surgical resection followed by adjuvant chemotherapy (adriamycin + dacarbazine [DTIC])21. It should be noted, however, that there was no tissue conﬁrmation of the brain metastasis in this case. More convincingly, Vaquero et al. reported a survival time of 51 months in a single patient after aggressive treatment comprised craniotomies for two consecutive leiomyosarcoma lesions, each of which was treated with adjuvant chemotherapy (methotrexate, 5-ﬂuorouracil [5-FU], cylclophosphamide, and cyclohexamethlyenemelamene, followed by methotrexate, 5-FU, cyclophosphamide, and adriamycin), followed by a third craniotomy for a tumor recurrence46. There is no evidence that the addition of WBRT improves efﬁcacy. A single patient treated with WBRT (30 Gy) and chemotherapy (adriamycin + DTIC) after resection by Feeney et al. survived for only six months45, whereas a patient treated with 54 Gy of WBRT followed by cytoxan chemotherapy survived for 30 months after resection of brain metastases42. However, it should be noted that both patients died of systemic, rather than intracranial, progression, suggesting the possibility that intracranial tumor control was good at the time of death.

Alveolar soft-part sarcoma Alveolar soft-part sarcoma (ASPS) accounts for less than 1% of all soft-tissue sarcomas observed3, 18. ASPS typically occurs in adolescents and young adults, with a median age of onset at 23 years and a male:female ratio of 1:114. The

Brain metastasis from sarcomas 399

primary tumors typically arise in the lower extremities14. Local tumor control in this disease approaches 80% in recent series, but the incidence of distant metastases approaches 70%14, with multiple metastases occurring in 14% of patients47. Size and location of ASPS metastases appear to have no bearing on patient prognosis14. However, ASPS is unique among soft-tissue sarcomas for its indolent, but inexorable progression. For ASPS, the median 5-year survival rate ranges from 59 to 67%14, 48, 49, with a median patient survival time of 10 to 12 years49 and reports of patients surviving for more than 20 years14. This slow progression and characteristically long survival is believed to account, in part, for the increased incidence of brain metastases in patients with ASPS, which has been reported to be as high as 67% in some series50. More than 100 occurrences of brain metastasis from ASPS have been reported in the literature, and there is an incidence of 15–29% of patients in most larger series7, 13, 14, 48, 49, 51–53, with one author reporting brain metastases in two of three patients50. Whether this high incidence, which is an order of magnitude larger than that seen in other sarcomas, is due to longer patient survival or tissue tropisms has not yet been determined. As with other sarcomas, brain metastases from ASPS are preceded by pulmonary metastases 85% of the time17, 19, 48, 49, 53 and typically occur 2 to 5 years after the diagnosis of the primary neoplasm. Recurrence of these brain metastases as late as 33 years after diagnosis has been reported54. Most metastases are single and supratentorial, though the presence of multiple brain metastases20, 24 and infratentorial metastases18 has been reported. The lack of published clinical trials treating patients with brain metastases from ASPS makes comparison of treatment modalities difﬁcult. However, it is clear that the results of conservative management are poor, with Ogose et al. reporting survival times of only four months after the diagnosis of brain metastasis in two patients treated with steroids or chemotherapy alone20 (Table 23.2). Lillehei et al. and Ogose et al. each report survival times of two years or more in single patients treated with surgery alone20, 54. Whereas Bryant et al.7 reported a survival time of 12 months after resection of brain metastasis followed by WBRT, Wronski et al. reported postoperative survival times of 23 and 73 months, respectively, in two patients who underwent surgical resection of their brain metastases with and without WBRT, respectively18. Later series by Bindal et al.17 and Salvati et al.19 reported two patients who each remained alive at the time of publication 15 to 25 months after resection of their brain metastases followed by WBRT, whereas Wang et al. reported on a patient who was alive and disease free six years after similar treatment for a sarcomatous brain metastasis53. A single patient was reported to be alive without recurrence of his brain metastasis 18 months after undergoing resection of it followed by WBRT and chemotherapy with doxorubicin and dacarbazine23.

Sarcomas of bone Sarcomas of bone, osteosarcoma, and Ewing’s sarcoma occur primarily in children. Unlike brain metastases in adults, which occur in 20 to 40% of patients

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with cancer55, brain metastases in children is less common, and occurs in 2.4 to 5% of children who have primary neoplasms4, 5. Unlike brain metastasis in adults, which is the initial manifestation of cancer in up to 15% of patients56 and occurs in a similar percentage in the setting of unknown primary tumors, brain metastasis in children typically occurs in the setting of widely metastatic disease57. Symptoms and signs of increased intracranial pressure also appear more rapidly in children than adults5. It is speculated that this may be due to the more rapid kinetics of tumor growth in this population5, but the smaller volume of the skull and brain, which results in a larger proportion of the volume for a tumor of a given size, and the lack of brain atrophy in this population may also contribute.

Osteosarcoma Osteosarcoma is the most common primary malignant bone tumor, with a yearly incidence of 1 per 5,000,000 population4. It occurs primarily in the long bones in adolescents and young adults 10 to 25 years old, and is one of the few tumors with well-identiﬁed risk factors. These include: exposure to ionizing radiation, exposure to thorium oxide (a radioactive substance used in nuclear medicine studies), ﬁbrous dysplasia, Paget’s disease, and retinoblastoma58. Generally, 4% of patients have a history of previous radiotherapy for other neoplasms4. Typically, the clinical and radiological ﬁndings are associated with an elevation in alkaline phosphatase (> 700 U/l)59. Osteosarcoma is also unusually chemosensitive, and chemotherapy has dramatically changed both management and outcome. Before the 1980s, 80% of patients developed distal metastases at a median of 6–8 months after diagnosis, with the most common sites being the lungs (95%) and bones (15–30%)60. The prognosis was dismal, with a survival time of less than one year. Adjuvant chemotherapy, which began to be used in the mid 1970s and early 1980s, improved prognosis, with a ﬁve-year disease-free survival rate of 50 to 60%60. The pattern of metastasis has also changed, with a decreased incidence of pulmonary metastases and an increase in extrapulmonary metastases60, 61. There have been approximately 50 osteosarcoma brain metastasis patients reported in the literature. Although brain metastases were rare (< 3%) in earlier series60, improved survival has resulted in a 5 to 13% incidence of brain metastases in more recent series60 – 62. Brain metastases are preceded by pulmonary metastases about two-thirds of the time, though several cases of brain metastasis have been reported in the absence of pulmonary metastases in some series17–19, 63, 64. These are usually considered preterminal events61, 62. Typically, brain metastases appear at a median of 14 months after lung metastases (range 2–124 months). In ten patients with lung metastases, the median delay between the diagnosis of the primary disease and brain metastases was 11 to 18 months (range 0–110 months)2, 17–19, 63, 64. The brain metastases are most commonly single, though multiple metastases have been reported in six patients5, 19, 20, 60, 64. The vast majority of these are supratentorial, but infratentorial metastases have also been described18, 63.

Brain metastasis from sarcomas 401

The disease course outcome of brain metastases from osteosarcoma in the pre-chemotherapy era was uniformly dismal. The incidence of clinical disease was only 3%, and this was usually considered to be a preterminal event in the setting of advanced disease35. The lack of adequate brain imaging may have contributed to this. However, the survival time reported for patients was only two months after conservative management, even for two more recently reported patients (Table 23.2)5, 20. Treatment with WBRT was associated with a slightly better prognosis, with posttreatment survival times of two and four months in one series5 and one patient who survived for eight months in another20. The impressive survival results in four patients treated with chemotherapy suggest that chemotherapy may be uniquely effective in certain patients with osteosarcoma. Although a single patient treated with adriamycin and DTIC by Gercovich et al. had progressive disease and survived for only 1.5 months, Ogose et al. reported a survival time of six months in a patient with intracranial metastasis who died of systemic rather than intracranial disease20, 21. Espana and colleagues reported survival of a patient for 34.5 months after treatment with adriamycin (and perhaps other agents) prior to his succumbing to brain metastasis8, whereas Marina and associates reported that treatment of a patient with ifosfamide led to his surviving for nine years after being diagnosed with brain metastases, the longest such survival reported60. Results of surgical treatment alone for osteosarcoma brain metastases range from days (in the pre-chemotherapy era)64, to a median 16-month survival time (range 3 to 39 months) in the series of ﬁve patients of Bindal et al.17, which included a single patient who was still alive 22 months after surgery. The median survival time for patients undergoing resection plus postoperative WBRT (45 to 55 Gy) ranges from ﬁve months in Salvati and coworkers’ series of six patients (range 5 to 13 months) to 7.5 months postoperatively in a single patient in the series of Bindal et al.17. Wexler and associates report a similar patient who was disease-free 5.6 years after such treatment60. There are two reports of patients having brain metastases from osteosarcoma who were treated with combined WBRT and chemotherapy64, 65. Outcome data can not be determined from one64, and the other patient died four months after undergoing WBRT (40 Gy) and chemotherapy with ifosfamide, carboplatin, and etoposide65. Two patients who were treated with surgery followed by postoperative chemotherapy by Ashkan and colleagues were reported alive and with no evidence of disease at ﬁve and 15 months postoperatively after treatment with methotrexate combined with either cisplatin and doxorubicin or etoposide and ifosfamide63. There have been no reports of combined adjuvant use of chemotherapy and radiotherapy after resection of brain metastases.

Ewing’s sarcoma Ewing’s sarcoma is the second most common primary malignant bone tumor in children and the most malignant28, accounting for 10% of all bone tumors66, 67. It accounts for 4% of all childhood and adolescent malignancies68. These sarcomas most commonly arise from the long bones of the extremities or the

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pelvis and less frequently, from soft tissue. They tend to recur locally as well as to metastasize to distant sites, with a high incidence of distant metastases at diagnosis that rises to 70% within the ﬁrst year after diagnosis67. The most common sites of metastasis are the lungs (38%), bones (31%), and bone marrow (11%)57. In most series, the median age of patients at diagnosis is 10 to 13 years, with a range of 1 to 26 years, and the disease occurs in an equal proportion of males and females57, 69, 70. Unlike most other sarcomas, Ewing’s sarcoma involves the brain both as parenchymal metastases by the hematogenous route and by local invasion from skull metastases57. The latter invasive route accounts for only 10 to 12% of brain disease and will not be further considered here57. Vertebral metastases also occur18, 69. Although Mehta and Henderson reported that brain metastases occur in as many as 56% of patients with Ewing’s sarcoma, this estimate is based primarily on symptoms and signs and was conﬁrmed by computed tomography (CT) scanning in less than 30% of patients in their series; none had undergone biopsy66. More recent series based on modern imaging methods and tissue diagnosis estimate the incidence of brain metastases from these tumors to be 2 to 10%5, 9, 57, 70. Brain metastases typically occur 2 to 4 years (range 1 to 11 years) after diagnosis of the primary disease57, 70. Single metastases are the most common, but the incidence of multiple metastases ranges from 27% to 43%57, 70. Metastases occur predominantly in the supratentorial space, though infratentorial metastases have been reported57. As with other sarcomas, pulmonary metastases usually precede brain metastases, though solitary brain metastases have also been reported57. Metastases from Ewing’s sarcoma can also present with hemorrhage25. Unlike the situation with most other sarcomas, brain metastases are a clearly negative prognostic indicator for patients with Ewing’s sarcoma, reducing the ﬁve-year survival rate from 51% to 25% in Shuper et al.’s series of 80 patients diagnosed and treated over the 25-year period from 1972 to 198757. Results of treatment have been reported for more than 50 patients with parenchymal brain metastases from Ewing’s sarcoma. The largest series includes 11 patients70, and most are described as single case reports. The outcome of patients with such brain metastases appears to be poor, with two patients who were treated only with steroids surviving for three days or less after diagnosis in one series70, and with two patients treated similarly in another series surviving for one and six months, respectively20 (Table 23.2). The success of chemotherapy in the treatment of other pediatric solid tumors led Trigg et al. to conduct a trial of prophylactic intrathecal chemotherapy combined with WBRT for children with Ewing’s sarcoma in the 1970’s, but this was found to be ineffective71. Treatment with WBRT alone resulted in survival times of one to three months in eight patients in four series5, 20, 70, 72, with another patient surviving for eight months after irradiation for brain metastases73. Likewise, chemotherapy alone has not proved particularly effective for patients with conﬁrmed brain metastases, with survival times of one and six months after diagnosis of brain metastasis reported in two individual

Brain metastasis from sarcomas 403

patients by Ogose et al. and Gercovich et al.20, 21. The results of combined chemotherapy and radiotherapy appear to be better than for WBRT alone in treating these lesions, with ﬁve patients surviving for a median of six months after treatment (range two to 21 months)66, 70. The longest reported survival times for patients with brain metastases from Ewing’s sarcoma have all included surgery as part of the treatment. Bindal et al. reported postoperative survival times of 1.9 to 30 months in three patients treated with surgery alone17. Mineura et al. reported a patient who survived for ﬁve months after surgery and chemotherapy (with cisplatin and ifosfamide) for a single metastasis27. Survival after surgery and WBRT appears to be better than this, however. Thus, Wronski et al. reported postoperative survival times of one and 22 months, whereas Bouffet et al. reported a survival time of 15 months, and Bindal et al. reported a survival time of 10 months in four patients5, 17, 18. Notably, the latter four patients all died of systemic metastases, rather than from progressive brain disease. The longest reported survival after treatment for brain metastases from Ewing’s sarcoma was in a single patient who survived for 112 months after surgery, WBRT, and chemotherapy (with etoposide and ifosfamide)70. Colak et al. reported survival times ranging from four to 69 months (median 16 months) postoperatively in ﬁve patients after resection of their brain metastases followed by WBRT and chemotherapy (with vincristine, actinomycin D, and cyclophosphamide)69. Finally, two investigators reported single cases of patients remaining alive and disease free for 15 and 19 months, respectively, after resection followed by 45–55 Gy WBRT and chemotherapy (with vincristine and cyclophosphamide, or etoposide and difosfamide, respectively)25, 74.

Conclusions and recommendations Because of the paucity of data and lack of randomized controlled studies on brain metastases from sarcomas, no deﬁnitive conclusions or recommendations can be made regarding their management. However, based on a review of the existing literature, and logical extension of the more well-established data on the treatment of metastatic carcinoma of the brain, it is possible to establish some general guidelines.

Natural history There have been few large series following the natural history of patients with sarcomatous brain metastases. However, from the few case reports and larger series of such brain metastases, it appears that outcome is poor, with median survival times of approximately two months or less (range 1–120)2, 6 – 8, 24. Because of the edema usually associated with sarcomatous brain metastases, steroids are usually administered to patients. In recent larger series of patients with symptomatic brain metastases reported by Bryant et al. and Ogose et al., the median survival time of the eight patients treated conservatively (with steroids alone) was two months after diagnosis of brain metastasis7, 20

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(Table 23.2). However, the fact that only one of these patients died of neurological complications and the remainder died of systemic disease suggests that this poor outcome in comparison with patients treated surgically in the same studies may reﬂect either a treatment bias or late diagnosis.

Radiotherapy Although sarcomas are observed to be relatively radioresistant, WBRT is the most common treatment administered to patients who have sarcomatous brain metastases. In most cases, 30 Gy has been administered in 10 fractions, sometimes with an additional boost to the tumor bed. The efﬁcacy of this treatment has been modest (Table 23.2).

Chemotherapy Chemotherapy has long been used for the treatment of systemic sarcoma at the time of diagnosis and is a subject of renewed interest amidst recent progress in targeted tumor treatment75. Indeed, the advent of chemotherapy for sarcoma led not only to increased patient survival but also to a change in the pattern of the disease, with a marked increase being observed in the incidence of brain metastases7, 8. Indeed, it has been hypothesized that this increased frequency of brain metastases is a consequence of the limited penetration of the bloodbrain barrier achieved by adriamycin and other chemotherapeutic agents of known efﬁcacy in the treatment of sarcoma76. This limited penetration makes the brain a “sanctuary” for residual metastases5, 6, 8. Espana et al. and Simpson et al. have suggested using prophylactic intrathecal chemotherapy combined with radiotherapy to prevent the occurrence of brain metastasis in patients with known pulmonary metastases8, 28; however, this did not prove to be efﬁcacious71, 77. There has been little study of chemotherapy alone for the treatment of sarcomatous brain metastases. However, despite studies demonstrating that most chemotherapeutic agents do not penetrate normal brain tissue to any signiﬁcant degree, anecdotal cases that show dramatically prolonged survival times ranging from 51 to 112 months have been reported for leiomyosarcoma, osteosarcoma, and Ewing’s sarcoma46, 59, 70, as well as for liposarcoma78 (Table 23.2). Thus, although there are no speciﬁc recommendations that can be made, adjuvant chemotherapy may be worthwhile in selected patients harboring brain metastases from particular subtypes of sarcomas.

Surgery Surgery notably improved survival time in most cases, and resulted in neurological improvement in 40 to 65% of patients in the larger series17–20 (Table 23.3). In these series, the median postoperative survival times range from 7 to 16 months, with median survival rates at one, two, and three years of 40 to 67%, 16 to 33%, and 0 to 12%, respectively. There was no signiﬁcant difference between postoperative survival time of patients with sarcomas of the soft tissues and that of those having sarcomas of the bones17, 20. However, alveolar soft-part sarcoma appears to be a special case such that patients’ median

Table 23.3 Outcomes in recent series of patients treated surgically for sarcomatous brain metastases. Authors and date of study Patient criteria

Bindal et al., 199417

Wronski et al., 199518

Salvati et al., 199819

Ogose et al., 1999 20

Number treated surgically Median age (years) Median KPS score at diagnosis Lung metastasis Multiple brain metastases (number of metastases) Postoperative survival (months) Fraction surviving at: 1 Yr 2 Yr 3 Yr Months of survival: Sarcomas of soft tissue Sarcomas of bone Alveolar soft-part sarcoma (number) Months of survival Cause of death Neurological Systemic Both Other Postoperative recurrence Survival after recurrence if re-resected (n = 1) If not re-resected (months) Patients undergoing WBRT (%) Median survival post WBRT (months) No WBRT (months)

21 28 80 57% 29% (1–8) 11.8 47% 28% — 11.8 10.5 (p = 0.6) 2 16–25 (alive)

25 25 70 76% 20% (1–3) 7 40% 16% 12% — — 2 23–73

15 28 80 60% 12.8% (?) 9.3 — — — — — 2 15–20 (alive)

33% 53% 7% 7% 29% 7 2.5 47.60% 11.2 12.6 (NS)

30% 45% 20% 5% 40% — — 52% 6.5 11.6 (NS)

23% 69% 8% — 20% 3.7 — 100% 9.3 —

3 43 — 80% 40.00% 5.1 67% 33% — 5.2 3.8 3 4–24 — Nonsurg:71% 29% — — — — — 25% 4 —

KPS, Karnofsky Performance Scale; WBRT, whole-brain radiotherapy; Nonsurg, patients not treated surgically; NS, not stated.

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postoperative survival times ranged from 15 to 24 months, and eight of the 15 (53%) reported patients were alive at the time of diagnosis17–20. In the series of Ogose et al., patients treated surgically survived more than twice as long as those treated with steroids alone, though there is evidence of a selection bias, as previously noted20. Interestingly, despite a high incidence of lung metastases in these patients, which ranged from 57 to 80%, the presence of active lung metastases did not signiﬁcantly inﬂuence survival time17–19. Similarly, patients with multiple brain metastases (13 to 29% of patients) did as well as those with single metastases, provided all lesions were resected17–19. Similar results have been found in the treatment of adults with carcinomatous brain metastases79. Lastly, Bindal et al. demonstrated that patients with Karnofsky Performance Scale (KPS) scores of 70 or more tended to survive longer than those with KPS scores below 7017. Based on the available data, it appears that indications for surgery of intracranial sarcomatous metastases are similar to those from carcinomas. The extent of disease, condition of the patient, lesion characteristics (number, type, size, and locations) disease-free interval, and patient’s expected survival time must all be considered. The literature appears to support aggressive resection of solitary intracranial metastases when these can be completely removed in patients in good medical condition who have limited, controlled systemic disease and are expected to survive for more than three months. It seems reasonable to extend to sarcomatous brain metastases the practice of using surgical resection for patients who have no more than three lesions, if they can be resected completely, as Bindal et al. have shown for carcinomatous brain metastases79. Thus, surgery should be recommended for patients meeting the following medical criteria: 1 being in suitable medical condition 2 having KPS scores of at least 60 to 70 3 having stable systemic disease (possible with active lung metastases) 4 having surgically accessible lesions. The incidence of postoperative recurrence of sarcomatous brain metastases ranged from 20 to 40%17–19 (Table 23.3). Surgery for recurrence of a single lesion was attempted in two series, and both patients survived for more than three months after recurrence, suggesting that reoperation may be reasonable in some patients17, 19. Notably, in the series of Bindal et al., the patient who had a recurrent lesion treated surgically survived much longer relative to those treated conservatively (7 months versus 2.5 months, respectively)17. Aggressive resection of recurrent metastases has also contributed to markedly improved survival in other anecdotal cases44, 46.

Stereotactic radiosurgery There has been little study of the efﬁcacy of stereotactic radiosurgery (SRS) on sarcomatous brain metastases80. Nonetheless, the proved efﬁcacy of this therapeutic modality in the treatment of other radioresistant neoplasms such as melanoma and renal cell carcinoma (as well as arteriovenous malformations)

Brain metastasis from sarcomas 407

suggests that it may be effective for the treatment of small intracranial sarcomas as well81. Thus, it seems reasonable to consider SRS for the treatment of sarcomatous brain metastases that are multiple, are located in deep or eloquent areas of the brain, or occur in patients who are poor surgical candidates for medical reasons.

Combined modality therapy Numerous patients have been treated with combined modality therapy for sarcomatous brain metastases. Postoperative WBRT has been most commonly employed. In the two largest operative series, postoperative WBRT (30 Gy) did not signiﬁcantly improve patient survival time17, 18 or decrease local tumor recurrence17 (Tables 23.2, 23.3). However, there is a trend towards improved survival in patients who have brain lesions from soft-tissue sarcoma when WBRT is added postoperatively (Tables 23.2, 23.3). Indeed, the patients with the longest survival times who have brain metastases from MFH, rhabdomyosarcoma, leiomyosarcoma, ASPS, and osteosarcoma have been treated in this fashion. Combined treatment with chemotherapy and WBRT in the absence of surgery has been employed in a few cases (Table 23.2). There is no evidence that such treatment improved survival times for patients with any of the more common sarcomas considered here. Anecdotal reports support possible efﬁcacy of postoperative chemotherapy for leiyomyosarcoma and osteosarcoma46, 63 (Table 23.2). This appears to be the treatment of choice for craniofacial osteosarcoma at present82. There have been only a few patients treated with surgery combined with postoperative WBRT and chemotherapy (Table 23.2). Anecdotal reports of increased survival times in patients with leiomyosarcoma and Ewing’s sarcoma suggest that further study of this combination may be indicated in these neoplasms42, 60.

Conclusions The natural history of sarcoma with brain metastasis is poor, with median survival times of three months or less observed in most series. Surgery appears to be the single most effective treatment, and craniotomy with complete resection should be the goal for most patients who are surgical candidates. There is anecdotal evidence that postoperative WBRT may be efﬁcacious in some patients. Though there has been little study of stereotactic radiosurgery for sarcomatous brain metastases, proved efﬁcacy in carcinomatous brain metastases of similarly radioresistant neoplasms suggests that this modality is likely to be effective, and further study is indicated. There is also anecdotal evidence that chemotherapy may be efﬁcacious in certain patients with leiomyosarcoma, sarcomas of bone, and liposarcoma, either administered alone or in combination with other treatment. However, it is likely that advances in the understanding of tumor biology and the identiﬁcation of targets of therapy will lead

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to both more effective treatment and to the development of more objective criteria for optimizing treatment in the decades to come.

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Brain metastasis from sarcomas 409 23 Perry JR, Bilbao JM: Metastatic alveolar soft part sarcoma presenting as a dural-based cerebral mass. Neurosurgery 1994; 34: 168 –170. 24 Ho KL: Sarcoma metastatic to the central nervous system: report of three cases and review of the literature. Neurosurgery 1979; 5: 44 – 48. 25 Olivi A, Donehower RC, Mann RB, et al.: Solitary, isolated metastasis from Ewing’s sarcoma to the brain: case report. Surg Neurol 1991; 35: 239–243. 26 Ahola DT, Provenzale JM, Longee DC: Metastatic rhabdomyosarcoma presenting as intracranial hemorrhage: imaging ﬁndings. Eur J Radiol 1998; 26: 241–243. 27 Mineura K, Yasuda T, Suda Y, et al.: Ewing’s sarcoma with intracranial metastasis presenting depressed cerebral blood ﬂow and metabolism in the contralateral gray matter. Comput Med Imaging Graph 1989; 13: 185 –190. 28 Simpson RK Jr, Bruner JM, Leavens ME: Metastatic Ewing’s sarcoma to the brain: case report and review of treatment. Surg Neurol 1989; 31: 234 –238. 29 Ho KL: Solitary pontine metastasis of sarcoma. Neurology 1980; 30: 348. 30 Kearney MM, Soule EH, Ivins JC: Malignant ﬁbrous histiocytomas: a retrospective study of 167 cases. Cancer 1980; 45: 167–178. 31 Weiss SW, Enzinger FM: Malignant ﬁbrous histiocytoma: an analysis of 200 cases. Cancer 1987; 41: 2250–2266. 32 Nikaido Y, Kawai S, Hisanaga M, et al.: Malignant histiocytoma with brain metastasis. Neurol Med Chir (Tokyo) 1986; 26: 628 – 633. 33 Biegal JA, Perilongo G, Rourke LB, et al.: Malignant ﬁbrous histiocytoma of the brain in a six year old girl. Genes Chrom Cancer 1992; 4: 309 –313. 34 Canalis RF, Green M, Konard HR, et al.: Malignant ﬁbrous xanthoma (xanthoﬁbrosarcoma) of the larynx. Arch Otolaryngol 1975; 101: 135 –137. 35 Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Cancer 1995; 75: 2186 –2195. 36 Crist W, Gehan EA, Ragab AH: The third intergroup rhabdomyosarcoma study. J Clin Oncol 1995; 13: 610 – 630. 37 Raney BR, Tefft M, Maurer HM, et al.: Disease patterns and survival rate in children with metastatic soft-tissue sarcoma. A report from the Intergroup Rhabdomyosarcoma Study (IRS)-1. Cancer 1988; 62: 1257–1266. 38 Sotelo-Avila C, Gonzalez-Crussi F, deMello D, et al.: Renal and extrarenal rhabdoid tumors in children: a clinicopathologic study of 14 patients. Semin Diagn Pathol 1986; 3: 151–163. 39 Horowitz ME, Etcubanas E, Webber BL, et al.: Hepatic undifferentiated (embryonal) sarcoma and rhabdomyosarcoma in children. Results of therapy. Cancer 1987; 59: 396 – 402. 40 Andersen-Ranberg F, Helmer-Hansen HB. Alveolar rhabdomyosarcoma with cerebral and cerebellar metastases and subarachnoidal bleeding: a case report. Clin Neuropathol 1987; 6: 120–122. 41 Dyment PG, Rothner AD, Duchesneau PM, et al.: Computerized tomography in the detection of intracranial metastases in children. Pediatrics 1976; 58: 72–77. 42 Wronski M, de Palma P, Arbit E: Leiomyosarcoma of the uterus metastatic to brain: a case report and a review of the literature. Gynecol Oncol 1994; 54: 237–241. 43 Adachi M, Wellmann KF, Garcia R: Metastatic leiomyosarcoma in brain and heart. J Pathol 1969; 98: 294–296. 44 Ziyal IM, Musluman M, Bejjani GK, et al.: Cerebral metastasis of a uterine leiomyosarcoma acase report. Neurol Med Chir (Tokyo). 1999; 39: 238 –241. 45 Feeney JJ, Popek EJ, Bergman WC: Leiomyosarcoma metastatic to the brain: case report and literature review. Neurosurgery 1985; 16: 398 – 401.

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46 Vaquero J, Martinez R, el Barkani A, et al.: Leiomyosarcoma metastatic to the brain with prolonged survival. J Neurosurg Sci 1989; 33: 291–292. 47 Lev-Chelouche D, Nakache R, Soffer D, et al.: Metastases to the retroperitoneum in patients with extremity soft tissue sarcoma: an unusual metastatic pattern. Cancer 2000; 88: 364–368. 48 Lieberman PH, Foote FW, Stewart FW, et al.: Alveolar soft-part sarcoma. JAMA 1966; 198: 121–125. 49 Lieberman PH, Brennan MF, Kimmel M, et al.: Alveolar soft-part sarcoma. A clinicopathologic study of half a century. Cancer 1989; 72: 1919 –1051. 50 Mukai M, Torikata C, Kageyama K, et al.: Alveolar soft-part sarcoma. A review of its histogenesis and further studies based on electron microscopy, immunohistochemistry, and biochemistry. Am J Surg Pathol 1983; 7: 679 – 689. 51 Christopherson WM, Foote FW, Steward FW: Alveolar soft-part sarcomas: structurally characteristic tumors of uncertain histogenesis. Cancer 1952; 5: 100 –111. 52 Potter DA, Glenn J, Kinsella T, et al.: Patterns of recurrence in patients with high grade soft tissue sarcoma. J Clin Oncol 1985; 3: 353 –366. 53 Wang CH, Lee N, Lee LS: Successful treatment for solitary brain metastasis from alveolar soft part sarcoma. J Neurooncol 1995; 25: 161–166. 54 Lillehei KO, Kleinschmidt-DeMasters B, Mitchell DH, et al.: Alveolar soft part sarcoma: an unusually long interval between presentation and brain metastasis. Hum Pathol 1993; 24: 1030–1034. 55 Posner JB: Management of brain metastasis. Rev Neurol 1992; 148: 477– 487. 56 Voorhies R, Sundaresan N, Thaler T: The single supratentorial lesion: an evaluation of preoperative diagnostic tests. J Neurosurg 1980; 53: 364 – 368. 57 Shuper A, Cohen IJ, Mor C, et al.: Metastatic brain involvement in Ewing family of tumors in children. Neurology 1998; 51: 1336 –1338. 58 Mark RJ, Sercarz JA, Tran L, et al.: Osteogenic sarcoma of the head and neck. The UCLA experience. Arch Otolaryngol Head Neck Surg 1991; 117: 761–766. 59 Marina NM, Pratt CB, Shema SJ, et al.: Brain metastases in osteosarcoma. Report of a longterm survivor and review of the St. Jude Children’s Research Hospital experience. Cancer 1993; 71: 3656–3660. 60 Wexler LH, DeLaney TF, Saris S, et al.: Long-term survival after central nervous system relapse in a patient with osteosarcoma. Cancer 1993; 72: 1203 –1208. 61 Giuliano AE, Feig S, Eilber FR: Changing metastatic patterns of osteosarcoma. Cancer 1984; 54: 2160–2164. 62 Baram TZ, van Tassel P, Jaffe NA: Brain metastases in osteosarcoma: incidence, clinical and neuroradiological ﬁndings and management options. J Neurooncol 1988; 6: 47–52. 63 Ashkan K, Pollock J, Corrado D, et al.: Intracranial osteosarcoma: report of four cases and review of the literature. J Neurooncol 1998; 40: 87–96. 64 Danziger J, Wallace S, Handel SF, et al.: Metastatic osteogenic sarcoma to the brain. Cancer 1979; 43: 707–710. 65 Hirota T, Konno K, Fujimoto T, et al.: Unusual late extrapulmonary metastasis in osteosarcoma. Pediatr Hematol Oncol 1999; 16: 545 –549. 66 Mehta Y, Hendrickson FR: CNS involvement in Ewing’s sarcoma. Cancer 1974; 33: 859–862. 67 Vlasak R, Sim F: Ewing’s Sarcoma. Orthop Clin North Am 1996; 27: 591– 603. 68 Ewing’s Family of Tumors Including Primitive Neuroectodermal Tumor (PNET). CancerNet, PDQ, published by the National Cancer Institute. (http://cancernet.nci.nih.gov/, accessed October 2, 2001)

Brain metastasis from sarcomas 411 69 Colak A, Berker M, Ozcan OE, et al.: CNS involvement in Ewing’s sarcoma: a report of 12 cases. Acta Neurochir (Wien) 1991; 113: 48 –51. 70 Parasuraman S, Langston J, Rao BN, et al.: Brain metastases in pediatric Ewing sarcoma and rhabdomyosarcoma: the St. Jude Children’s Research Hospital experience. J Pediatr Hematol Oncol 1999; 21: 370 –377. 71 Trigg ME, Makuch R, Glaubiger D: Actuarial risk of isolated CNS involvement in Ewing’s sarcoma following prophylactic cranial irradiation and intrathecal methotrexate. Int J Radiat Oncol Biol Phys 1985; 11: 699 –702. 72 Biousse V, Newman NJ, Eggenberger E, et al.: Intracranial Ewing’s sarcoma. J Neuroophthalmol 1998; 18: 187–191. 73 Turgut M, Colak A, Gurcay O: Multiple intracranial metastases with skull and scalp involvement in Ewing’s sarcoma. Cent Afr J Med 1994; 40: 104 –106. 74 Doval DC, Pavithran K, Acharya RS, et al.: Ewing’s sarcoma with central nervous system metastasisareport of two cases. Indian J Cancer 1997; 34: 26 –29. 75 Joensuu H, Roberts PJ, Sarlamno-Rikola M, et al.: Effect of the tyrosine kinase inhibitor STI-571 in a patient with metastatic gastrointestinal stromal tumor. N Engl J Med 2001; 34: 1052–1056. 76 Cortes EP, Holland JF, Wang JJ, et al.: Adriamycin in 87 patients with osteosarcoma. Cancer Chemother Rep 1975; 6: 305 –313. 77 Pratt CB, Horowitz ME, Meyer WH, et al.: Phase II trial of ifosfamide in children with malignant solid tumors. Cancer Treat Rep 1987; 71: 131–135. 78 Haft H, Wang GC: Metastatic liposarcoma of the brain with response to chemotherapy: case report. Neurosurgery 1988; 23: 777–780. 79 Bindal RK, Sawaya R, Leavens ME, et al.: Surgical treatment of multiple brain metastases. J Neurosurg 1993; 79: 210 –216. 80 Sloan AE, Fontanessi J: Stereotactic radiosurgery for sarcomatous brain metastasis. (Submitted). 81 Alexander E, Loefﬂer J: Radiosurgery using a modiﬁed linear accelerator. Neurosurg Clin N Am 1992; 3: 167–190. 82 Smeele LE, Kostense PJ, van der Waal I, et al.: Osteosarcoma: a systematic review of 201 patients. J Clin Oncol 1997; 15: 363–367.

PA RT IV

Special considerations

CHAPTER 24

Metastatic tumors of the skull base Fadi Hanbali, Franco DeMonte

The management of tumors involving the skull base is complex due to the density of critical neurovascular structures, the proximity of these structures to the relatively contaminated spaces of the paranasal sinuses or the ear and mastoid, the varied pathological entities encountered, and because the anatomy is relatively unfamiliar1. Various types of tumors involve the skull base. All cause symptoms by either invasion or compression of the cranial nerves as they exit through the basal foramina2. Benign tumors are by far the most common tumors of the skull base. Metastatic lesions to the basal cranium, in contrast, are among the least common3. Patients with cranial base metastases usually present with cranial neuropathies, although headache or pain is not uncommon4. Table 24.1 summarizes the histological types of tumors that may involve the cranial base.

Incidence The true incidence of skull base metastases is not known. They are certainly rare among skull base tumors reported in surgical series. Jackson et al., reporting on 97 patients with malignant tumors of the skull base, included metastases in a subgroup labeled “rare tumors” that represented less than 8% of the

Table 24.1 Classiﬁcation of cranial base tumors*.

Benign tumors Meningioma Schwannoma Hemangioma Paraganglioma Pituitary adenoma Epidermoid cyst Juvenile angioﬁbroma Fibrous dysplasia Cholesterol granuloma

Intermediate malignant tumors (low grade, slow growing)

Highly malignant tumors (fast growing)

Chordoma Chondrosarcoma Low grade esthesioneuroblastoma Adenoid cystic carcinoma

Carcinoma Sarcoma High grade esthesioneuroblastoma Lymphoma Myeloma Metastasis

*From Morita et al. Current concepts in the management of tumors of the skull base. Cancer Control 1998; 5: 1403.

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Table 24.2 Metastases to the base of the skull: localization*. Site of metastasis

Primary Tumor

N

Orbit

Parasellar

Middle fossa

Jugular foramen

Occipital condyle

Breast Lung Prostate Head and Neck Lymphoma Miscellaneous Total

17 6 5 6 3 6 43

2 1 0 0 0 0 3

2 1 2 0 1 1 7

7 2 1 2 1 2 15

2 1 1 4 0 1 9

4 1 1 0 1 2 9

*From Greenberg et al. Metastasis to the base of the skull: clinical ﬁndings in 43 patients. Neurology 1981; 3: 5316.

total cases5. Of 734 patients with cranial base tumors treated at The George Washington University Medical Center between 1993 and 1997, metastatic tumors accounted for less than 0.55% of the patients3. A better appreciation of the rarity of skull base metastases can be gleaned from reports from centers that treat a large population of patients with malignancy. Greenberg et al. at Memorial Sloan-Kettering Cancer Center identiﬁed breast, lung, prostate, and head and neck carcinomas as the most common malignancies to metastasize to the skull base (Table 24.2)6 – 8. Hall et al. noted a 0.13% incidence of cranial neuropathy due to osseous metastases in 7,725 new patients with carcinoma of the breast evaluated at The University of Texas M. D. Anderson Cancer Center (M. D. Anderson)9. Sagoh et al. noted a 4% incidence of metastatic lesions to the skull base from other locations10. Reports of metastases to speciﬁc anatomic sites can supply further incidence data. Belal reviewed 703 temporal bones from 357 patients and found a 3% incidence of temporal bone metastasis in the general population11. Jung and colleagues reported metastasis to the temporal bone in approximately 24% of 249 temporal bones taken from patients with a history of malignancy12. GloriaCruz et al. examined 415 temporal bones from 212 patients with primary nondisseminated malignant neoplasms and showed that 22.2% of these had cancer cells characteristic of the primary tumor13. The breast and lung were the most common primary sites11, 13, 14. In a series of 877 consecutive cases of orbital neoplasms examined histopathologically at the Institute of Ophthalmology in New York, Reese noted an incidence of metastatic carcinoma of about 3%15. A similar incidence was reported by Zizmor et al. in 200 cases of unilateral exophthalmos16. The breast and the lung were the most common primary tumor sites, followed by the genitourinary tract and the gastrointestinal tract17. Paranasal sinus metastasis may become symptomatic before the primary tumor is diagnosed in 50% to 65% of cases18 –20. At other times, metastasis to the

Metastatic tumors of the skull base 417

paranasal sinuses is diagnosed many years after treatment of the primary tumor20, 21. Renal cell carcinoma is by far the most common primary tumor metastasizing to the paranasal sinuses, with tumors from lung, breast, and the remainder of the urogenital tract and the gastrointestinal tract following distantly20, 22. The maxillary sinus is the most common site of metastasis, accounting for almost 50% of all metastases to the nose and the paranasal sinuses. The maxillary sinus is followed, in decreasing order of frequency, by the ethmoid sinus, frontal sinus, nasal cavity, and sphenoid sinus20. Mickel et al. reported on seven patients with metastatic disease to the sphenoid sinus, with the prostate and the lung being the most frequent primary tumor sites23.

Pathophysiology Blood-borne emboli may reach the basal cranium through small arteries that freely anastomose and branch at the neural foramina, and tumor-derived factors enhance invasion of the thick arterial walls5. Batson’s plexus of veins has also been incriminated in the dissemination of tumor emboli. With increased intra-abdominal and intrathoracic pressure, blood is shunted through the valveless vertebral, prevertebral, and epidural veins to reach the basilar plexus of veins without transiting through the lungs5, 24, 25. This plexus of veins is continuous with the venous plexi of the basicranium. Tumors may also extend from adjacent regions such as the paranasal sinuses, external ear, and nasopharynx. Although these may not represent true metastases, they can either invade the cranial nerves or compress them, accounting for a signiﬁcant proportion of secondary skull base neoplasms. Neural foramen invasion is a common complication of nasopharyngeal carcinoma occurring in about 15% to 35% of patients2, 5, 26, 27. Other pathways of tumor extension include the muscles attached to the skull base, the ﬁbrofatty spaces between these muscles, and along the neurovascular bundles, speciﬁcally along the perineural spaces28, 29, 30.

Diagnosis The development of a cranial neuropathy in patients with known neoplasia is a strong indication of metastasis. Other malignant disorders, however, including leptomeningeal carcinomatosis, basilar meningitis, and metastasis to the brain stem and cerebellum may cause the same clinical picture but require different therapy6. Examination of the cerebrospinal ﬂuid for tumor cells is essential. High opening pressure and elevated protein may be present5. If the spinal ﬂuid is normal, skull base metastasis becomes the most likely cause of the multiple cranial neuropathies. Plain radiograms of the cranial base may show evidence of bone erosion, but interpretation is often difﬁcult and these examinations have a low yield31, 32. Most metastatic tumors to the skull base produce lytic lesions, with the exception of prostate and lung cancers that may produce either lytic or blastic lesions5, 8.

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Figure 24.1 Axial computed tomogram, set at bone window, reveals destruction of the left anterior clinoid process. (Arrows) This focal destruction was caused by a metastatic renal cell carcinoma (see Figure 24.2).

Figure 24.2 Coronal T1-weighted, postcontrast MR image clearly depicts a large renal cell carcinoma metastasis in the ethmoid sinus. There is extension of the tumor into the left orbit, displacing the periorbital fat, and into the anterior cranial fossa.

Computed tomography (CT) scans with high spatial resolution, bone algorithm, and bone windowing are ideal for outlining subtle osseous destruction or sclerosis of the skull base (Figure 24.1). Bone window and threedimensional CT scans are helpful in determining the surgical approach3, 5, 32, 33. Magnetic resonance (MR) imaging is superior to CT for deﬁning the soft tissue component of metastases and for delineating invasion of cranial nerves, the underlying dura, leptomeninges, and brain (Figure 24.2)5, 31, 34. In the presence of negative cerebrospinal ﬂuid studies and inconclusive CT and MR image analysis, other imaging modalities may be required in order to establish the diagnosis in patients where a high index of suspicion of a skull base metastasis remains. Radionuclide scanning is the most sensitive method of detecting skull base metastasis2, 4 – 6. About 30% to 50% of lesions seen on the bone scans are not identiﬁed on other radiographic studies35 –37. One major drawback of bone scintigraphy is the increased activity associated with conditions such as sinusitis, mastoiditis, or temporomandibular joint arthrosis.

Metastatic tumors of the skull base 419

Bone single photon emission computed tomography (SPECT) offers a considerable advantage compared with planar bone scintigraphy because superimposed activity of adjacent structures is eliminated, and transaxial, coronal, and sagittal sections improve localization value in the complex anatomy of the skull base and allow better discrimination between inﬂammatory and malignant skull base diseases4, 38 – 40. Angiography is being replaced by MR angiography and three-dimensional CT angiography as a means of determining the major arterial and venous anatomy. Angiograms remain superior, however, in identifying the vascular anatomy and blood supply to the tumor, and are necessary if tumor embolization or surgical manipulation of major vessels should be indicated3.

Clinical ﬁndings Metastases to the skull base become symptomatic by affecting the neurovascular structures exiting the foramina at the basicranium. Cranial neuropathies may be the ﬁrst sign of cancer that originates elsewhere in the body41– 43. They may also be a manifestation of metastatic disease years after a cancer has been successfully treated2, 44. Invasion of bone by a metastatic tumor is the most common cause of pain, and such pain usually precedes neurological signs and symptoms by weeks5. Several clinical syndromes have been reported describing the entrapment of one or more cranial nerves at different sites in the skull base (Table 24.3).

Orbital syndrome Tumors usually metastasize to the skull and grow into the orbit or, in rare cases, metastasize directly to the soft tissues of the orbit itself2, 45. Orbital metastases usually occur with carcinoma of the breast, lung, and prostate in a decreasing order of frequency2, 6, 17, 43. Greenberg reported a 2.5% incidence of orbital metastasis out of 213 patients examined for eye disorders6. Font documented 28 patients with orbital metastasis out of 235 patients with metastases to the eye, an incidence of 11.9%17. A progressive, dull, continuous pain in the supraorbital area is usually the ﬁrst manifestation of an orbital metastasis2, 6, 43. According to Henderson, slowly increasing orbital pain is an early feature in metastatic orbital disease, not observed with other orbital neoplasms46. The ﬁrst symptom other than pain is usually proptosis of the involved eye, accompanied by some degree of external ophthalmoplegia (Figure 24.3). Other prominent symptoms include blurred binocular vision, periorbital swelling and tenderness, palpable intraorbital mass, and decreased vision2, 6, 17. Decreased vision, visual ﬁeld cuts, and papilledema rarely occur until very late in the disease course, probably because the tumors grow into the orbit from bone and do not invade the muscle cone where the optic nerve is located6, 47. Many patients have decreased sensation along the ophthalmic division of the trigeminal nerve. Enophthalmos, rarely reported, is most typically associated with scirrous carcinoma of the breast17, 48.

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Table 24.3 Manifestations of the various syndromes Involved in skull base metastases. Location

Syndrome

Neural Structures

Manifestations

Anterior skull base

Orbital

Extraocular muscles CN III, IV, V1 and VI

• • • • • • •

Middle skull base

Parasellar (sphenocavernous)

CN III, IV, V1 and VI

• Unilateral frontal headache • No proptosis • No visual loss • Ocular paresis • Periorbital edema • Diplopia • Papilledema • Facial pain/numbness along cranial nerve V1, 2

Gasserian Ganglion

CN V (all branches, sensory and motor) Possible CN III, IV, VI, VII

• Numbness, paresthesias and pain along cranial nerve V2, 3 • Unilateral pterygoid and/or masseter weakness • Abducens weakness

Temporal bone

Middle ear CN VII, VIII

• • • •

Jugular foramen

CN IX, X, XI, XII

• Unilateral occipital/post-auricular pain • Dysphagia • Hoarseness • Weakness of palate, vocal cord paralysis, SCM/ trapezius atrophy, tongue atrophy, Horner’s syndrome

Occipital condyle

CN XII

• • • • •

Posterior skull base

Supraorbital and orbital pain Blurred vision Proptosis No diplopia External ophthalmoplegia Enophthalmos Periorbital swelling and tenderness

Hearing loss Otalgia Periauricular swelling Facial paresis

Occipital pain Neck stiffness/pain Dysarthria Dysphagia Ipsilateral tongue weakness

CN, cranial nerve(s); SCM, sternocleidomastoid.

Parasellar or sphenocavernous syndrome This syndrome is usually secondary to metastases to either the petrous apex or the sella turcica with extension into the cavernous sinus49. It may less commonly be due to a direct metastasis to the cavernous sinus. Cavernous sinus involvement is usually unilateral, but may be bilateral2, 50. The parasellar syndrome manifests as a unilateral frontal supraorbital headache and ocular

Metastatic tumors of the skull base 421

Figure 24.3 Axial T1-weighted, post-contrast MR image of the patient shown in Figure 24.2. This renal cell metastasis to the ethmoid sinus has extended into the orbit, producing proptosis and ophthalmoplegia.

paresis. The periorbital swelling is usually more prominent than in the orbital syndrome because the orbital veins draining into the cavernous sinus may be compressed or occluded. Proptosis, however, if present, is less. Diplopia usually evolves rapidly or abruptly31. One or both of the oculomotor or abducens nerves are most frequently involved as they traverse the cavernous sinus. Sometimes the ophthalmic division, and rarely the maxillary division, of the trigeminal nerve is involved. Some patients complain of numbness, hypesthesia, or continuous painful dysesthesia of the face not typical of trigeminal neuralgia2, 6, 32. The parasellar syndrome is relatively common in patients with systemic cancer. Roessmann et al.51 reported 16 parasellar bony lesions (27%) in a postmortem examination of 60 consecutive cases of carcinoma; nine were due to breast cancer. Metastatic carcinoma accounted for 23 cases out of 102 patients (25%) with parasellar syndrome described by Thomas and Yost49. Breast, prostate, or lung primaries were typically responsible.

Middle fossa (Gasserian ganglion) syndrome Numbness, paresthesias, and pain referred to the trigeminal nerve distribution are the typical presenting complaints of the middle fossa or Gasserian ganglion syndrome. The numbness or sensory loss usually begins close to the midline on the upper lip or chin and progresses laterally to the anterior part of the ear. Pain consists of either a dull ache in the cheek, jaw, or forehead, or lightning-like pain similar to trigeminal neuralgia. Trigeminal neuralgia, on the other hand, is distinguished from this syndrome by the absence of sensory loss. Headache rarely forms part of this syndrome. In Greenberg’s series, it was reported in 28% of the cases, compared with 83% of patients with the parasellar syndrome6. The symptoms may be present for two weeks to 1 year before diagnosis, with a median interval of about three weeks. At the time of diagnosis, there is usually sensory loss in the distribution of one or more of the trigeminal nerves in almost all patients, with some evidence of dysfunction of the motor root as well. Obvious weakness of the pterygoids or the masseter

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muscles may not be present; electromyography, however, may show evidence of denervation. Ocular muscle paresis may also be present. Tumor extension beyond the Gasserian ganglion and over the anterior surface of the petrous ridge may compress the abducens nerve in Dorello’s canal. Tumor propagation medially into the parasellar area may involve other ocular motor nerves. Growth along the posterior ridge of the petrous bone may compress the facial nerve52. Of 15 patients with the metastatic middle fossa syndrome, four had an isolated abducens nerve palsy, another four had a combination of extraocular palsies, and three had involvement of the facial nerve6.

Temporal bone syndrome Metastasis to the temporal bone is typically of hematogenous origin. The vascular channels of the petrous apex marrow ﬁlter out tumor cells in the circulation and provide a suitable environment for proliferation. Metastatic involvement of the pneumatized portions is not uncommon and the mastoid airspaces can become ﬁlled with metastatic deposits, which at times extend into the middle ear cleft13, 14, 53. Hearing loss is the most common manifestation of temporal bone metastasis and is characteristically of the conductive type. It is present in about 30–40% of symptomatic patients. It is almost always due to dysfunction of the eustachian tube and secondary otitis media13, 53, 54. A sensorineural hearing loss, if it occurs, is usually due to either compression or destruction of the cochlear ﬁbers in the internal auditory meatus54. Tumors in the petrous apex are asymptomatic until extension occurs into areas that cause otologic dysfunction or pain. Maddox emphasized the triad of symptoms of otalgia, periauricular swelling, and facial nerve paresis as being the most suspicious for malignant involvement of the temporal bone52. He reported an incidence of facial nerve paralysis of 34% in his series. Schuknecht and coworkers also reported a high incidence of facial palsy55. Saito and coworkers found that only 50% of patients with invasion of the facial canal manifested facial paralysis, whereas 100% of those who had tumors extending beyond the epineural sheath had complete paralysis56. Much less frequent ﬁndings are otorrhea, vertigo, tinnitus, or a middle ear effusion. The inner ear seems resistant to invasion by tumors. The otic capsule may be involved with tumor approaching the endosteum, but the cochlea is rarely invaded, and seldom is the membranous labyrinth affected13, 53.

Jugular foramen syndrome Patients with lesions of the jugular foramen usually present with a combination of cranial nerve palsies. The jugular foramen syndrome may include a unilateral occipital or postauricular pain and progressive hoarseness and/ or dysphagia. Signs include weakness of the palate, vocal cord paralysis, weakness and atrophy of the ipsilateral sternocleidomastoid muscle and the upper part of the trapezius, and occasionally a Horner’s syndrome. Papilledema has been reported as a result of compression of the sigmoid sinus

Metastatic tumors of the skull base 423

or the jugular vein by the tumor. Ipsilateral weakness and atrophy of the tongue is sometimes noted, indicating extension of the tumor to the hypoglossal nerve. Metastasis to the jugular foramen is the most common etiology of this syndrome2, 6, 57– 60.

Occipital condyle syndrome Metastasis to the area of the occipital condyle is more common than to the jugular foramen. The clinical picture is uniform. This syndrome is characterized by a continuous, severe, localized, unilateral occipital pain that worsens upon neck ﬂexion. The pain sometimes radiates towards the ipsilateral temporal area or eye and is often associated with a stiff neck. About half of the patients will complain of dysarthria, dysphagia, or both, speciﬁcally related to difﬁculty in moving the tongue. The ipsilateral tongue is atrophic, and sometimes fasciculations can be noted. Seven of nine patients with the occipital condyle syndrome in Greenberg’s series6 had the typical occipital pain, four had dysarthria, two had dysphagia, and all had ipsilateral tongue weakness. Symptoms usually precede diagnosis by two to 16 weeks before diagnosis, with a median of seven weeks2, 6.

Treatment The treatment of skull base metastases depends on the nature of the underlying tumor and its location. The available treatment modalities for cranial base metastases include surgical resection, irradiation, and/or chemotherapy. Recent technical advancements in the surgical therapy for primary skull base tumors occasionally make such approaches feasible in patients with a solitary metastasis2, 61, 62. Surgical patients should be critically selected based on their clinical status, the extent of primary and metastatic disease, pertinent radiographic studies, and the tumor’s biological nature. Small cell lung cancer, breast cancer, and prostate tumors are particularly sensitive to radiation and chemotherapy and/or hormone therapy. On the other hand, renal cell carcinoma and melanoma are relatively radioresistant and other modalities of treatment should be considered5. Only the minority of patients with skull base metastases, however, are candidates for surgical resection. Over the past eight years, only eight patients have undergone resection of skull base metastases at M. D. Anderson (Table 24.4). Over the same time period, 347 other skull base tumor resections were performed (overall incidence of operations for skull base metastasis of 2.3%). Of these eight patients, the diagnosis of skull base metastasis was established preoperatively in six. In the patients with metastatic carcinoma of the breast and thyroid, a preoperative presumptive diagnosis of meningioma had been made (Figure 24.4). Five of the eight patients experienced local tumor recurrence, with the mean time to recurrence being a mere 3.9 months (range, 1.5–8 months). Three patients remained free of recurrence at a mean of 19 months post resection (range 13–28 months). These results are generally disappointing. The local control rate has

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Table 24.4 Patients with metastases to the skull base treated surgically at M. D. Anderson (November 1992–December 2000). Reason for operation

Adjuvant therapy

Time to recurrence

Frontal and ethmoid sinuses, orbit

Progressive proptosis

None

3 months

Renal cell carcinoma

Anterior clinoid

Progressive optic neuropathy

5-Fu, alpha- Stable disease interferon, at 13 months fractionated stereotactic radiation

3

Leiomyosarcoma

Orbit, frontal bone

Progressive proptosis

None

NED at 16 months

4

Ductal carcinoma Sella of breast

Progressive optic neuropathy, bilateral

None

Died at 2 months

5

Melanoma

Orbit, ethmoid sinus

Progressive local recurrence following maxillectomy

None

1.5 months

6

Follicular carcinoma of thyroid

Orbit, greater wing of sphenoid bone

Progressive proptosis

I131, NED at suppression 28 months therapy

7

Mesenchymal chondrosarcoma

Infratemporal fossa

Massive None disease, pain, temporomandibular joint dysfunction

8 months

8

Renal cell carcinoma

Frontal and ethmoid sinuses, orbit

Progressive diplopia

5 months

Pt no.

Pathology

Location

1

Renal cell carcinoma

2

None

Pt, patient; 5-Fu, 5-ﬂuorouracil; NED, no evidence of disease.

been quite poor for the patients with malignant epithelial tumors such as renal cell carcinoma and melanoma. An exception is the patient with follicular carcinoma of the thyroid. These patients probably represent a more favorable group in which to consider surgical resection. Very effective postsurgical therapy is available with radioactive iodine and thyroid suppression. Another category of patients that should be considered for surgical resection is those with metastatic sarcomas, especially those of low or intermediate grade. Of the two patients with metastatic sarcomas operated upon by the senior author, one patient remained free of local disease 16 months after surgery, whereas the patient with metastatic mesenchymal chondrosarcoma achieved local control for eight months initially, and a further six months after re-resection (Figure 24.5).

Metastatic tumors of the skull base 425

(A)

(B) Figure 24.4 (A) Axial T1-weighted, post-contrast, fat-suppressed MR image reveals a homogeneously contrast-enhancing mass affecting the greater wing of the sphenoid bone. The imaging features of this tumor were most characteristic for a diagnosis of meningioma of the greater sphenoid wing. At the time of surgery this was discovered to be a metastatic follicular carcinoma of the thyroid. (B) Total excision of the tumor, including its intracranial and intraorbital components, was accomplished and is identiﬁed on this axial T1-weighted, post-contrast, fat-suppressed MR image.

In most cases, however, conventional fractionated radiotherapy remains the primary treatment for malignant tumors of the skull base. Vikram noted a 78% improvement of symptoms in 46 patients with skull base metastases treated with conventional fractionated radiation, with a 90% response rate among those who received a total dose of 3,600 rads63. When treatment is delivered early, symptomatic relief can be expected in most patients6, 63.

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(A)

(B) Figure 24.5 (A) Coronal T1-weighted, post-contrast MR image reveals a large tumor within the right infratemporal fossa. This mesenchymal chondrosarcoma was resected via a preauricular infratemporal fossa approach. (B) Coronal T1-weighted, post-contrast MR image of the same patient after gross total resection of the tumor. Local control was achieved for eight months.

Table 24.5 Recent series of patients treated with radiosurgery for metastases to the skull base.

Authors (reference)

Number of patients

Radiosurgery type

Median dose (Gy)

Median F/U (months)

Tumor control (%)

Iwai and Yamanaka66 Miller et al.67 Kocher et al.68 Cmelak et al.69

8 32 13 47

GK GK LAC LAC

16.2 15 15 20

10.5 27.6 22.6 9

67 91 77 69

GK, Gamma Knife; LAC, linear accelerator; F/U, follow-up period.

The effectiveness of stereotactic radiosurgery in the treatment of tumors of the skull base has been well-documented64, 65. Iwai reported a 67% tumor control rate and a 61% improvement of cranial neuropathies in 18 patients with skull base metastases, with a median follow-up interval of 10.5 months66. Miller et al. treated 32 patients with malignant skull base tumors that were 4 cm or less in maximum diameter. Local control of tumor was excellent, and relief of symptoms was achieved in a majority of patients. At a median followup interval of 2.3 years, 75% of the patients remained alive, 41% had stable disease, 28% had partial regression, 22% had complete resolution of the disease, and 9% had tumor progression67. Similar ﬁndings were reported by Kocher68 and Cmelak (Table 24.5)69. Radiosurgery is a reasonable treatment modality for selected patients with skull base recurrences and metastases, particularly in patients who are inoperable because of lesion location, medical contraindications, or refusal to undergo surgery. Early results suggest that radiosurgery provides good tumor control with complications comparable to standard

Metastatic tumors of the skull base 427

radiotherapy. Patients with larger lesions near sensitive structures or in previously irradiated ﬁelds might beneﬁt from fractionated stereotactic radiation techniques.

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22 Batsakis JG: The pathology of head and neck tumors: the occult primary and metastases to the head and neck, Part 10. Head Neck Surg 1981; 3: 409 – 423. 23 Mickel RA, Zimmerman MC: The sphenoid sinusaa site for metastasis. Otolaryngol Head Neck Surg 1990; 102: 709 –716. 24. Batson OV: The function of the vertebral veins and their role in the spread of metastases. 1940 [classical article]. Clin Orthop 1995; Issue 312: 4 –9. 25 Delattre JY, Krol G, Thaler HT, et al.: Distribution of brain metastases. Arch Neurol 1988; 45: 741–744. 26 Turgman J, Braham J, Modan B, et al.: Neurological complications in patients with malignant tumors of the nasopharynx. Eur Neurol 1978; 17: 149 –154. 27 Thomas J, Waltz AG: Neurologic manifestations of nasopharyngeal carcinoma. JAMA 1965; 192: 103–106. 28 Vignaud J, Pharabaz C, Mourag M: Tumors of the skull base. In: Portman M (ed). Rhinootological Microsurgery of the Skull Base. Edinburgh, Churchill Livingstone, 1995, pp. 40–65. 29 Ginsberg LE, DeMonte F: Imaging of perineural tumor spread from palatal carcinoma. AJNR Am J Neuroradiol 1998; 19: 1417–1422. 30 Ginsberg LE, DeMonte, F: Palatal adenoid cystic carcinoma presenting as perineural spread to the cavernous sinus. Skull Base Surgery 1998; 8: 39 – 43. 31 Bumpous JM, Maves MD, Gomez SM, et al.: Cavernous sinus involvement in head and neck cancer. Head Neck 1993; 15: 62– 66. 32 Bitoh S, Hasegawa H, Ohtsuki H, et al.: Parasellar metastases: four autopsied cases. Surg Neurol 1985; 23: 41–48. 33 Morita A, Piepgras DG: Tumors of the skull base. In: Vecht CJ (ed). Handbook of Clinical Neurology: Neurooncology, Part I. Amsterdam, Elsevier Science, 1997, pp. 1–32. 34 Delpassand ES, Kirkpatrick JB: Cavernous sinus syndrome as the presentation of malignant lymphoma: case report and review of the literature. Neurosurgery 1988; 23: 501–504. 35 McNeil BJ: Rationale for the use of bone scans in selected metastatic and primary bone tumors. Semin Nucl Med 1978; 8: 336 –345. 36 Krishnamurthy GT, Tubis M, Hiss J, et al.: Distribution pattern of metastatic bone disease. A need for total body skeletal image. JAMA 1977; 237: 2504 –2506. 37 Osmond JD, 3rd, Pendergrass HP, Potsaid MS: Accuracy of 99 mTC-diphosphonate bone scans and roentgenograms in the detection of prostate, breast and lung carcinoma metastases. Am J Roentgenol Radium Ther Nucl Med 1975; 125: 972–977. 38 Jansen BP, Pillay M, de Bruin HG, et al.: 99 mTc-SPECT in the diagnosis of skull base metastasis. Neurology 1997; 48: 1326 –1330. 39 Murray IP, Dixon J: The role of single photon emission computed tomography in bone scintigraphy. Skeletal Radiol 1989; 18: 493 –505. 40 Collier BD, Jr, Hellman RS, Krasnow AZ: Bone SPECT. Semin Nucl Med 1987; 17: 247–266. 41 Massey EW, Moore J, Schold SC, Jr: Mental neuropathy from systemic cancer. Neurology 1981; 31: 1277–1281. 42 Rubinstein MK: Cranial mononeuropathy as the ﬁrst sign of intracranial metastases. Ann Intern Med 1969; 70: 49 –54. 43 Tijl J, Koornneef L, Eijpe A, et al.: Metastatic tumors to the orbitamanagement and prognosis. Graefes Arch Clin Exp Ophthalmol 1992; 230: 527–530. 44 Gupta SR, Zdonczyk DE, Rubino FA: Cranial neuropathy in systemic malignancy in a VA population. Neurology 1990; 40: 997–999. 45 Liu GT, Schatz NJ, Curtin VT, et al.: Bilateral extraocular muscle metastases in ZollingerEllison syndrome. Arch Ophthalmol 1994; 112: 451– 452.

Metastatic tumors of the skull base 429 46 Henderson J: Metastatic carcinoma. In: Henderson J (ed): Orbital Tumors. 2nd Ed. New York, Decker, 1980, pp. 451–471. 47 Arger PH, Mishkin MM, Nenninger RH: An approach to orbital lesions. Am J Roentgenol Radium Ther Nucl Med 1972; 115: 595 – 606. 48 Sacks JG, O’Grady RB: Painful ophthalmoplegia and enophthalmos due to metastatic carcinoma: simulation of essential facial hemiatrophy. Trans Am Acad Ophthalmol Otolaryngol 1971; 75: 351–354. 49 Thomas JE, Yoss RE: The parasellar syndrome: problems in determining etiology. Mayo Clin Proc 1970; 45: 617– 623. 50 Mills RP, Insalaco SJ, Joseph A: Bilateral cavernous sinus metastasis and ophthalmoplegia. Case report. J Neurosurg 1981; 55: 463 – 466. 51 Roessmann U, Kaufman B, Friede RL: Metastatic lesions in the sella turcica and pituitary gland. Cancer 1970; 25: 478 – 480. 52 Maddox HE, 3rd: Metastatic tumors of the temporal bone. Ann Otol Rhinol Laryngol 1967; 76: 149–165. 53 Berlinger NT, Koutroupas S, Adams G, et al.: Patterns of involvement of the temporal bone in metastatic and systemic malignancy. Laryngoscope 1980; 90: 619 – 627. 54 Saldanha CB, Bennett JD, Evans JN, et al.: Metastasis to the temporal bone, secondary to carcinoma of the bladder. J Laryngol Otol 1989; 103: 599 – 601. 55 Schuknecht HF, Allam AF, Murakami Y: Pathology of secondary malignant tumors of the temporal bone. Ann Otol Rhinol Laryngol 1968; 77: 5 –22. 56 Saito H, Chinzei K, Furuta M: Pathological features of peripheral facial paralysis caused by malignant tumour. Acta Otolaryngol Suppl 1988; 446: 165 –171. 57. Graus F, Slatkin NE: Papilledema in the metastatic jugular foramen syndrome. Arch Neurol 1983; 40: 816 – 818. 58. Rivers M, Svien HJ, Baker HL: Diagnostic principles in the Jugular Foramen syndrome. Surg Clin North Am 1963; 43: 1129 –1133. 59. Svien H, Baker HL, Rivers, MH: Jugular foramen syndrome and allied syndromes. Neurology 1963; 13: 797– 809. 60. DiChiro G, Fisher RL, Nelson KB: The jugular foramen. J Neurosurg 1964; 21: 447– 460. 61 Janecka IP, Sekhar LN: Surgical management of cranial base tumors: a report on 91 patients. Oncology (Huntingt) 1989; 3: 69 –74. 62 Jackson CG, Netterville JL, Glasscock ME, 3rd, et al.: Defect reconstruction and cerebrospinal ﬂuid management in neurotologic skull base tumors with intracranial extension. Laryngoscope 1992; 102: 1205–1214. 63 Vikram B, Chu FC: Radiation therapy for metastases to the base of the skull. Radiology 1979; 130: 465–468. 64 Tanaka T, Kobayashi T, Kida Y, et al.: The results of gamma knife radiosurgery for malignant skull base tumors. No Shinkei Geka 1996; 24: 235 –239. 65 Kondziolka D, Lunsford LD: Stereotactic radiosurgery for squamous cell carcinoma of the nasopharynx. Laryngoscope 1991; 101: 519 –522. 66 Iwai Y, Yamanaka K: Gamma Knife radiosurgery for skull base metastasis and invasion. Stereotact Funct Neurosurg 1999; 72: 81– 87. 67 Miller RC, Foote RL, Coffey RJ, et al.: The role of stereotactic radiosurgery in the treatment of malignant skull base tumors. Int J Radiat Oncol Biol Phys 1997; 39: 977–981. 68 Kocher M, Voges J, Staar S, et al.: Linear accelerator radiosurgery for recurrent malignant tumors of the skull base. Am J Clin Oncol 1998; 21: 18 –22. 69 Cmelak AJ, Cox RS, Adler JR, et al.: Radiosurgery for skull base malignancies and nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1997; 37: 997–1003.

CHAPTER 25

Neuropsychological impact of brain metastasis and its treatment Anne E Kayl, Christina A Meyers

Introduction Metastatic brain lesions are a common complication of systemic cancer1–3. Although some primary cancers (e.g., breast, lung, and melanoma) are more likely to do so, any solid tumor is capable of metastasizing to the brain4. By most estimates, 20–40% of cancer patients will develop metastatic brain disease during their illness, with the majority of these lesions occurring in patients who are 50 to 70 years old4 – 6. The effects of the metastatic tumor, its treatment, and other factors that have the potential to impact brain functioning and the patient’s quality of life can be differentiated by appropriate evaluation methods. The ﬁndings of such an evaluation may then be used to guide the institution of therapeutic and palliative intervention strategies. An appreciation of the cognitive deﬁcits and behavioral changes that may be associated with metastatic brain disease will aid intervention strategies, enhance patient care, and ultimately improve the overall quality of life for patients and their families.

Neurobehavioral changes due to metastatic brain tumors Whereas some lesions may only be discovered during a routine work-up for metastatic disease and remain “silent” throughout the patient’s life, the majority of brain metastases will become symptomatic4, 7. The signs and symptoms of metastatic tumors are the same as signs and symptoms of other expanding intracranial mass lesions. Thus, metastatic brain tumors have the potential to alter cognitive function, personality, and to affect psychological well-being. The patterns of neurobehavioral and cognitive changes attributable to metastatic brain lesions have not been as well studied as changes secondary to primary brain lesions, but some data are available for review. For example, we completed neuropsychological assessments of 55 patients with brain metastases (unpublished data). The majority of these patients carried a primary diagnosis of lung cancer, melanoma, renal cancer, or breast cancer. In most cases, patients had a single metastatic lesion. However, individuals with 430

Neuropsychological impact of brain metastasis and its treatment 431

multiple metastases were not excluded from the study. Impaired cognitive performance (deﬁned as a score greater than one standard deviation from the normative mean) was demonstrated on measures of ﬁne motor coordination speed (42% of patients), memory (free recall: 29%), and verbal ﬂuency (20%) prior to treatment for their brain disease. For reference, approximately 15% of persons in a normal control group would be expected to score within the impaired range, if a “cut-off” score of greater than one standard deviation is used. So, frequency rates of the magnitude observed in this study exceeded expectations due to normal interindividual variability. As in others with metastatic brain disease, in this group of patients the etiology of these impairments is unclear, but several factors are probably inﬂuencing their cognitive functioning. Among patients diagnosed with primary brain tumors, various factors underlie neurobehavioral changes, and the manifestations of this disease vary substantially between patients. However, some general comments regarding tumor-related and treatment-related factors and their impact on cognition are warranted.

Location Brain tumors, whether primary or metastatic, almost always cause deﬁcits of cognitive function. Metastatic tumors do not appear randomly in the brain, but have a tendency to develop along the gray- and white-matter junction of brain parenchyma where tumor emboli are likely to become lodged in narrowing blood vessels. The nature of the neuropsychological impairment observed in the individual patient is in part related to the site of the lesion. For instance, patients with left hemisphere tumors may have language disorders that impair the patient’s ability to communicate with others and to comprehend spoken or written language8. Tumors in the right hemisphere of the brain may cause deﬁcits in visual perception and visual scanning, resulting in impaired driving skills or the inability to navigate in familiar places9. Memory loss is often seen in association with tumors of either hemisphere. Impairments of frontal lobe function (executive deﬁcits manifested by impairments of cognitive ﬂexibility, abstraction, motivation, planning and organizational skills, ability to beneﬁt from experience, personality changes, etc.) are very common in brain tumor patients10–12. One obvious reason is that the frontal lobes comprise one-third of the cerebrum, so a large proportion of tumors are located here. However, many patients with nonfrontal tumors also exhibit executive deﬁcits13. This is due in part to the fact that the frontal lobes have rich afferent and efferent connections with all other brain regions. Thus, a lesion in a nonfrontal location will disconnect the frontal lobe from information from that region, and will also interrupt modulatory frontal inﬂuences on its function. The site of the metastatic brain lesion also has an impact on mood. Patients with tumors in ventromedial frontal or parietal association areas are more likely to experience anxiety, irritability, and fatigue than patients with lesions in other locations. Patients with lesions in dorsolateral frontal and

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somatosensory regions tend to exhibit emotional indifference or even euphoria14. In addition, tumor patients have been found to mimic nearly every psychiatric illness, such as obsessive-compulsive disorder and personality disorder15, 16.

Treatment of the metastatic lesion Cognitive dysfunction in the cancer patient with metastatic brain disease is often more generalized than might be expected for a focal lesion. This may be due to microscopic tumor inﬁltration, a high rate of tumor growth causing diaschisis, or to the adverse effects of treatment17. For example, Hochberg and Slotnick found diffuse cognitive difﬁculties that were unrelated to tumor type, location, other medical factors, or psychiatric factors, and were felt to be due to aggressive treatment for primary brain disease18. As is the case in the management of primary brain tumor patients, different adverse effects may arise during treatment of metastatic brain disease. These effects may be attributable to the use of steroids, radiation, chemotherapy, and adjunctive medications.

Steroids Patients with symptomatic brain metastases are initially treated with corticosteroids. This “ﬁrst line” treatment has the potential to decrease edema and greatly improve neurological function and performance status. Unfortunately, steroids may also have adverse effects on mental and emotional functioning. The incidence of steroid-induced psychiatric syndromes ranges from 5.7% to 50%19. Potential side-effects include euphoria, mania, insomnia, restlessness, and increased motor activity. Some patients become anxious and depressed. Steroids are also known to have adverse effects on memory, even in normal control subjects, and have been implicated in the pathophysiology of major depression and Alzheimer’s disease20, 21.

Surgery Surgical resection of the metastatic tumor also has the potential to rapidly relieve symptoms and improve patient functioning. The primary beneﬁts of surgery are similar to those associated with steroid administration (i.e., rapid reduction of intracranial pressure and compression). Surgery has another beneﬁt, however. Speciﬁcally, patients treated surgically may be managed on a lower steroid dose or for a shorter period of time in the postoperative period, thereby reducing the chances of cognitive impairment associated with those medications. Unfortunately, some metastatic lesions are not amenable to surgical resection. For example, the surgical resection of lesions in the basal ganglia, thalamus, and brain stem may result in signiﬁcant neurologic impairment7. Surgery remains an important treatment modality, however, because studies have demonstrated that surgical removal of brain metastases followed by postoperative radiation results in better local control of disease and improved quality of life than treatment with radiotherapy alone22, 23.

Neuropsychological impact of brain metastasis and its treatment 433

Whole-brain radiation therapy Whole-brain radiation therapy (WBRT) has been used in the management of metastatic brain lesions for many years and may be used as a primary therapy or after surgical resection or stereotactic radiosurgery. This treatment modality has several characteristics that make it appealing as a treatment for metastatic brain tumors. For example, WBRT is a relatively simple, noninvasive method of treating the entire brain, and its capacity to destroy small, microscopic metastatic deposits makes it well suited for use in patients with multiple brain metastases7. As an adjunctive treatment, this type of therapy has been used on patients treated with surgery or radiosurgery in an attempt to lessen the chances of tumor recurrence.

Adverse effects of radiation Although few studies have speciﬁcally focused on patients with metastatic brain tumors, studies have found brain irradiation to be associated with delayed brain injury and cognitive deﬁcits. Research conducted with patients diagnosed with primary brain tumors has shown that damage from radiation treatments may be evident several years after treatment24 and may be progressive and irreversible. The area of injury may present as an expanding mass of necrosis that is difﬁcult to distinguish from recurrent tumor, or as diffuse progressive white matter disease (leukoencephalopathy). Symptoms in adults generally include memory loss, gait disturbance, weakness, and tremor. Radiation causes injury to subcortical white matter, with larger treatment volumes causing more impairment25. Most neuropsychological studies of primary brain tumor patients tested before and after radiation therapy reveal signiﬁcant impairments of information-processing speed, executive functions, memory, sustained attention, and motor coordination in those with no evidence of disease recurrence9, 18, 26–30. Several studies have focused on memory deﬁcits as the primary adverse effect of radiation therapy in brain tumor patients. Salander et al. found that patients with malignant gliomas (Grade III–IV) who were disease-free and without neurologic deﬁcits developed impairments of verbal learning and memory but did not differ from their partners on tests of verbal comprehension, visual-spatial skills, or abstract reasoning ﬁve months after their initial treatment26. Archibald et al. found that memory and concentration tended to be most impaired 18 months after treatment, with further declines in frontal lobe executive functions and new learning ability occurring over the ensuing two years27. Kleinberg et al., in contrast, reported that 65% of their glioma patients had only mild memory deﬁcits that did not prevent them from returning to work31. However, memory impairment was rated by patient selfreport and not formally tested, and it could not be determined if the patients required any assistance or compensation techniques to maintain their level of function31. In a recent study, Mehta et al. examined neurocognitive functioning in 25 patients with brain metastases, primarily from lung and breast cancer, prior

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to treatment with WBRT and at regularly scheduled follow-up points32. Interestingly, signiﬁcant impairment in neurocognitive function was evident prior to administration of WBRT in the majority of subjects. Memory and motor speed functions were the most commonly affected, but the majority of patients did not decline following WBRT. In fact, 47% of patients showed improved neurocognitive function one month post-WBRT. Also of note, neurocognitive test scores were independent of performance states. In some cases, patients whose neurocognitive test scores declined maintained high Karnofsky Performance Scale (KPS)33 scores. The use of prophylactic cranial irradiation (PCI) in patients diagnosed with small cell lung cancer (SCLC) may reduce the occurrence of brain metastases, but this treatment remains controversial34, 35. Brain abnormalities visible on computed tomography (CT) scans and neuropsychological syndromes have been reported as possible toxic side effects of PCI35. In one study, 46% of SCLC patients receiving high-dose PCI experienced delayed neurologic complications or psychometric impairment34. The source of these impairments is unclear however, because other studies have documented cognitive deﬁcits in SCLC patients prior to PCI36 and prior to chemoradiation37. Interestingly, cognitive impairments have also been documented in non-small cell lung cancer (NSCLC) patients who had and had not received PCI38. Neuroimaging correlated these impairments with periventricular and subcortical white matter changes. As the previous discussion suggests, the use of WBRT in the treatment and prevention of metastatic brain tumors is associated with some degree of risk because it exposes normal brain tissue to the effects of radiation. Cognitive disturbances have been described in patients who undergo WBRT, and the severity of side-effects is generally related to treatment-related variables such as total radiation dose and dosing interval. The acute and subacute effects (i.e., hair loss, headaches, vomiting, and lethargy) of WBRT can be troublesome and do not always resolve once treatment has concluded. For example, studies have demonstrated that cognitive impairments may be evident in long-term survivors (> 6 months) following WBRT2. The late effects of WBRT can be more debilitating and can include radiation necrosis, brain atrophy, white matter changes, and signiﬁcant cognitive decline7.

Stereotactic radiosurgery Stereotactic radiosurgery uses small, focused beams of radiation to destroy tumors and has become an important treatment modality for metastatic brain disease39, 40. The main advantage of stereotactic radiosurgery relative to WBRT is that little normal brain tissue receives the radiation dose. This type of therapy is useful for patients with single or few cerebral metastases41– 43. Some studies have shown that radiographic response rates and survival rates may be improved using this technique3, 40, 44. Thus far, there have been no reports on the neurocognitive sequelae of stereotactic radiosurgery.

Neuropsychological impact of brain metastasis and its treatment 435

Assessment issues Differential diagnosis Identiﬁcation of cognitive impairment is important for a number of reasons. Cancer patients with metastatic brain disease frequently have complicated treatment regimens, and compliance may be adversely affected by cognitive deﬁcits. For example, problems with memory or the inability to initiate activity can negatively impact adherence to treatment regimens. Further, patients may be offered experimental treatments, and the decision to participate and give informed consent requires intact reasoning, the ability to weigh risks and beneﬁts, and the appreciation of long-term consequences. Many patients with brain tumors, at least early in their course, do not have overt evidence of impaired cognitive functioning on casual observation or during routine medical examinations, yet have cognitive deﬁcits that limit their ability to function in their normal activities. Standard assessments of performance status, such as the Karnofsky Performance Scale, which globally measures the patient’s ability for self-care and ambulation, do not address cognitive impairments in brain tumor patients and have questionable reliability and validity45. For example, a patient who is able to walk and perform basic activities of daily living may be rated as having a good performance status, even though he or she may be unreliable in following treatment regimens, lacks judgement, is unable to perform his/her usual work, or has temper outbursts that compromise family function. The use of appropriate assessment tools is particularly important for this population because the cognitive impairments of brain tumor patients may be subtle and are frequently more diffuse than expected for focal lesions. In a recent report from the Radiation Therapy Oncology Group (RTOG), the importance of pre-treatment Mini-Mental Status Exam (MMSE) scores on long-term survival and neurologic function was evaluated46. Data were presented from 182 patients to whom the MMSE was administered before and after they received accelerated fractionated radiotherapy for unresectable brain metastases. Of those patients available for follow up, 54.5% evidenced improvement (an increase of one point) in the MMSE scores. The authors also reported that the MMSE score remained above 23 in 81% of patients at six months after treatment and in 66% of patients at one year. From these data, it was concluded that the MMSE is useful in evaluating patient outcome after radiation therapy. Speciﬁcally, Murray et al. reported that accelerated fractionated radiotherapy may be associated with improved MMSE scores and a lack of decline in MMSE score below 23 in long-term survivors. However, several statistical issues complicate the interpretation of these results. Of primary concern is the authors’ assertion that a change of one point on the MMSE is signiﬁcant and can be considered an improvement. A review of the statistical properties of the MMSE reveals that a change of one point on the MMSE is within the standard error of the test. Actually, an individual’s score

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on this measure would have to change by three points or more to be considered a true and reliable change, one unlikely to occur by chance. The authors’ description of patients who have MMSE scores above 23 as having a “lack of neurologic deterioration” is also misleading. This suggests that patients in this group have not declined either cognitively or neurologically, and the MMSE is not a tool that measures change in either area adequately. Promoting use of the MMSE may result in the collection of misleading data, especially on clinical trials in which subtler, but still meaningful, changes in neurocognitive functioning may occur.

Neuropsychological assessment Neuropsychological assessment involves the administration of standardized psychometric tests that comprehensively evaluate brain functioning. These functions include attention, ability to acquire new memories, recall of stored memories, expressive speech, language comprehension, visual perception, reasoning, emotional behavior, interpersonal behavior, and executive functions. Assessment batteries (groups of tests administered) are carefully tailored to the referral question and to the patient’s ability level. For example, the Neuropsychology Service at The University of Texas M. D. Anderson Cancer Center is involved in a variety of clinical trials evaluating the efﬁcacy of novel and innovative treatments. The clinical trial battery is briefer than a typical neuropsychological assessment and is able to be completed by most patients in 45 minutes or less. The clinical trial battery also includes measures that are sensitive to changes in patient function, regardless of the patient’s prior exposure to the test. Finally, the clinical trial battery is inexpensive to administer. In many cases, however, a more extensive testing battery is needed to fully delineate the patient’s strengths and weaknesses. Providing physicians with a detailed description of their patient’s cognitive abilities and personality characteristics allows for more rational management and treatment planning. Knowledge of the patient’s capabilities and limitations should be incorporated into conferences held with the patient, family members, and the health care team. Such information is helpful as participants work to set realistic goals, to determine the patient’s capacity for independent self-care (including the ability to drive, manage ﬁnances, and to handle emergencies), and to determine what types of compensation and management techniques might be most useful.

Interventions and management strategies The majority of cancer patients who develop brain metastases experience behavioral, emotional, and intellectual changes that rapidly compromise their ability to live independently and return to work. In fact, very few patients with metastatic brain disease will return to their usual work and activities. For patients receiving WBRT, a median survival time of three to six months is expected. For patients with a single metastatic lesion treated by surgical

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resection, median survival time ranges from eight to 16 months. However, recent advances in management techniques (i.e., surgical improvements and the development of stereotactic radiosurgery) have increased the number of long-term survivors of metastatic brain disease. As the number of long-term survivors increases, clariﬁcation of the costs to the patient, family, and society (which include loss of self-esteem, lost income, and the necessity for disability payments) becomes even more important. The implementation of cognitive rehabilitation techniques has the potential to improve quality of life by enabling the patient to maintain his independence to the highest possible degree. To date, the utility and appropriateness of rehabilitation for patients with metastatic brain disease has not been evaluated. In fact, there is little established knowledge about the major rehabilitation problem areas of primary brain tumor patients, and there are no rehabilitation approaches to address the problems that have been speciﬁcally validated in this clinical population. Nevertheless, there is increasing interest in the remediation of cognitive impairments, and the initial steps toward establishment of an appropriate program are being made. The goal of this section is to describe current rehabilitation methods used with primary brain tumor patients and to identify trends in new programs designed for cancer patients with metastatic brain disease.

Rehabilitation problems of brain tumor patients One obstacle to the development of specialized brain tumor rehabilitation services is the identiﬁcation of the major rehabilitation problems within this patient population. It has often been assumed that the rehabilitation problems of brain tumor patients are similar to those of stroke patients, survivors of traumatic brain injury, and other groups of people receiving rehabilitation services. In fact, the available data support a different and more complex picture of brain tumor patients’ needs47–49. Not only do brain tumor patients have different types of problems, the progressive nature of their disease complicates treatment planning and decisions. Although the goals of treatment and the duration of intervention programs need to be ﬂexible for all rehabilitation patients, this is especially true for patients diagnosed with brain tumors50. It is undoubtedly true that patients with brain tumors may beneﬁt from many of the same types of services that are helpful for other rehabilitation populations, such as stroke or traumatic brain injury survivors. For example, physical therapy can improve strength and mobility, occupational therapy improves self-care skills, and speech and language therapy may help patients overcome various aphasic conditions. Despite similarities in the types of therapies employed, the nature of the problems faced by cancer patients necessitates an adjustment in the approach to rehabilitation and the goals of services. For many patients, especially those diagnosed with a metastatic brain tumor, deterioration of function over time is the most likely course of the disease. But even if gains achieved in physical, occupational, or speech therapy are

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temporary, they may signiﬁcantly improve the patient’s quality of life by improving productivity and independence51, 52.

Traditional rehabilitation approaches Implementing traditional cognitive and vocational rehabilitation for brain tumor patients is complicated by the fact that existing programs are not entirely appropriate. First, brain tumor patients have different patterns and types of cognitive deﬁcits than do stroke or trauma patients. One study found that patients with brain tumors have milder cognitive deﬁcits and greater variability in the nature and extent of their deﬁcits than people with strokes in the same neuroanatomical site53. Secondly, the natural history of the disease process is different from that of cerebrovascular disease or traumatic brain injury. An acute onset and gradual recovery usually characterize the latter two conditions. In the case of brain tumors, the onset of the disease is relatively insidious, and although some recovery of function may be seen following surgery or other therapy, most patients experience a gradual deterioration of function as the tumor progresses. Hence, the goals of rehabilitation may be different from those in stroke or brain trauma rehabilitation. Finally, most existing rehabilitation programs take at least six months to complete and are costly (frequently more than $20,000). Complicating the cost, funding agencies and insurance carriers may be reluctant to provide or reimburse services for brain tumor patients. Although several different approaches to rehabilitation have been described54, the majority of rehabilitation methods used with brain tumor patients follow a supportive approach. This approach attempts to improve patient functioning within the limits set by neurologic deﬁcits that are assumed to be permanent. Our experience suggests that a model that includes a preventive approach may also be useful in this population. In this approach, the goal is to prevent complications that are anticipated to result from disease or treatment. For patients with metastatic brain disease facing progressive cognitive deterioration, the early acquisition and implementation of compensatory strategies may alleviate some of the anxiety associated with an uncertain future.

Cognitive rehabilitation The major components of a holistic neuropsychological rehabilitation program include: the establishment of a therapeutic milieu, cognitive rehabilitation or retraining sessions, psychotherapy, involvement and education of family members, and a protected work trial55. While the early aim of such programs was to restore cerebral functioning to the highest degree possible, more contemporary cognitive remediation programs strive to manage the individual’s disability rather than to treat the underlying impairment56. Although there is little evidence that cognitive retraining (the restorative approach) directly improves higher cerebral functioning in adults after acquired brain injury55,

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there are beneﬁts to participation in cognitive rehabilitation programs. Initially, cognitive retraining sessions may help patients better understand the nature and degree of their impairment or disability, and as the program advances, cognitive rehabilitation helps patients use their residual skills to improve their abilities to problem solve and adapt to their changing circumstances. Modiﬁcations of special programs dedicated to rehabilitating the neurobehavioral problems of traumatic brain injury patients are being developed for brain tumor patients52. The ﬁrst step in cognitive and vocational rehabilitation is to identify realistic goals for the patient, often through formal neuropsychological and vocational testing to identify preserved skills. The major therapeutic strategy is to train patients to compensate for their neurobehavioral deﬁcits. Brain tumor patients would appear to be excellent candidates for cognitive rehabilitation because patients with focal lesions and relatively restricted cognitive deﬁcits may be in a better position to recognize the need to use compensatory strategies than people with more diffuse impairments55. Typical areas targeted for retraining include memory, problem solving, and social behavior. In examining the efﬁcacy of cognitive remediation, the greatest success has been in compensating for memory disorders57. For instance, patients with memory deﬁcits may compensate by using written reminders, alarm watches, pagers, etc. Unfortunately, the efﬁcacy of compensation strategies in addressing deﬁcits in other areas of functioning (i.e., judgment and problem solving) has not been conclusively demonstrated58. For some patients, a major treatment goal may be to improve the appropriateness of behavior. This may include teaching the patient to inhibit socially inappropriate remarks or to improve frustration tolerance. Patients and family members often need counseling about the brain tumor patient’s need to accept a less demanding job that is not as ﬁnancially rewarding and prestigious. The majority of the brain tumor patients seen in our clinic are experiencing cognitive difﬁculties. Feelings of confusion and frustration often accompany cognitive changes and can affect not only the patient but also those persons close to him or her. For many patients, whether they have been recently diagnosed with a primary or metastatic brain tumor or are already undergoing treatment, a neuropsychological assessment can be helpful in delineating an individual’s cognitive strengths and weaknesses, as well as in validating the concerns of patients and their families. In some instances, the neuropsychological evaluation provides concrete evidence of impairment for the patient who is unable or unwilling to acknowledge the impact of the disease and/or his treatment on cognition. Many of our patients reside out of state or at a distance from the facility that prohibits frequent visits for cognitive remediation. Although referrals to accredited rehabilitation facilities are provided when appropriate, some patients beneﬁt from an intensive “problem-solving” approach that can be completed in conjunction with scheduled clinic visits. Maintaining a strong therapeutic alliance with the patient and close professional relationships with

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speech and language pathologists, physical therapists, occupational therapists, psychiatrists, and primary care physicians is crucial to the success of this approach.

Pharmacological strategies Neurobehavioral slowing is the hallmark of frontal lobe dysfunction and treatment-related adverse effects in brain tumor patients. The syndrome of neurobehavioral slowing is generally due to involvement of the monoamine pathways of the frontal-brainstem reticular system. In addition, catecholamines also have an important role in the modulation of attention and working memory. The use of neurostimulants in the brain-injured population has been shown to increase participation in therapy by improving arousal and attention59. Methylphenidate has proved efﬁcacious in improving the cognitive and emotional symptoms of HIV disease60, alleviating apathy in a patient with multiple subcortical infarcts61, improving attention and functional outcome in braininjured adults59, and in enhancing recovery rates in patients with moderately severe brain injuries62. Stimulant treatment has also been reported to be useful in the treatment of concentration difﬁculties, psychomotor retardation, and fatigue frequently seen in brain tumor patients, and it helped to elevate mood as well63. A conservative dose of 10 mg BID signiﬁcantly improved cognitive function, as assessed by objective tests, and doses in excess of 60 mg BID were well tolerated. Subjective improvements included improved gait, increased stamina and motivation to perform activities, and improved bladder control. There were no signiﬁcant side-effects, and many patients taking steroids were able to decrease their dose63. Long-term experience with this agent is lacking to determine if tolerance to therapeutic effects can develop.

Conclusion Brain metastases are a common complication of systemic cancer. Although advances in surgical technique and radiotherapy have the potential to improve survival for patients with metastatic brain disease, treatment effects may also cause deterioration of cognitive functioning. Discovering means of preserving/improving cognitive functioning must become a priority as we strive to enhance patients’ quality of life. Neuropsychological assessment and cognitive rehabilitation techniques provide us with the tools to evaluate patient cognition and to teach them appropriate compensatory strategies. In recent years, rehabilitation efforts with brain tumor patients, and indeed with cancer patients in general, have focused on symptom management (i.e., pain control), psychological support, nutritional support, and management of the medical complications of treatment64. Historically, a “good outcome” for primary brain tumor patients has been considered to be preservation of life by the medical personnel, and possibly, rehabilitation of motor deﬁcits by

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physical therapy. However, there has been little or no effort to offer cognitive rehabilitation to brain tumor patients who may have the ability to beneﬁt from such services. The current lack of sophisticated rehabilitation effort is due to several factors. One reason is a lack of awareness on the part of rehabilitation professionals, patients, and medical care givers about services that are available. Second, many patients may not be encouraged to seek rehabilitation because they may not have marked sensory, linguistic, or motor deﬁcits such as those seen in stroke patients, even though most experience subtle cognitive problems in daily life. Finally, there may be concern about expending resources on individuals who will probably die from their disease. However, the resources expended on brain tumor patients may compare favorably with those expended on patients with heart disease, diabetic complications, mental disorders, and other chronic disabling conditions when the patient’s overall quality of life is considered. In addition to formal rehabilitation, helping cancer patients attain an acceptable quality of life may include helping them accept the permanent changes, both cognitive and social, that having metastatic brain disease might cause. Among the most disturbing losses sustained by these patients are the loss of self-esteem, the loss of work and working relationships, and the loss of self-conﬁdence. Patients and their families may need to invest their efforts in new activities and interests and learn to enjoy leisure time. Quality of life needs to be deﬁned on a highly individualized basis, requiring a great deal of ﬂexibility on the part of the health care team, consultative services, and the patients and families. The need for continued psychosocial and neuropsychological assessment, rehabilitation, and counseling services will continue to grow as cancer patients survive for increasingly longer periods of time.

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8 Haas J, Vogt G, Schiemann M, et al.: Aphasia and non-verbal intelligence in brain tumour patients. J Neurol 1982; 227: 209 –218. 9 Scheibel RS, Meyers CA, Levin VA: Cognitive dysfunction following surgery for intracerebral glioma: inﬂuence of histopathology, lesion location, and treatment. J Neurooncol 1996; 30: 61–69. 10 Vilkki J: Cognitive ﬂexibility and mental programming after closed head injury and anterior or posterior cerebral excisions. Neuropsychologia 1992; 30: 807– 814. 11 Goldstein LH, Bernard S, Fenwick PBC, et al.: Unilateral frontal lobectomy can produce strategy application disorder. J Neurol Neurosurg Psychiatry 1993; 56: 274 –276. 12 Ackermann H, Daum I, Schugens MM, et al.: Impaired procedural learning after damage to the left supplementary motor area (SMA). J Neurol Neurosurg Psychiatry 1996; 60: 94 –97. 13 Lilja Å, Brun A, Salford LG, et al.: Neuropsychological indexes of a partial frontal syndrome in patients with nonfrontal gliomas. Neuropsychology 1992; 6: 315 –326. 14 Irle E, Peper M, Wowra B, et al.: Mood changes after surgery for tumors of the cerebral cortex. Arch Neurol 1994; 51: 164 –174. 15 Paradis CM, Friedman S, Hatch M, et al.: Obsessive-compulsive disorder onset after removal of a brain tumor. J Nerv Ment Dis 1992; 180: 535 –536. 16 Meyers CA, Berman SA, Scheibel RS, et al.: Case report: acquired antisocial personality disorder associated with unilateral left orbital frontal lobe damage. J Psychiatry Neurosci 1992; 17: 121–125. 17 Meyers CA: Neuropsychological deﬁcits in brain tumor patients: effects of location, chronicity, and treatment. Cancer Bull 1986; 38: 30 –32. 18 Hochberg FH, Slotnick B: Neuropsychologic impairment in astrocytoma survivors. Neurology 1980; 30: 172–177. 19 Lewis DA, Smith RE: Steroid-induced psychiatric syndromes. A report of 14 cases and a review of the literature. J Affect Disord 1983; 5: 319 –332. 20 Wolkowitz OM, Reus VI, Weingartner H, et al.: Cognitive effects of corticosteroids. Am J Psychiatry 1990; 147: 1297–1303. 21 Martignoni E, Costa A, Sinforiani E, et al.: The brain as a target for adrenocortical steroids: cognitive implications. Psychoneuroendocrinology 1992; 17: 343 –354. 22 Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494 –500. 23 Iwadate Y, Namba H, Yamaura A: Signiﬁcance of surgical resection for the treatment of multiple brain metastases. Anticancer Res 2000; 20(1B): 573–577. 24 Leibel SA, Sheline GE: Radiation therapy for neoplasms of the brain. J Neurosurg 1987; 66: 1–22. 25 Gregor A, Cull A, Traynor E, et al.: Neuropsychometric evaluation of long-term survivors of adult brain tumours: relationship with tumour and treatment parameters. Radiother Oncol 1996; 41: 55–59. 26 Salander P, Karlsson T, Bergenheim T, et al.: Long-term memory deﬁcits in patients with malignant gliomas. J Neurooncol 1995; 25: 227–238. 27 Archibald YM, Lunn D, Ruttan LA, et al.: Cognitive functioning in long-term survivors of high-grade glioma. J Neurosurg 1994; 80: 247–253. 28 Taphoorn MJB, Schiphorst CP, Snoek JF, et al.: Cognitive functions and quality of life in patients with low-grade gliomas: the impact of radiotherapy. Ann Neurol 1994; 36: 48 –54. 29 Imperato JP, Paleologos NE, Vich NA: Effects of treatment on long-term survivors with malignant astrocytomas. Ann Neurol 1990; 28: 818 – 822. 30 Lieberman AN, Foo SH, Ransohoff J: Long term survival among patients with malignant brain tumors. Neurosurgery 1982; 10: 450 – 453.

Neuropsychological impact of brain metastasis and its treatment 443 31 Kleinberg L, Wallner K, Malkin MG: Good performance status of long-term disease-free survivors of intracranial gliomas. Int J Radiat Oncol Biol Phys 1993; 26: 129 –133. 32 Mehta MP, Meyers CA, Schultz CJ, et al.: Neurocognitive function predicts outcome in patients with brain metastases treated with whole brain radiation and Xcytrin. Proceedings of the American Society of Clinical Oncology, 2000. 33 Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In MacLeod CM (ed): Evaluation of Chemotherapeutic Agents. New York, Columbia University Press, 1949: 191–205. 34 Tomio L, Romano M, Zanchin G, et al.: Ultrarapid high-dose course of prophylactic cranial irradiation in small-cell lung cancer: evaluation of late neurologic morbidity in 16 longterm survivors. Am J Clin Oncol 1998; 21: 84 –90. 35 Mornex, F: Small cell lung cancer: cranial irradiation (Meeting Abstract). Lung Cancer: Strategies for the 21st Century. Biology, Prevention, and Management. Continuing Education, Faculty of Medicine, University of Toronto Symposium, 2000; p. 26. 36 Stuschke M, Eberhardt W, Pottgen C, et al.: Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer afer multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects. J Clin Oncol 1999; 17: 2700 –2709. 37 Komaki R, Meyers CA, Cox JD: Neuropsychological functioning of patients with small cell lung cancer prior to and shortly following prophylactic cranial irradiation: evidence for pre-existing cognitive impairments (Abstr). Proc A Soc Clin Oncol 1993; 12: 1084. 38 Meyers CA, Byrne KS, Komaki R: Cognitive deﬁcits in patients with small cell lung cancer before and after chemotherapy. Lung Cancer 1995; 12: 231–235. 39 Chen JCT, Petrovich Z, Giannotta SL, et al.: Radiosurgical salvage therapy for patients presenting with recurrence of metastatic disease to the brain. Neurosurgery 2000; 46: 860 – 867. 40 Friedman WA, Foote KD: Linear accelerator radiosurgery in the management of brain tumors. Ann Med 2000; 32: 64 – 80. 41 Maor MH, Dubey P, Tucker SL, et al.: Stereotactic radiosurgery for brain metastases: results and prognostic factors. Int J Cancer 2000; 90: 157–162. 42 Plowman PN: Stereotactic cranial radiotherapy/radiosurgery has come of age. J R Coll Physicians Lond 2000; 34: 273 –281. 43 Yang CC, Ting J, Wu X, et al.: Dose volume histogram analysis of the gamma knife radiosurgery treating twenty-ﬁve metastatic intracranial tumors. Stereotact Funct Neurosurg 1998; 70 (Suppl 1): 41–49. 44 Corn BW, Mehta MP, Buatti JM, et al.: Stereotactic irradiation: potential new treatment method for brain metastases resulting from ovarian cancer. Am J Clin Oncol 1999; 22: 143–146. 45 Orr ST, Aisner J: Performance status assessment among oncology patients: a review. Cancer Treat Rep 1986; 70: 1423 –1429. 46 Murray KJ, Nelson DF, Scott C, et al.: Quality-adjusted survival analysis of malignant glioma. Patients treated with twice-daily radiation (RT) and carmustine: a report of radiation therapy oncology group (RTOG) 83–02. Int J Radiat Oncol Biol Phys 1995; 31: 453 – 459. 47 Lehmann JF, DeLisa JA, Warren CG, et al.: Cancer rehabilitation: Assessment of need, development, and evaluation of a model of care. Arch Phys Med Rehabil 1978; 59: 410 – 419. 48 Taphoorn MJ, Heimans JJ, Snoek FJ, et al.: Assessment of quality of life in patients treated for low-grade glioma: a preliminary report. J Neurol Neurosurg Psychiatry 1992; 55: 372– 376. 49 Marciniak CM, Sliwa JA, Spill G, et al.: Functional outcome following rehabilitation of the cancer patient. Arch Phys Med Rehabil 1996; 77: 54 –57.

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50 Gamble GL, Brown PS, Kinney CL, et al.: Cardiovascular, pulmonary, and cancer rehabilitation. 4. Cancer rehabilitation: principles and psychosocial aspects. Arch Phys Med Rehabil 1990; 71: s244 –247. 51 Haut MW, Haut JS, Bloomﬁeld SS: Family issues in rehabilitation of patients with malignant brain tumors. Neurorehabilitation 1991; 1: 39. 52 Sherer M, Meyers CA, Bergloff P: Efﬁcacy of postacute brain injury rehabilitation for patients with primary malignant brain tumors. Cancer 1997; 80: 250 –257. 53 Anderson SW, Damasio H, Tranel D: Neuropsychological impairments associated with lesions caused by tumor or stroke. Arch Neurol 1990; 47: 397– 405. 54 Dietz JH: Rehabilitation and reconstruction for the cancer patient. In: Pilch YH (ed): Surgical Oncology. New York, McGraw-Hill, 1984, pp. 1041–1076. 55 Prigatano GP: Principles of Neuropsychological Rehabilitation. New York, Oxford University Press, 1999. 56 Wilson BA: Cognitive rehabilitation: how it is and how it might be. J Int Neuropsychol Soc 1997; 3: 487–496. 57 Baddeley AD, Wilson BA, Watts FN: Handbook of Memory Disorders. Chichester, England, John Wiley and Sons, 1995. 58 von Cramen DY, Matthes-von Cramen G: Reﬂections on the treatment of brain-injured patients suffering from problem-solving disorders. Neuropsychol Rehabil 1992; 2: 207–229. 59 Kaelin DL, Cifu DX, Matthies B: Methylphenidate effect on attention deﬁcit in the acutely brain-injured adult. Arch Phys Med Rehabil 1996; 77: 6 –9. 60 Brown G: The use of methyphenidate for cognitive decline associated with HIV disease. Int J Psychiatry Med, 1995; 25: 21–37. 61 Watanabe MD, Martin EM, DeLeon OA, et al.: Successful methylphenidate treatment of apathy after subcortical infarcts. J Neuropsychiatry 1995; 7: 502–504. 62 Plenger PM, Dixon CE, Castillo RM, et al.: Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil 1996; 77: 536 –540. 63 Meyers CA, Weitzner MA, Valentine AD, et al.: Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 1998; 16: 2522–2527. 64 McLaughlin WJ: Cancer rehabilitation: people investing in people. J Rehabil 1984; 50: 57.

CHAPTER 26

Adjuvant approaches for preventing brain metastases David G Menter, Anita L Sabichi, Scott M Lippman

Introduction Although the incidence of brain metastasis is very low in certain cancers, such as prostate cancer (5%), it is very high in certain other cancers, such as malignant melanoma, which produces symptomatic and overall (at autopsy) brain metastasis in 40% and 70%–80% of cases, respectively1–3. Metastatic brain lesions also commonly occur in breast4, 5, lung6, 7, colon8, and renal cancer9, 10. Primary brain tumors usually spread locally (if at all) and rarely metastasize distantly11–18. A major complication of brain tumors is cerebral edema, resulting from a lack of effective lymphatic drainage in the brain19. Brain metastases frequently induce severe and debilitating neurological complications20, 21. Even a small brain metastasis can cause severe symptoms, such as paralysis, headaches, seizures, and impaired cognition20, 21. Although metastatic lesions in other organs often can be tolerated for variable periods of time, the quality of life declines quickly after metastasis to the brain. Therapy of brain metastases often is merely palliative and accompanied by clinical complications22–28. All these data illustrate the need for new adjuvant approaches for preventing brain metastasis. The development of new clinical approaches to brain metastases is complicated by a unique combination of molecular and biological properties that contribute to the formation of brain metastases and to difﬁculties in their clinical management29 –32. Adjuvant research approaches for preventing metastasis to the brain or primary brain cancer are at a rudimentary stage of development. This chapter will outline the biology of solid-tumor metastasis to the brain and the current status of and prospects for adjuvant approaches for improving the control of this deadly process.

Biological considerations The brain is biologically responsive to the slightest change in the local microenvironment and is protected from molecular insult by the blood-brain barrier (BBB) (Plate 26.1, facing p. 82)33 – 44. There are a number of molecular, cellular, and anatomic factors involved in the formation of hematogenous metastases 445

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in the brain45, and speciﬁc genetic lesions have been associated with brain metastasis. Under normal physiological conditions, there are mechanisms that limit material ﬂow, uncontrolled cell movement, and cell proliferation in the brain. Material ﬂow into the brain is strictly regulated by the BBB (Plate 26.1). Inhibitory cytokines, such as TGF-β, help limit cell growth in the conﬁned environment of the brain. These tightly regulated processes contribute to the barrier that metastatic cells must breach to invade and colonize the brain parenchyma. Metastatic cells must increase their expression of certain cell-surface receptors, degradative enzymes, growth factors, and possibly, cytokines before they can invade the brain. The anatomic patterns of brain metastasis formation vary with cancer type. Brain metastases of melanoma, which tend to colonize either the meninges or the brain parenchyma, are well studied32. Similar patterns can occur with other cancers, but meninges colonization occurs most frequently with melanoma9, 46 – 48. Primary brain cancers can develop in a broader spectrum of brain tissues, including the brain parenchyma, meninges, mesenchyma, and epithelia49.

Trophic support of brain colonization Trophic factors regulate cell development and survival. Changes seen in neurotrophin and neurotrophin-receptor expression during embryonal brain and peripheral nervous system development50, 51 are also seen during the formation of certain tumors. For example, there is a progressive increase in neurotrophin receptor p75NTR protein expression in vitro and in vivo during the progression of melanocytes to malignant melanoma cells and further, to metastatic melanoma cells. Increased synthesis of p75NTR protein occurs in advanced malignant melanoma tumors52, especially in human melanoma brain metastases, which have the highest levels of p75NTR expression53. Studies of the effects of neurotrophins on the ability of melanoma cells metastatic to the brain to invade a reconstituted basement membrane have shown that overexpression of p75NTR is associated with brain colonization and the enhancement of extracellular matrix invasion due to the increased production of matrix-degrading enzymes53. Brain metastatic melanoma cells recently were shown to activate cyclic AMP response element (CRE) transcription through a cyclic AMP response element binding-based (CREB-based) mechanism that supports survival through a p75NTR-based mechanism54. Following these observations of associations between neurotrophins and melanoma cells, many other cancer types have been shown to be associated with neurotrophin receptor changes that may mediate brain colonization55 –58. Human melanoma cells established in short-term tissue culture from brain metastases show characteristic chromosomal alterations59. For example, there are high frequencies of translocation or deletion breakpoints at the 23q locus on chromosome 11 and of terminal translocations at the q25 locus on chromosome 17 or of formation of an isochromosome of the long arm of chromosome

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1759. It is worth noting that the neural cell adhesion molecule (NCAM) locus is at 11q23 and may also be important in establishing melanoma metastases in the brain. The p75NTR gene is located at 17q21–22 and may be ampliﬁed in tumor cells containing the isochromosome of the long arm of chromosome 17. A number of consistent chromosomal changes also occur in brain metastases from other solid tumors, including lung, breast, colon, kidney, adrenal gland, and thyroid cancers60.

Brain tissue responses to metastatic invasion The brain’s response to invading malignant cells (which have increased expression of certain cell-surface receptors, degradative enzymes, growth factors, and possibly cytokines) is similar to its better-studied response to brain injury. The molecular and cellular interactions among invading cells, the BBB, and surrounding perivascular tissues can create cytokine feedback loops that amplify brain inﬂammation and edema. Astrocyte and microglial cells manifest the primary cellular response after brain injury61– 67. Astrocytes are very heterogeneous with respect to their cellular phenotypes68, 69. They are the predominant cell type in the brain, outnumber neurons by a factor of ten to one, and constitute one-third of all cerebral cortex cells. Astrocytes regulate important functions in the brain, including the BBB (Plate 26.1); water and ion movement, and basal metabolism; immune responses; neuronal cell migration; neurite outgrowth; and functional synapse formation61. Large numbers of astrocytes respond to injury or metastatic invasion in the brain by forming reactive astrocytes exhibiting morphological and pathophysiological changes. One of the earliest cellular responses to brain trauma involves the early reactive astrocytosis event of astrocyte swelling (predominantly in the perivascular astrocytic endings)19, 61, 68. In experimental brain tumors, cerebral edema has been associated with signiﬁcant alterations in vascular permeability due to the astrocytic changes42, 43, 70, 71. If the BBB is compromised during injury or invasion, astrocyte swelling may result in vasogenic edema caused by the increased uptake of proteins, water, potassium ions, and glutamate by the astrocytes42, 43, 70 –72. This process also may include the production of linoleic and arachidonic acid metabolites (prostaglandins, hydroxyeicosatetraenoic acids, and leukotrienes) and diffusion of cytokines into the astrocytic cell compartment (Plate 26.2, facing p. 82)73 –77. Brain tissues express high levels of cyclooxygenase-2 (COX-2) and certain lipoxygenases (LOXs), which provide the substrates for these bioreactive fatty acids that mediate growth and inﬂammation73, 78 – 85. These tumor-induced responses by astrocytes may cause the severe symptoms, such as paralysis, headache, seizures, and impaired cognition, that can afﬂict patients even with relatively small brain metastases. There also are increases in the expression of cellular receptors, including transforming growth factor-beta (TGF-β), interleukin-6 (IL-6), and purinergic (P2Y) receptors86 – 89. The induction of reactive astrocytes probably involves the release of a number of factors from different brain cells, such as lipocortin;

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glial maturation factor (GMF) and S100 protein from astrocytes; interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), IL-6, and interferon-gamma (IFNγ) from microglial cells; myelin basic protein from oligodendrocytes; and K+, ATP, and basic ﬁbroblast growth factor (bFGF) from neurons (Plate 26.2)83. Prostaglandins and hydroxyeicosatetraenoic acids (HETEs) produced by COX-2 and LOX enzymes, respectively, also are produced by reactive astrocytes and microglial cells86, 90 –96. Vasogenic edema in the brain also leads to the inﬂux of thrombin, platelet-derived growth factor, steroids, insulin and various cytokines from the circulation, cytokines from invading lymphocytes, as well as endothelin, ATP, and bFGF from brain microvessel endothelial cells (Plate 26.2).

Adjuvant strategies for preventing brain metastases Adjuvant approaches to prevent brain metastases have been impeded by unique molecular and biological features of the brain. The foremost impediment has been the BBB, which (along with surrounding brain tissues) poses a formidable obstacle to both malignant cell colonization and effective agent delivery. Various chemotherapeutic regimens have been employed in clinical trials targeting brain micrometastasis97–99. Radiotherapy is also employed to eliminate suspected brain micrometastases in some cancer settings, such as limitedstage small cell lung cancer97, 100 –102. The difﬁculty in developing effective preventive strategies is due partly to a lack of useful predictors for identifying cancer patients at a high risk of developing brain metastasis (notwithstanding certain genetic patterns that have been associated with the development of brain metastases)59, 60 in addition to the BBB and other special brain characteristics. Potential endpoints also pose a major obstacle to adjuvant trials in brain metastasis prevention.

Circumventing the BBB In order to access brain tissue, an agent should be either permeable to the BBB or subject to active transport into the brain parenchyma. Several approaches currently in development for delivering agents to the brain by circumventing the BBB include use of agents that osmotically open the BBB in combination with other therapy38, 103 –109, viral injection delivery methods using suppressive gene therapy110 –113, stereotactic implantation of drug-containing microspheres in the brain114, and delivery of drug-laden nanoparticulates or selective delivery of macromolecular drugs that are actively taken up and transported across the BBB115. Controlled drug-release microchips also may be used eventually to elude the BBB108, 116. Most of the previously mentioned BBB-circumvention methods are reserved for aggressive brain cancer therapy. Small-molecule (BBB-permeable) or actively-transported (into the brain parenchyma) chemopreventive agents will probably be more useful in (and may need to be developed speciﬁcally for) the setting of preventing brain metastasis.

Adjuvant approaches for preventing brain metastases 449

Angiogenesis regulators Inhibiting angiogenesis is an experimental approach for suppressing or eliminating a tumor by restricting its blood supply19. The vascular complexity of the brain complicates any antiangiogenesis approaches in this setting. Primary brain tumors and metastases are among the most highly vascularized tumors117, 118. Brain tumors are unique in having complex glomeruloid vessels. They also have a heterogeneity of microvasculature that may show incorporation of pre-existing vessels or development of new vessels11. Despite this complexity, methods for antiangiogenic therapy of brain metastases and brain tumors are being developed19, 45, 117, 119 –121. There is an important BBB-related concern, however, regarding the potential of antiangiogenic therapy in this setting. Inhibiting angiogenesis in a brain containing a neovascularized tumor may aid the BBB in preventing therapeutic agents from entering a metastatic area, whereas stimulating angiogenesis that supplies blood to a lesion rendered inaccessible by the BBB may give drugs access to a metastatic brain tumor. The advantages and disadvantages of altering blood vessel biology during brain metastasis formation remain to be determined.

Treating brain micrometastases versus preventing in-transit metastases from entering the brain Cancer metastatic to the brain is associated with a poor prognosis122, and treating occult brain micrometastases123 after deﬁnitive local therapy is an important clinical consideration. Prophylactic cranial irradiation is a measure commonly employed to prevent clinical brain metastasis in patients after chemoradiotherapy of primary limited-disease small cell lung cancer124, 125. Although cancer cells with phenotypic properties enabling them to colonize the brain may be circulating in the blood at the time of cancer diagnosis or during its treatment, they may not yet have metastasized to the brain. Preventing tumor cells from seeding the blood from the primary tumor site (intravasation) and/or from exiting the bloodstream to the metastatic site (extravasation) may be useful approaches126. These approaches could involve speciﬁc inhibitors of invasion, such as antisense oligonucleotides or antibodies to suppress the production of invasive enzymes127, or inhibitors of adhesion and motility (e.g., integrins)128 or of the type-I insulin-like growth factor receptor (IGF-1) and other cell-surface receptors129. Another proposed related treatment approach is to control hematogenous factors supporting the survival and dissemination of metastases in transit126.

Potential agents for preventing brain metastasis Few chemopreventive agents have been studied for potential activity in the brain. Studies of these agents to date have mostly examined their distribution to brain tissues and not efﬁcacy. Radiolabeled epigallocatechin, a compound found in green tea, was shown to be distributed to the brain (and other organs)130. Sodium selenite has been used in radioisotope form to diagnose neuroblastomas131, 132.

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Nonsteroidal anti-inﬂammatory drugs (NSAIDs) and other agents capable of modulating cyclooxygenases (COXs) and lipoxygenases (LOXs) are among general chemoprevention’s most promising agents133 –136. Although these agents are little studied in brain carcinogenesis, there are biological data supporting their potential for activity in this setting. COX-1 and COX-2 are heme-containing enzymes, constitutively expressed in brain tissue, that convert arachidonic acid to prostaglandin H2 (PGH2) during prostaglandin (PG) biosynthesis137–139. COX-2 is not constitutively expressed in most other tissues140. COX-1 and -2 are constitutively expressed in many brain neurons and are distributed similarly in the brain. COX-2 is constitutively expressed in the forebrain and in neurons of the cerebral cortex, hippocampus, and amygdala78, 140 –142. COX-2 is also induced by inﬂammatory cytokines and lipopolysaccharides in the brain microvasculature of the BBB and in perivascular microglial cells143 –146. COX-2 is involved in controlling astrogliosis and brain inﬂammation91, 147. Brain-speciﬁc overexpression of COX-2 in transgenic mice resulted in an age-related cognitive deﬁciency that was similar in pattern to that seen in age-related human diseases, such as Alzheimer’s disease148, for which there is a reduced risk in people taking NSAIDs149. Arachidonic acid is an abundant substrate in brain tissue for COX to use in producing PGH2, which in turn is acted on by PG synthases to form bioactive PGs78. The two primary PG synthases in the brain are PGE synthase and PGD synthase78, 150, 151. PGE synthase produces PGE2, which is involved in regulating inﬂammation152–154, pain146, 155, and fever156 –158. PGD synthase produces PGD2, which promotes sleep78, 151. Although normal homeostasis in the brain relies heavily on PGs, inﬂammation throughout the central nervous system (CNS) induces dramatic increases in PG biosynthesis78, accompanied by increased COX-2 expression159. COX-2 expression increases in many types of cancer, including a variety of brain tumors160, 161, and carcinogenesis associated with overproduction of this enzyme can be inhibited by NSAIDs162, 163. Increased PG levels in brain tumors are a downstream product of COX enzymes82. Matsuo and coworkers164 showed that COX-2 was elevated above the COX-1 level in a number of glioma cell lines and in a variety of brain tumors, including one metastasis, and that nonadjacent normal brain cells also expressed high levels of COX-2. Others have reported profound intratumoral and peritumoral cellular reactions to the presence of brain primary tumors and metastases33, 164. Intratumoral and peritumoral cells, including microvascular endothelial cells, reactive astrocytes, and microglial cells, expressed high levels of COX-2164. NSAIDs have been used on cultured glioma cells to inhibit their growth and to increase their level of apoptosis as well as their radiosensitivity165. Little is known about the potential efﬁcacy of NSAIDs on brain metastasis formation and growth. The successes of NSAIDs and COX-2-speciﬁc inhibitors in the prevention of colon cancer may warrant investigating these types of inhibitors in the prevention of brain metastasis.

Adjuvant approaches for preventing brain metastases 451

LOXs are non-heme iron-containing enzymes that catalyze peroxidation of free fatty acids at speciﬁc carbon atoms166. The various LOX enzymes are characterized by the carbon position at which they catalyze peroxidation on their respective fatty acid substrates. For example, 5-LOX, 12-LOX and 15-LOX produce peroxidation of arachidonic acid carbons 5, 12, and 15, respectively166, 167. The predominant forms of LOX in the brain are 5-LOX168, 169 and 12-LOX170, 171. Neither 15-LOX isoform (15-LOX–1 or 15-LOX–2) has been reported to be expressed in brain tissue. In association with 5-LOX-activating protein (FLAP) and cytoplasmic phospholipase A2, 5-LOX migrates to the nuclear envelope, where it exerts its peroxidase function172–174. The product of 5-LOX, 5-hydroxyeicosatetraenoic acid (5-HETE), is processed further to form leukotrienes that can bind to G-protein-coupled leukotriene plasma-membrane receptors175 or peroxisome proliferator-activated receptors (PPARs) in the nucleus138, 176. PPARs are a family of nuclear receptors that can bind many of the products of LOX pathway enzymes, including various HETEs176, 177 and linoleic-acid products (including 13-S-hyroxyoctadecadienoic acid [13-S-HODE]), to initiate cell death135, 178, 179. The PPARs also bind cyclopentenone prostaglandins, such as 15-deoxy-delta 12,14-PGJ2, to activate gene transcription180, 181. LOX enzymes play important functional roles in regulating inﬂammation138, arteriosclerosis182, 183, programmed cell death184, aging in the brain79 and in modulating carcinogenesis.135 Speciﬁc roles of LOX in brain function are poorly understood other than in aging79 and inﬂammation138, 185, 186. Little also is known about the role of LOXs in brain cancer or metastasis formation. 12LOX-catalyzed production of 12-HETE may be particularly important during metastasis formation, but speciﬁc roles for it in brain colonization are not known187, 188. 5-LOX has been observed in brain tumors in which it may affect BBB permeability189, 190, and LOX inhibitors, such as nordihydroguaiaretic acid (NDGA) and caffeic acid, inhibit brain tumor cell growth191, 192. The evolution of more LOX-speciﬁc inhibitors or LOX-product-receptor antagonists may help determine not only the importance of LOX activity in brain function but also tumor growth and metastasis formation in the brain193, 194.

Conclusions Controlling cancer metastasis to the brain is very difﬁcult to achieve because of complex biological and clinical issues involved in brain carcinogenesis that need further development. We need a better understanding of the following issues: reactive astrocytosis and other brain-tissue host responses to invading malignant cells; trophic responses of micrometastatic tumor cells that affect brain invasion, colonization, and tumor cell survival; speciﬁc agents with chemopreventive activity against brain metastases (e.g., COX-2 and LOX modulators); and the role of the BBB in allowing potential chemopreventive agents to reach brain tissues. Advances in these areas of study, especially the impediment to chemoprevention posed by the BBB, will lead to a more robust

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program of adjuvant trials designed to prevent and control cancer metastatic to the brain.

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Adjuvant approaches for preventing brain metastases 457 110 Mohan PM, Chintala SK, Mohanam S, et al.: Adenovirus-mediated delivery of antisense gene to urokinase-type plasminogen activator receptor suppresses glioma invasion and tumor growth. Cancer Res 1999; 59: 3369 –3373. 111 Lang FF, Yung WK, Sawaya R, et al.: Adenovirus-mediated p53 gene therapy for human gliomas. Neurosurgery 1999; 45: 1093 –1104. 112 Chung RY, Chiocca EA: Gene therapy for tumors of the central nervous system. Surg Oncol Clin N Am 1998; 7: 589 – 602. 113 Qureshi NH, Chiocca EA: A review of gene therapy for the treatment of central nervous system tumors. Crit Rev Oncog 1999; 10: 261–274. 114 Benoit JP, Faisant N, Venier-Julienne MC, et al.: Development of microspheres for neurological disorders: from basics to clinical applications. J Control Release 2000; 65: 285–296. 115 Kreuter J: Nanoparticulate systems for brain delivery of drugs. Adv Drug Deliv Rev 2001; 47: 65–81. 116 Maeda H: SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv Drug Deliv Rev 2001; 46: 169 –185. 117 Kirsch M, Schackert G, Black PM: Anti-angiogenic treatment strategies for malignant brain tumors. J Neurooncol 2000; 50: 149 –163. 118 Grotzer MA, Wiewrodt R, Janss AJ, et al.: High microvessel density in primitive neuroectodermal brain tumors of childhood. Neuropediatrics 2001; 32: 75 –79. 119 Sipos EP, Brem H: Local anti-angiogenic brain tumor therapies. J Neurooncol 2000; 50: 181–188. 120 Puduvalli VK, Sawaya R: Antiangiogenesisatherapeutic strategies and clinical implications for brain tumors. J Neurooncol 2000; 50: 189 –200. 121 Kirsch M, Schackert G, Black PM: Angiogenesis, metastasis, and endogenous inhibition. J Neurooncol 2000; 50: 173 –180. 122 Hall WA, Djalilian HR, Nussbaum ES, et al.: Long-term survival with metastatic cancer to the brain. Med Oncol 2000; 17: 279 –286. 123 Guinebretiere JM, Contesso G: “Micrometastases”: the pathologist’s point of view. Bull Cancer 2001; 88: 549 –550, 555 –560. 124 Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission. Cochrane Database Syst Rev 2000; 4. 125 Arriagada R, Le Chevalier T, Borie F, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 1995; 87: 183–190. 126 Fidler IJ: Critical determinants of cancer metastasis: rationale for therapy. Cancer Chemother Pharmacol 1999; 43: S3 –10. 127 Miyazaki K, Koshikawa N, Hasegawa S, et al.: Matrilysin as a target for chemotherapy for colon cancer: use of antisense oligonucleotides as antimetastatic agents. Cancer Chemother Pharmacol 1999; 43: S52–55. 128 Saiki I: Cell adhesion molecules and cancer metastasis. Jpn J Pharmacol 1997; 75: 215 –242. 129 Brodt P, Samani A, Navab R: Inhibition of the type I insulin-like growth factor receptor expression and signaling: novel strategies for antimetastatic therapy. Biochem Pharmacol 2000; 60: 1101–1107. 130 Suganuma M, Okabe S, Sueoka N, et al.: Green tea and cancer chemoprevention. Mutat Res 1999; 428: 339 –344. 131 Nordman E: 75se-sodium selenite scintigraphy in diagnosis of tumours. Acta Radiol Suppl 1974; 340: 3 –78. 132 D’Angio GJ, Loken M, Nesbit M. Radionuclear (75Se) identiﬁcation of tumor in children with neuroblastoma. Radiology 1969; 93: 615 – 617.

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133 Gwyn K, Sinicrope FA: Chemoprevention of colorectal cancer. Am J Gastroenterol 2002; 97: 13–21. 134 Krishnan K, Brenner DE: Prostaglandin inhibitors and the chemoprevention of noncolonic malignancy. Gastroenterol Clin North Am 2001; 30: 981–1000. 135 Shureiqi I, Lippman SM: Lipoxygenase modulation to reverse carcinogenesis. Cancer Res 2001; 61: 6307–6312. 136 Cuendet M, Pezzuto JM: The role of cyclooxygenase and lipoxygenase in cancer chemoprevention. Drug Metabol Drug Interact 2000; 17: 109 –157. 137 Vane JR, Bakhle YS, Botting RM: Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38: 97–120. 138 Funk CD: Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001; 294: 1871–1875. 139 Marnett LJ: Cyclooxygenase mechanisms. Curr Opin Chem Biol 2000; 4: 545 –552. 140 Yamagata K, Andreasson KI, Kaufmann WE, et al.: Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 1993; 11: 371–386. 141 Kaufmann WE, Worley PF, Pegg J, et al.: COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A 1996; 93: 2317–2321. 142 Breder CD, Dewitt D, Kraig RP: Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 1995; 355: 296 –315. 143 Matsumura K, Cao C, Ozaki M, et al.: Electron microscopic evidence for induction of cyclooxygenase-2 in brain endothelial cells. Ann N Y Acad Sci 1998; 856: 278 –280. 144 Cao C, Matsumura K, Yamagata K, et al.: Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor. Brain Res Mol Brain Res 1998; 56: 45 –56. 145 Elmquist JK, Breder CD, Sherin JE, et al.: Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages. J Comp Neurol 1997; 381: 119 –129. 146 Ek M, Engblom D, Saha S, et al.: Inﬂammatory response: pathway across the blood-brain barrier. Nature 2001; 410: 430 – 431. 147 Bazan NG, Rodriguez de Turco EB, Allan G: Mediators of injury in neurotrauma: intracellular signal transduction and gene expression. J Neurotrauma 1995; 12: 791– 814. 148 Andreasson KI, Savonenko A, Vidensky S, et al.: Age-dependent cognitive deﬁcits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J Neurosci 2001; 21: 8198– 8209. 149 in t’Veld BA, Ruitenberg A, Hofman A, et al.: Nonsteroidal antiinﬂammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001; 345: 1515 –1521. 150 Herschman HR: Function and regulation of prostaglandin synthase 2. Adv Exp Med Biol 1999; 469: 3–8. 151 Hayaishi O: Prostaglandin D2 and sleepaa molecular genetic approach. J Sleep Res 1999; 8 (Suppl 1): 60–64. 152 Romanovsky AA, Ivanov AI, Szekely M: Neural route of pyrogen signaling to the brain. Clin Infect Dis 2000; 31 (Suppl 5): S162–167. 153 Bezzi P, Volterra A: A neuron-glia signalling network in the active brain. Curr Opin Neurobiol 2001; 11: 387–394. 154 Vanegas H, Schaible HG: Prostaglandins and cycloxygenases in the spinal cord. Prog Neurobiol 2001; 64: 327–363. 155 Bartfai T: Immunology. Telling the brain about pain. Nature 2001; 410: 425 – 427.

Adjuvant approaches for preventing brain metastases 459 156 Blatteis CM, Sehic E, Li S: Pyrogen sensing and signaling: old views and new concepts. Clin Infect Dis 2000; 31 (Suppl 5): S168–177. 157 Sugimoto Y, Narumiya S, Ichikawa A: Distribution and function of prostanoid receptors: studies from knockout mice. Prog Lipid Res 2000; 39: 289–314. 158 Ushikubi F, Segi E, Sugimoto Y, et al.: Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 1998; 395: 281–284. 159 Samad TA, Moore KA, Sapirstein A, et al.: Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inﬂammatory pain hypersensitivity. Nature 2001; 410: 471– 475. 160 Hoozemans JJ, Veerhuis R, Janssen I, et al.: Interleukin-1 beta induced cyclooxygenase 2 expression and prostaglandin E2 secretion by human neuroblastoma cells: implications for Alzheimer’s disease. Exp Gerontol 2001; 36: 559 –570. 161 Shono T, Toﬁlon PJ, Bruner JM, et al.: Cyclooxygenase-2 expression in human gliomas: prognostic signiﬁcance and molecular correlations. Cancer Res 2001; 61: 4375 – 4381. 162 Lynch PM: COX-2 inhibition in clinical cancer prevention. Oncology (Huntingt) 2001; 15: 21–26. 163 Prescott SM, Fitzpatrick FA: Cyclooxygenase-2 and carcinogenesis. Biochim Biophys Acta 2000; 1470: M69 –78. 164 Matsuo M, Yonemitsu N, Zaitsu M, et al.: Expression of prostaglandin H synthase-2 in human brain tumors. Acta Neuropathol (Berl) 2001; 102: 181–187. 165 Casper D, Lekhraj R, Yaparpalvi US, et al.: Acetaminophen selectively reduces glioma cell growth and increases radiosensitivity in culture. J Neurooncol 2000; 46: 215 –229. 166 Brash AR: Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem 1999; 274: 23679 –23682. 167 Kuhn H: Structural basis for the positional speciﬁcity of lipoxygenases. Prostaglandins Other Lipid Mediat 2000; 62: 255 –270. 168 Lammers CH, Schweitzer P, Facchinetti P, et al.: Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling. J Neurochem 1996; 66: 147–152. 169 Ohtsuki T, Matsumoto M, Hayashi Y, et al.: Reperfusion induces 5-lipoxygenase translocation and leukotriene C4 production in ischemic brain. Am J Physiol 1995; 268: H1249 – 1257. 170 Palluy O, Bendani M, Vallat JM, et al.: 12-lipoxygenase mRNA expression by cultured neurons. C R Acad Sci III 1994; 317: 813– 818. 171 Li S, Li Y, Carthew RW, et al.: Photoreceptor cell differentiation requires regulated proteolysis of the transcriptional repressor Tramtrack. Cell 1997; 90: 469 – 478. 172 Peters-Golden M, Brock TG: Intracellular compartmentalization of leukotriene synthesis: unexpected nuclear secrets. FEBS Lett 2001; 487: 323 –326. 173 Chen XS, Funk CD: The N-terminal “beta-barrel” domain of 5-lipoxygenase is essential for nuclear membrane translocation. J Biol Chem 2001; 276: 811– 818. 174 Hammarberg T, Provost P, Persson B, et al.: The N-terminal domain of 5-lipoxygenase binds calcium and mediates calcium stimulation of enzyme activity. J Biol Chem 2000; 275: 38787–38793. 175 Yokomizo T, Izumi T, Chang K, et al.: A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997; 387: 620 – 624. 176 Nagy L, Tontonoz P, Alvarez JG, et al.: Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998; 93: 229 –240. 177 Chawla A, Repa JJ, Evans RM, et al.: Nuclear receptors and lipid physiology: opening the X-ﬁles. Science 2001; 294: 1866 –1870.

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178 Escher P, Wahli W: Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 2000; 448: 121–138. 179 Shureiqi I, Xu X, Chen D, et al.: Nonsteroidal anti-inﬂammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression. Cancer Res 2001; 61: 4879–4884. 180 Straus DS, Glass CK: Cyclopentenone prostaglandins: new insights on biological activities and cellular targets. Med Res Rev 2001; 21: 185 –210. 181 Rosen ED, Spiegelman BM: Ppargamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 2001; 276: 37731–37734. 182 Cathcart MK, Folcik VA: Lipoxygenases and atherosclerosis: protection versus pathogenesis. Free Radic Biol Med 2000; 28: 1726 –1734. 183 Glass CK, Witztum JL: Atherosclerosis. The road ahead. Cell 2001; 104: 503 –516. 184 Maccarrone M, Melino G, Finazzi-Agro A: Lipoxygenases and their involvement in programmed cell death. Cell Death Differ 2001; 8: 776 –784. 185 Funk CD: The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deﬁcient mice. Biochim Biophys Acta 1996; 1304: 65–84. 186 Johnson EN, Sun D, Chen XS, et al.: Lipoxygenase gene disruption studies. Status and applications. Adv Exp Med Biol 1999; 447: 63 –73. 187 Tang K, Honn KV: Lipoxygenase metabolites and cancer metastasis. Adv Exp Med Biol 1997; 422: 71–84. 188 Nie D, Tang K, Szekeres K, et al.: The role of eicosanoids in tumor growth and metastasis. Ernst Schering Res Found Workshop 2000; 31: 201–217. 189 Boado RJ, Pardridge WM, Vinters HV, et al.: Differential expression of arachidonate 5-lipoxygenase transcripts in human brain tumors: evidence for the expression of a multitranscript family. Proc Natl Acad Sci U S A 1992; 89: 9044 –9048. 190 Chio CC, Baba T, Black KL: Selective blood-tumor barrier disruption by leukotrienes. J Neurosurg 1992; 77: 407– 410. 191 Kim JA, Chung YJ, Lee YS: Intracellular Ca2+ mediates lipoxygenase-induced proliferation of U-373 MG human astrocytoma cells. Arch Pharm Res 1998; 21: 664 – 670. 192 Bian X, Shi J, Xin R: [Effects of nordihydroguaiaretic acid on the growth and differentiation of SHG-44 glioma cell line]. Zhonghua Bing Li Xue Za Zhi 1997; 26: 285 –288. 193 Horizoe T, Nagakura N, Chiba K, et al.: ER-34122, a novel dual 5-lipoxygenase/ cyclooxygenase inhibitor with potent anti-inﬂammatory activity in an arachidonic acidinduced ear inﬂammation model. Inﬂamm Res 1998; 47: 375 –383. 194 Leff AR: Discovery of leukotrienes and development of antileukotriene agents. Ann Allergy Asthma Immunol 2001; 86: 4 – 8.

CHAPTER 27

Intracranial metastases: management guidelines and decision-making Syed Enam, Jack P Rock

Introduction Guidelines (practice parameters) for the management of patients with brain metastases, as for any other medical management question, may be formulated in several ways based on differing inputs. Traditionally, the recommendations of a clinically experienced physician have been recorded, compiled, and accepted as reasonable. This process is, at its best, derived from a careful retrospective consideration of a series of cases and may well lead to useful guidelines; however, case series reporting can be biased and thereby lead to erroneous recommendations. By bringing together several clinically experienced physicians, we hope to eliminate some of this inherent bias, and the promulgation of consensus-based guidelines follows. Here, too, some bias remains, although in more subtle forms. To further avoid bias, evidence-based guidelines have also been introduced. This format requires focusing on speciﬁc clinical questions and paying close attention to design, implementation, statistical techniques, and follow-up aspects of clinical investigations. Ultimately, only those studies that provide valid and useful data are included in the ﬁnal management guidelines product. When dealing with brain metastases in clinical practice, controversies are always lurking just below the surface of almost all management recommendations. Given the fact that treatment of patients with brain metastases is a multidisciplinary process, these controversies impact several subspecialties including neurosurgery, neurology, radiation oncology, and medical oncology, and can lead, ultimately, to vastly divergent attitudes and recommendations. A clinician’s focus will vary based on differing clinical perspectives and patient factors such as the functional status, systemic extent of cancer, and preference, among others. Decision-making is complicated further by the fact that several treatment modalities are available to treat metastatic brain tumors including various forms and combinations of surgery, radiation, and chemotherapy. The modalities also differ in terms of their anatomic focus (i.e., local versus global). Surgery is primarily a local treatment modality whereas radiation can be delivered either locally or globally (i.e., radiosurgery, brachytherapy, and whole-brain radiation therapy [WBRT]). Chemotherapy is 461

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primarily thought of as a global or distant agent but more recently has been utilized locally (i.e., chemotherapy-laden polymers used in conjunction with surgical resection). Evidence can be found in the literature supporting all of these treatment alternatives. Some clinical questions remain: 1 Is surgery or radiosurgery better treatment for a single brain metastasis? 2 Should surgery and/or radiosurgery be supplemented with WBRT? 3 What is more suitable for the treatment of multiple brain metastases, surgery, radiosurgery or WBRT? 4 Is chemotherapy an appropriate adjuvant? 5 Do situations occur in which surgery and/or radiosurgery with or without WBRT should be performed in patients with advanced systemic disease? Whereas various management guidelines have been published and serve as a basis on which to manage patients, clinical decision-making remains an art based on each physician’s education and experience and each patient’s background and preference. In this chapter, we will examine various guidelines processes, discuss their products and limitations, and provide speciﬁc clinical examples.

What do we learn from literature? At the outset, it would seem that based on the amount of scientiﬁc literature available, one could easily determine a strategy for treating patients with metastatic brain tumors; however, on closer inspection, the literature fails to provide unanimously acceptable conclusions. This is partially because the data quality varies from case reports and case series to randomized prospective clinical trials, the latter of which are few. Based on the quality of data (or evidence), clinical research literature can be classiﬁed into three categories1. • Class I: well-designed randomized controlled clinical trials. • Class II: well-designed nonrandomized controlled studies such as casecontrol retrospective analyses or cohort studies. • Class III: expert opinion, nonrandomized historical controls or case series and case reports. How clearly the practice parameter deﬁnes and guides a particular management issue depends on the quality of the evidence in the study. This has been reviewed by Eddy1, and suggestions in designing a practice policy have been proposed. Generally, three types of practice parameters can be formed: 1 Standards: These are generally accepted principles for patient management that reﬂect a high degree of clinical certainty. With rare exceptions, particular standards should be followed and are based on Class I evidence or, when circumstances preclude randomized controlled clinical trials, are based on overwhelming evidence from Class II studies that directly address the question at hand or from decision analysis that directly addresses all the issues. 2 Guidelines: Guidelines are more ﬂexible and, although they should be followed in most cases, they may be tailored to individual patients. These recommendations for patient management may identify a particular strategy

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or range of strategies and reﬂect moderate clinical certainty. Guidelines are based on Class II evidence, decision analysis that directly addresses the issue, or a strong consensus of Class III evidence. 3 Options: Options are strategies for patient management that are based on inconclusive or conﬂicting evidence or opinion. Options are considered when the outcome of an intervention is unclear, when the outcome is known but patients’ preferences are unknown, when outcome is known but the patient has no preference or is indifferent, or when the patients differ in their preferences toward various outcomes. Whereas recommendations for the management of patients with speciﬁc diseases may often come in the form of statements from acknowledged clinical experts, contemporary guideline processes usually fall into two major categories: consensus-based and evidence-based. Consensus-based processes involve a panel of practitioners from various subspecialties with recognized clinical expertise in the speciﬁc medical topic at issue. Based on the panel’s combined education and experience, a step-by-step outline is developed, from diagnosis through treatment and follow up, that summarizes the best plan for the management of the patient. An example of a consensus-based process is the National Comprehensive Cancer Network’s (NCCN) adult brain tumor guidelines2. These guidelines represent the consensus of individuals from neurosurgery, neuro-oncology, medical oncology, and radiation oncology regarding the management of patients with either one to two or more than two brain metastases. A publication note states that “these guidelines are a statement of consensus of the authors of the publication regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent clinical judgement, keeping in mind individual clinical circumstances to determine any patient’s care or treatment.” This type of guideline process can address management questions in a broad fashion because it incorporates the literature-based and experience-based knowledge of participating clinicians. By deﬁnition, therefore, this type of guideline process, though an important attempt to summarize reasonable practice, may be subject to the biases that normally result from the everyday practice of medicine. Ultimately, these biases ﬂavor the guidelines statement and limit the validity and reliability of the recommendations. This limitation has led to the concept of the evidence-based guidelines process. In hopes of eliminating bias, the evidence-based guideline team narrowly deﬁnes the clinical question, reviews the relevant literature, and selects references that contain data addressing the speciﬁc question. The data must be signiﬁcant not only from a statistical point of view but also from a meaningful clinical point of view. It is this latter requirement that enables the team to sift through an extensive body of literature to ﬁnd studies that speciﬁcally support the ﬁnal guidelines statement. The main limitation of the evidencebased process is that, to produce valid guidelines statements, speciﬁc clinical questions must be formatted, and although many references may in some way touch on the particular clinical question, relatively few references will

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speciﬁcally address the clinical question and produce data that adequately support conclusions. Therefore, evidence-based processes must be focused on a narrow clinical question and, unlike consensus-based processes, may only answer a speciﬁc clinical question if they are able to provide any answer at all. Evidence-based processes usually lead to clinical options, less often to clinical guidelines, and rarely to clinical standards (see above). A recent evidence-based guidelines effort supported by the Joint Tumor Section of the American Association of Neurological Surgeons ( JTS/AANS) and focusing on management issues for a patient with brain metastases was composed of clinicians from neurosurgery (one with extensive methodology experience), neuro-oncology, and radiation oncology3. Given the various contemporary strategies for the clinical management of a patient with a single brain metastasis, the team composed a clinical question regarding the optimal management of an adult with a single brain metastasis. A literature review utilizing Medline and Embase formats and spanning the years 1966–1998 used MeSH subject headings incorporating all key words relevant to the clinical question. Of the 602 references found, all team members selected 76 after careful analysis. After further discussion, 26 key articles were chosen that, based on design and methodology, led to data supporting the authors’ conclusions in a way that provided answers to the clinical question. The following is a review of the literature that addresses the question, “What is the optimal management of an adult with a single lesion in the brain consistent with a metastasis?”

The role of surgical resection and WBRT There are three randomized trials (class I evidence) that address the role of surgical resection in addition to WBRT. The study by Patchell et al.4 was a prospective randomized trial on 48 patients. The two randomized arms in this clinical trial consisted of patients undergoing either surgical resection plus postoperative WBRT or WBRT alone. The median survival time of 40 weeks in the cohort undergoing surgical resection and WBRT compared favorably with the 15 weeks in the WBRT-alone cohort. The rate of recurrence at the initial site of metastasis in the surgical cohort was lower and the time to recurrence was prolonged (median 59 weeks versus 21 weeks for the WBRT-alone cohort, p < 0.001). Death from neurological causes was also reduced in the surgical cohort. The study by Vecht et al.5 was also a prospectively randomized trial on 63 patients. Median survival time was 10 months in patients treated with surgical excision and radiotherapy and six months in patients treated with radiotherapy alone. Functionally independent survival was longer in the surgical group (nine months versus 4 months with radiotherapy alone, p < 0.06). The prospective randomized trial by Mintz et al.6, in contrast to the other two studies, failed to show a signiﬁcant difference in survival time for patients in the surgical and postoperative WBRT arm versus the WBRT-alone arm (5.6 months versus 6.3 months, respectively, p < 0.24). In this study, deaths from

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neurological causes, nevertheless, were lower in the surgical group (14.6%) than in the radiation-alone group (27.9%). There is one reference (class I) that focuses on the role of WBRT after surgery. This study by Patchell et al.7 is a prospective randomized trial on a group of 95 patients who underwent surgical resection of metastasis. Of the 95 patients, 49 had postoperative radiation, and 46 were observed only after surgery. Although there was no signiﬁcant overall survival difference between the two groups (43 weeks versus 48 weeks, respectively), the patients who underwent radiation were less likely to die of neurological disease (14% versus 44%, respectively) and had a lower incidence of recurrence at the site of initial resection in the brain (14% versus 37%, respectively). Another (class II) retrospective analysis examining the value of postoperative radiation therapy compares 32 patients who underwent postoperative radiation to 32 matched patients who did not8. This study also failed to show any signiﬁcant survival prolongation, but the results suggested that patients who underwent radiation after surgery had better tumor control in terms of freedom from local recurrence.

The role of radiosurgery Before the advent of radiosurgery, surgical excision followed by WBRT was the undisputed management strategy for patients with single brain metastases and stable systemic disease. With the growing popularity of radiosurgery, the question has arisen as to whether surgical excision with WBRT should remain the gold standard for the treatment of a metastatic brain lesion. Based on the evidence in the literature, there is no prospectively randomized clinical trial on the role of radiosurgery in the treatment of brain metastasis; however, important Class III information does exist (although it is of low quality). In a retrospective analysis of 116 patients by Flickinger et al.9, the median survival time for all patients was 11 months after radiosurgery and 20 months after diagnosis. Local tumor control was better in patients treated with radiosurgery and WBRT relative to those treated by radiosurgery alone. In another retrospective analysis of 123 patients by Auchter et al.10, the actuarial median survival time from radiosurgery was 56 weeks. Although the latter study used inclusion criteria similar to those of Patchell et al.4, various biases inherent in this methodology preclude a true comparison of results; however, the results of radiosurgical treatment are encouraging. Another class III investigation compared the results of radiosurgery and surgical excision in retrospectively matched groups of patients11. In this study, one group consisted of 31 patients treated with radiosurgery and another group consisted of 62 patients treated with surgery. Although both groups included patients treated with WBRT, median survival rates in the radiosurgical group and surgical group were 7.5 months and 16.4 months, respectively. Of deaths in the radiosurgical group, 50% were related to neurological causes, compared with 19% in the surgical group. Recurrence in the radiosurgical

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group was local in 38.7% and distant in 9.7% versus 8.1% local and 21% distant recurrence in the surgical group. Complications in the radiosurgical group included symptomatic radionecrosis in 12.9% and intratumoral hemorrhage in 9.7%, resulting in one death. Complications in the surgical group included postoperative hematoma in two patients that did not require a reoperation and wound infection treated by antibiotics in one patient.

The role of brachytherapy Brachytherapy (interstitial implant radiation therapy) is an alternative way to deliver focal radiation to the metastatic brain tumor. Although considerable literature exists on the topic, one retrospective review of case series (class III evidence) in particular provided information that appropriately addressed the clinical question12. Of the four groups of patients, one group consisted of 38 patients (35 with a solitary metastasis, three with multiple metastases) treated with combined brachytherapy and WBRT, a second group consisted of 49 patients treated with WBRT alone, a third group consisted of 21 patients treated with brachytherapy alone, and a fourth group consisted of 22 patients treated with brachytherapy for recurrent disease. Patients undergoing combined treatment had a median survival time of 17 months compared with 12 and 7.7 months for brachytherapy and WBRT alone, respectively. A valid comparison with other class II studies in the literature is not possible due to lack of cohort analysis in these data, inability to relate systemic disease status for individual patients, and inability to separate data between solitary and multiple metastases. These shortcomings limit the value of the data on patients undergoing combined treatment, which does seem favorable otherwise.

Practice parameters After reviewing many of these recent studies, a practice parameter (i.e., practice guideline) was developed for patients with a single metastatic brain tumor3. It is important to remember one of the limitations of evidencebased guidelines: these parameters are developed for a precisely deﬁned case scenario, that of an adult patient with a single metastasis of cancer to the brain in whom the primary cancer is not highly radiosensitive and systemic disease is stable. The following summarizes the literature analysis. • The preponderance of class I evidence suggests that in patients who meet the eligibility criteria, and who receive at least 36 Gy of WBRT, surgical excision of the metastasis can be expected to more than double survival time. WBRT in addition to surgical excision, studied in only one class I reference, did not demonstrate a signiﬁcant survival increase, although there was a signiﬁcant decrease in local and distant recurrence in the brain. • No data are available that establish WBRT alone as a treatment modality that can signiﬁcantly prolong survival and achieve better control over recurrence relative to no treatment. Although various estimates of survival can be

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found, historical controls in retrospective analysis studies suggest that the mean survival time of patients with untreated brain metastases is under six months, and median survival time is approximately one month6. Survival time may be doubled by treating these patients with corticosteroids, and the addition of WBRT may increase survival to between three and six months. Most of the data that address survival of patients with metastatic brain tumors without WBRT are class III evidence and should therefore be interpreted with caution. These survival estimates nevertheless remain the basis for considering the efﬁcacy of the treatments in improving the survival of patients with metastatic brain tumors. • Theoretically, stereotactic radiosurgery would seem a safer and more feasible method with which to treat metastatic brain tumors, given certain restrictions such as size and resultant mass effect, location of the tumor, and previous history of radiation therapy; however, stereotactic radiosurgery, in contrast to surgical excision, has not been subjected to a high quality randomized trial. In addition, except for survival, the studies on radiosurgery look at different outcome criteria, which confounds direct comparison with surgical excision as a treatment modality. For example, an increase in the size of the tumor by 20% might be considered as stable in certain investigations, thereby constituting a success in the trial, whereas success in a surgical trial would be easier to appreciate. As a direct result of the lack of a high quality class I or II trial, it remains impossible to conclude that radiosurgery is comparable or superior to surgical resection in its effect on patient survival time or quality of life. That said, there is sufﬁcient retrospective evidence to suggest that radiosurgery is a reasonable way to manage patients based on survival, functional status, and recurrence data. As a result of the relative inadequacy of the literature and the likely impossibility of accruing patients to a high quality class I clinical trial that directly compares surgical excision with radiosurgery, the question arises as to what, in fact, is the superior treatment modality. The literature states that surgical excision remains the gold standard for treatment of single metastasis to the brain, but many clinicians are turning to radiosurgery for their patients. The cancer patient’s current quality of life, anticipated length of life, surgical risks, and cost all play a role (i.e., bias) in the ﬁnal decision. Evidence-based work will always come up against these poorly deﬁned limits, and ultimately the decision of how to treat is the dilemma with which clinician, patient, and family must struggle. Based on the information available, the Joint Tumor Section guidelines are as follows: 1 There is insufﬁcient information to establish any recommendation as standard. 2 There is a preponderance of class I evidence that suggests surgical resection with WBRT provides the best survival time, but one trial does not support this conclusion6. Therefore, the recommendation of surgical excision with WBRT as providing the best survival cannot be considered as a standard but must be considered as a guideline at best.

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3 Class III evidence suggests that radiosurgery with WBRT may provide an effective alternative to surgical excision with WBRT. But because this option is supported by class III evidence only, the use of radiosurgery could not be established as a guideline, and should be considered as an option.

Decision-making Evidence-based practice parameters are developed for a speciﬁc group of patients and, unfortunately, the best answer (that supported by a welldesigned class I study) is often lacking. When it comes to making treatment recommendations for an individual patient, the practice parameters can only serve as a blueprint from which the practitioner must work. An awareness that limitations exist in the interpretation and application of practice parameters is essential. When there is a standard of care, the treatment is restricted by narrow limits, whereas there is more freedom (i.e., less certainty) in guidelines and even less certainty in options available to the practitioner. Although the JTS/AANS practice parameters were developed after an exhaustive review of the available information, one quickly realizes that standards could not be proposed based on the information available. Inclusion and exclusion criteria are considerable and include, at a minimum, an adult patient with a single brain metastasis and stable systemic disease, but exclude the following: 1 patients who have lesions that are not surgically resectable, 2 patients with multiple metastases, leptomeningeal disease, small cell lung cancer, lymphoma, leukemia, germ-cell tumors or multiple myeloma, 3 patients who had prior cranial irradiation, and 4 patients who need emergency surgery. This leaves the clinician with many scenarios that have not been wellstudied, such as patients with multiple brain metastases. Additional factors that affect the decision-making process include the following (evidence-based recommendations for each clinical scenario have not been developed, and comments represent the authors’ experience): • Urgency in relieving mass effect • Extent of systemic disease • Radiosensitivity of the tumor • Location and size of metastasis • Conﬁrmed pathological diagnosis • Multiple versus single lesions • Radionecrosis • Patient condition Urgency of the condition. Impending uncal herniation caused by the lesion and its surrounding mass effect in a patient with stable systemic disease requires surgical intervention. Radiosurgery and WBRT do not work in as timely a manner as surgery in this situation.

Intracranial metastases: management guidelines and decision-making 469 Table 27.1 Categorization of radiosensitivity of brain metastases*.

Highly responsive: Lymphoma Germinoma Lung (small cell) cancer Choriocarcinoma Intermediately responsive: Breast cancer Lung (non-small cell) cancer Colorectal cancer Minimally responsive: Melanoma Renal cell cancer Sarcoma *Adapted with permission from Lang FF, Sawaya R: Surgical management of cerebral metastases. Neurosurg Clin N Am 1996; 7: 459–48413.

Mass effect. Even if the situation does not require urgent intervention, the mass effect caused by the large size of the metastatic lesion and/or its surrounding vasogenic edema may require surgical intervention, although treating the patient with steroids may help create the time for employing adjuvant radiation therapy or radiosurgery. A metastatic mass causing intractable seizures will often beneﬁt from timely excision. Extent of the systemic disease. The extent of systemic disease is the most important negative predictor of survival in most investigations, but not infrequently, the quality of life for a patient with advanced and/or progressing systemic disease may beneﬁt, for a limited time, from surgical excision of a lesion causing neurological deterioration such as intractable seizures, hemiparesis, and speech impairment. The guideline cited above was drawn from investigations in which patients with survival projections of less than three months were excluded. Radiosensitivity of the tumor. Radiosensitive tumors (Table 27.1) are generally not considered for surgical excision unless previous radiation therapy has failed (a relatively uncommon occurrence), thereby demonstrating that the lesion is no longer as radiosensitive as predicted. Location of metastasis. The anatomical location of the metastatic lesion is also important. Treatment of tumors located in eloquent versus noneloquent brain regions will engender risks for both surgical and radiosurgical strategies, although the timing of complications will differ. Tumors located in the posterior fossa or anteromedial temporal lobe also need special consideration because swelling after therapy can lead to grave consequences. A metastasis in the posterior

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fossa may cause lethal compression of the brainstem or acute hydrocephalus, and temporal lobe lesions can lead to uncal herniation. Neither of these scenarios leaves enough time for radiation or chemotherapy to act. In both situations, resection may prolong survival so that other treatments can be effective. This resection strategy may remain valid even for a patient with multiple metastases in whom only the posterior fossa or temporal lobe lesion is life threatening. Size of the tumor. There is a size limit for tumor masses that can be considered for focal radiation. In the radiosurgical study by Flickinger et al.9, the average tumor ranged from three to 36 mm in maximum diameter. Currently, a diameter of 25 mm is generally thought to be the limit of the tumor size for radiosurgical treatment. For a larger lesion, surgical resection should be considered. Histopathological diagnosis. Most would agree (consensus statement) that if radiation treatment is being considered for a single brain lesion, even in a patient with known cancer, a histological diagnosis is recommended because radiographic imaging will be incorrect a signiﬁcant percent of the time4. Occasionally a patient presents with a very small lesion, and if the primary site cannot be located, frequent follow-up imaging will be indicated; but when the primary site is unknown, resection or biopsy of the brain lesion may reveal the tumor type. Number of metastases. Multiple metastases to the brain are generally considered a contraindication to surgery. However, in a recent retrospective matched study on patients with multiple metastases who underwent resection of all the metastatic tumors, Bindal et al. suggest that patient survival was comparable to that after resection of a single metastasis14. This class III evidence supports resection for more than one metastasis. Recurrent mass. A recurrent mass at a previously irradiated site raises the possibility of radionecrosis. Imaging studies and the clinical course of the patient cannot reliably differentiate recurrent tumor from radionecrosis. Surgical excision for the purpose of biopsy may be indicated. Conﬁrming the distinction between recurrent tumor and radionecrosis is necessary as the treatment for each would be vastly different. Medical condition of patient and performance status. The health of the patient and his performance status are important factors that are considered by neurosurgeons, radiation oncologists, and medical oncologists; however, the extent of systemic disease is the primary determinant of survival.

Practical case scenarios Several representative (actual) cases are presented here. There may not be only one right answer for any of these cases, but we present our recommendations as options in decision making.

Intracranial metastases: management guidelines and decision-making 471

(A)

(B) Figure 27.1 Magnetic resonance (MR) images (A, coronal and B, axial) of right frontal lobe metastasis in premotor/motor cortex with signiﬁcant mass effect on the motor strip.

Case 1. A 56-year-old, right-handed male with stable lung cancer was referred to the neurosurgical clinic for evaluation of left upper extremity weakness. A lesion was found in the right premotor/motor cortex. Systemic disease was stable. Surgical excision was performed. Intraoperative motor mapping identiﬁed the motor cortex, the lesion was entered from the premotor aspect, and total resection was accomplished. No complications were encountered (Figure 27.1). Case 2. A 62-year-old active male was found to have lung cancer localized to the mediastinum and one brain metastasis in the posterior fossa, with two smaller masses in the supratentorial compartment. The patient was in good health. Surgical excision of the posterior fossa lesion was performed without complication and provided the patient with sufﬁcient time in good functional status to undergo further adjuvant radiosurgery without WBRT (Figure 27.2). Case 3. A 76-year-old female with a 5-year history of breast cancer presented with right foot drop. Magnetic resonance (MR) imaging revealed a 1.5-cm mass based on the falx and the presence of vasogenic edema. Considering the age and preference of the patient and the size of the metastatic lesion, radiosurgery was performed (Figure 27.3). Case 4. A 73-year-old, right-handed male without a known history of cancer presented with new onset seizures. A computed tomography (CT) scan and MR imaging of the brain revealed three cerebral metastases. A search for the

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(A)

(C)

(B)

Figure 27.2 MR images of a patient with multiple metastases. The cerebellar lesion (A and C) exhibited signiﬁcant local mass effect, whereas the right temporo-parietal lesion (B) and left frontal lesion (C) were cystic and small.

Figure 27.3 MR image of the brain of a 76year-old woman showing a dura-based lesion near the superior sagittal sinus, causing signiﬁcant edema in the region of the motor cortex representing the lower extremity.

primary tumor revealed a lung lesion, which was biopsied and found to be small cell lung cancer. The patient underwent WBRT without neurosurgical intervention and was neurologically normal at his six-month follow up visit with excellent radiographic resolution of his cerebral lesions (Figure 27.4).

Intracranial metastases: management guidelines and decision-making 473

Figure 27.4 MR image of the brain showing two of the three metastatic lesions (left frontal and left parietal) in a 73-year-old male.

Figure 27.5 MR image of the right frontal dura-based parasagittal lesion in a patient with a known history of metastatic breast cancer.

Case 5. A 68-year-old female with metastatic breast cancer had been treated with WBRT despite the lack of evidence of brain metastasis. On follow up she was found not only to have metastasis to the spine but also to the cerebral hemisphere. Because of progressive left hemiparesis, she received steroids. Her neurological status continued to deteriorate. The differential diagnosis of brain radionecrosis versus the presence of metastatic lesions prompted surgical biopsy and excision, which conﬁrmed radionecrosis and relieved the mass effect. Steroid administration was tapered till it could be completely withdrawn (Figure 27.5). Case 6. A 70-year-old male presented to the emergency room (ER) with mild confusion, headache, and left homonymous hemianopsia. A CT scan of the brain revealed three hemorrhagic lesions. This presentation of synchronous hemorrhagic lesions is typical of melanoma. The patient did not have a primary diagnosis. Excisional biopsy of the right occipital lesion was offered, but the patient declined intervention (Figure 27.6).

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Figure 27.6 Computed tomography (CT) scan of the brain of a 70-year-old man revealing intracerebral hemorrhages that appeared synchronously at three locations: right frontal, left frontal, and right parieto-occipital.

Case 7. A 79-year-old male with a history of prostate cancer presented to the ER with acute onset expressive aphasia. Based on a CT scan of the brain (Figure 27.7A) and initial assessment, a diagnosis of intracerebral hemorrhage was made. The subsequent work-up with MR imaging (Figure 27.7B,7C) and electroencephalography suggested a dural-based lesion causing seizures. The patient underwent craniotomy for resection of the tumor along with overlying tumor-inﬁltrated skull (Figure 27.7).

Tumor boards The practice of medicine is inexact. We are biased by many factors such as training inﬂuences, subspecialty practice philosophy, and personal clinical experiences, among others. The practical knowledge required to manage a given disease process rarely is the property of any one clinician. Additionally, there is often more than one reasonable management strategy for a disease process, and as a result, the patient will frequently beneﬁt from the advice of a team of clinicians. These considerations have given rise to the popular concept of the “tumor board.” Although the tumor board’s recommendation avoids some of the biases implicit in an individual clinician’s recommendation, the board’s recommendation remains a consensus-based statement formulated primarily from nonrandomized, retrospective experience where bias still plays a role. Despite these reservations, the opinion of a multidisciplinary panel of clinicians is most likely to provide optimal recommendations given the nature of the practice of medicine.

Conclusions Guidelines represent our best effort to organize clinical material and enumerate consistently reasonable steps for the management of patients with various

Intracranial metastases: management guidelines and decision-making 475

(B)

(A)

Figure 27.7 CT scan of the brain in this patient suggested a left frontal cortical hemorrhage (A). MR images of the same brain (with contrast) revealed a dura-based lesion over the left temporofrontal convexity (B and C).

disease entities. The value of the various types of guidelines and their impact on decision making may be controversial. Guidelines are used not only by medical practitioners but also by third-party payers and lawmakers among others. When using any given set of guidelines, it is best to remember that although the text may provide reasonable recommendations for patient management, the practice of medicine requires the independent judgement of the clinician and tailoring of the guidelines to meet the needs of the speciﬁc patient and disease process at hand.

References 1 Eddy DM: Designing a practice policy: Standards, guidelines and options. JAMA 1990; 263: 3077–3084. 2 NCCN Adult Brain Tumor Practice Guidelines. Oncology 1997; 11: 237–277.

(C)

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3 Rock JP, Haines S, Recht L, et al.: Practice parameters for the management of single brain metastasis. Neurosurg Focus 2000; 9: Clinical Pearl 2, 9pp. (http://www.neurosurgery.org/ focus/dec00/9-6-cp2.pdf). 4 Patchell R, Tibbs P, Walsh J, et al.: A randomized trial of surgery in the treatment of single metastasis to the brain. N Engl J Med 1990; 322: 494 –500. 5 Vecht C, Haaxma-Reiche H, Noordijk E, et al.: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993; 33: 583 –590. 6 Mintz A, Kestle J, Rathbone M, et al.: A randomized trial to assess the efﬁcacy of surgery in addition to radiotherapy in patients with single brain metastasis. Cancer 1996; 78: 1470 – 1476. 7 Patchell R, Tibbs P, Regine W, et al.: Postoperative radiotherapy in the treatment of single metastasis to the brain: a randomized trial. JAMA 1998; 280: 1–7. 8 Armstrong J, Wronski M, Galicich J, et al.: Postoperative radiation for lung cancer metastatic to the brain. J Clin Oncol 1994; 12: 22340 –22344. 9 Flickinger J, Kondziolka D, Lunsford L, et al.: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994; 28: 797–802. 10 Auchter R, Lamond J, Alexander E, et al.: A multi-institutional outcomes and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996; 35: 27–35. 11 Bindal A, Bindal R, Hess K, et al.: Surgery versus radiosurgery in the treatment of brain metastases. J Neurosurg 1996; 84: 748 –754. 12 Kreth F, Warnke P, Ostertag C: Interstitial implant radiosurgery for cerebral metastases. Acta Neurochir Suppl (Wien) 1993; 58: 112–114. 13 Lang FF, Sawaya R: Surgical management of cerebral metastases. Neurosurg Clin N Am 1996; 7: 459–484. 14 Bindal R, Sawaya R, Leavens M, et al.: Surgical treatment of multiple brain metastases. J Neurosurg 1993; 79: 210 –216.

Index

Note: subentries with speciﬁc cancers primarily refer to intracranial metastases. For example “colorectal cancer, management” refers to management of intracranial metastases. Where entries refer to metastases in general or primary tumors it is made clear. Abbreviations used: WBRT, whole-brain radiation therapy. abdominal organs, unknown primaries from 297 abscess, cerebral, imaging 77–78 vs breast cancer metastases 234 accelerated fractionation/hyperfractionation study 141, 435–436 N-acetylaspartate in MR spectroscopy 89 ACNU (nimustine), leptomeningeal carcinomatosis 318 adenocarcinoma colorectal 284 imaging 78 histology and differential diagnosis 303 poorly differentiated forms 63 lung 201 pancreatic 374, 375 parotid gland, imaging 76 adhesion, cell (and adhesion molecules) 184 melanoma 246–247 mouse 39 adjuvant chemotherapy (postoperative; surgery + chemotherapy) cervical cancer 334 choriocarcinoma 342 sarcomas 396, 407 leiomyosarcoma 398 osteosarcoma 400 rhabdomyosarcoma 397 soft-tissue sarcoma 395

adjuvant radiation (postoperative; surgery + radiation) intracranial/whole brain see surgery plus radiation lung cancer local disease 207 adjuvant treatment gallbladder cancer 372 in prevention of brain metastases 448– 45 1 unknown primary with systemic metastatic disease 303–305 adolescents, thyroid cancer 382–383 adrenal corticosteroids see steroids adrenocortical cancer 384 adrenomedullary cancer 384–385 Adriamycin see doxorubicin adverse effects of treatment see complications affective (mood) disorders 431–432 age (patient) 27 breast cancer risk related to 221 epidemiology related to 27 melanoma presentation related to 246 radiosurgery and prognosis related to 153 surgical complications related to 122 unknown primary presentation related to 293 alopecia, radiosurgery 159 alpha-fetoprotein hepatocellular carcinoma and 368 testicular cancer and 353, 356 alveolar soft-part sarcoma 398–399 management 396, 399 aminoglutethimide, metastatic breast cancer 228 anastrozole, metastatic breast cancer 228 anatomy, surgical 112–114 see also location

477

478

Index

angiogenesis 44–45, 184 inhibitors of 188, 449 in intracranial metastases 44–45, 71–72 breast cancer and 230 in primary site 35 melanoma 246 angiography, cranial base metastases 418 angiotropic lymphoma 58 histology and identiﬁcation of 62–64 macroscopic appearance 60 animal studies of biology 37–40 origin of metastases 42–43 antiangiogenic therapy 188, 449 antibodies monoclonal see monoclonal antibodies unknown primary diagnosis 303 anticoagulants 100–101 anticonvulsants 100 melanoma 259 anti-Hu antibodies 135 antihypertensive drugs and renal cell carcinoma 267 apparent diffusion coefﬁcient images 85 ara-C, leptomeningeal carcinomatosis 316–317, 317 arachidonic acid metabolites 447, 450 aromatase inhibitors, metastatic breast cancer 228–229 arterial drug delivery see intra-arterial chemotherapy arterial spin tagging (AST) 83 astrocytes, response to metastatic invasion 447–448 auditory symptoms, temporal bone metastases 422 autopsy series, epidemiologic data 22–23 AZQ (diaziquone), leptomeningeal carcinomatosis 318 “b” factor value (diffusion MR imaging) 85 B16 melanoma cells 38–40 Barrett’s esophagus 363 basilar plexus of veins 417 Batson’s plexus of veins 417 BCNU (carmustine) local delivery 190 melanoma 15, 257 bcr-abl kinase, drugs targeting 188

behavioral changes/problems 430–432 pharmacological treatment 440 rehabilitation 439 biochemical tests see laboratory tests biodegradable polymer wafers for drug delivery 190 biological agents 187–188, 189 see also immunotherapy biological effective dose (radiation therapy) 141 biology 35 –5 4, 445–446 biopsy, intracranial breast cancer metastases 234 bladder cancer clinical staging 353–354 epidemiology 352 imaging 354, 355–356 pathology 352 presentation 353 treatment 357–358 see also urinary tract/urothelial cancer blood-brain barrier (BBB) 45–47, 184, 185, 445–446 , 448 breast cancer and 230 drugs and 448 circumvention of BBB 448 cytotoxic see chemotherapy experimental studies of metastasis 37–41, 45–47 leptomeningeal carcinomatosis and 310 melanoma and 247 blood-oxygen level dependent (BOLD) functional MRI 86–87 blood pressure, high, and renal cell carcinoma 267 blood vessels, new see angiogenesis blue-cell tumor see small blue-cell tumors; small round blue-cell tumors BOLD functional MRI 86–87 bone metastases, images 74 nonmalignant tumors, classiﬁcation 392 sarcomas 399–403 classiﬁcation 392 incidence 391 bowel cancer see colorectal cancer brachytherapy 165, 168–17 2, 180, 466 indications 168 as initial treatment 170–171

Index 479 methods 168–170 for recurrent metastases 171–172 studies addressing role of 466 brain location in see location responses to metastatic invasion 447–448 Bramwell B 3 breast cancer (primarily carcinoma) 221–244 cranial metastases 230–231 imaging 234 surgery 424 epidemiology of primary disease 221–222 intracranial metastases 230–240 biology/pathophysiology 43–44, 230 cranial see subheading above epidemiology 23–24 histology and identiﬁcation 61, 303 imaging 73, 80, 81, 233–234 , 471 presentation 233 intracranial metastases, therapy 234–240 decision-making 471, 473 history 9, 13 multiple metastases 236–237 radiation therapy 9, 235–236 of recurrent disease 238 single/solitary metastases 235–236 surgery 13, 238–239 undiagnosed patient 235 metastatic disease (in general) prognostic indicators 226–227 therapy 227–230 pathology of invasive disease 222–224 staging 224–226 as unknown primary 297, 303 imaging 299 bronchoscopy, lung cancer 204 CA-19 and pancreatic cancer 374 CA-125 and ovarian carcinoma 337 calvarial metastases 72, 74 capecitabine 187 capillary bed, melanoma cell arrest in 39 carbamazepine 100 carboplatin, ovarian carcinoma 340 carcinoembryonic antigen, colorectal cancer 284 carcinogens and lung cancer 199–200 carcinoid tumors 383–384 lung 202

carcinoma, different, unique patterns of brain metastasis produced by 43–44 see also speciﬁc sites of origin and subtypes carcinomatosis, meningeal see meninges carmustine see BCNU carotid artery injection of melanoma cells 37–38 cavernous sinus metastases 420 CBDT regimen, melanoma 257 CCI-779 188 CCNU, melanoma 15 CD44 antigen and mouse melanoma 39 cell adhesion see adhesion cell cycle, drugs restoring normal control 188 cerebellar metastases colorectal cancer 283 survival 288 unknown primary 296–297 surgical anatomy 112, 113 cerebral blood ﬂow, regional, MR mapping techniques 82–83, 86, 87 cerebral blood volume, regional, MR mapping techniques 82–83, 86, 87 cerebrospinal ﬂuid dissemination through 64–65, 75 breast cancer and 232, 234 in leptomeningeal carcinomatosis 310 on FLAIR image 75 ﬂow studies, leptomeningeal carcinomatosis 313 tests, leptomeningeal carcinomatosis 312 not conﬁrming imaging results 314 cervical cancer (carcinoma) 331–332 epidemiology of metastases 26 of primary disease 331 chemoimmunotherapy, melanoma 258 chemopreventive agents 449–451 chemoradiation (chemotherapy + radiation) for brain metastases (incl. WBRT) 101–102, 189 lung cancer 211 melanoma 258 sarcomas 396, 407 Ewing’s sarcoma 402, 403 osteosarcoma 401 testicular cancer 357 see also surgery plus radiation plus chemotherapy

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Index

chemoradiation (chemotherapy + radiation) for primary tumors esophageal cancer 364 lung cancer 207, 207–208 chemoradiation plus surgery see surgery plus radiation plus chemotherapy chemotherapy (brain metastases) 14–16, 101–102, 183–19 5 bladder cancer 357 blood–brain barrier and 15, 45, 101, 185, 189 agents disrupting barrier 189–190 breast cancer 237–238, 239–24 0 cervical cancer, adjuvant 334 choriocarcinoma 343–344 adjuvant 342 failure, causes 183 histology in determination of sensitivity to 111 history 14–16 leptomeningeal carcinomatosis 321 intrathecal 315–318, 322 side-effects 322 lung cancer 185, 186, 187, 210 melanoma 15, 257–258 ovarian carcinoma 339–340 sarcomas 396, 404 Ewing’s sarcoma 402 leiomyosarcoma 398 osteosarcoma 400, 401 rhabdomysarcoma 397 testicular tumors 356, 357 whole-brain radiation therapy plus see chemoradiation for brain metastases chemotherapy (excluding brain metastases speciﬁcally) breast cancer metastases 229 cervical cancer 332 esophageal cancer 364 lung cancer 206, 207, 207–208 ovarian carcinoma 337 renal cell carcinoma metastases 270 chemotherapy plus radiation therapy see chemoradiation; surgery plus radiation plus chemotherapy children epidemiology 27 hepatoblastoma 370–371

sarcomas see sarcomas thyroid cancer 382–383 cholangiocarcinoma 371 cholecystectomy 372 choline-to-creatine ratio in MR spectroscopy 89 choline-to-NAA ratio in MR spectroscopy 89 chondrosarcomas 391 cranial base metastases, surgery 424 chordomas 391 choriocarcinoma men (testicular), treatment 356 women (in gestational trophoblastic disease) 342–343 epidemiology 26 treatment 342, 344 choroid plexus metastases 73–74 imaging 74 chromafﬁn tissue origin, cancer of 384–385 chromophobic renal cell carcinoma 268 cisplatin bladder cancer 357 melanoma 257 ovarian carcinoma 340 testicular cancer 357 clear cell tumor, histology and differential diagnosis 63 clinical assessment 110–111 clinical decision-making see decisionmaking clinical presentation (signs and symptoms) brain metastases 97–98 bone sarcoma 400 breast cancer 233 colorectal cancer 283 in cranial base 419–423 gastric cancer 367 genitourinary cancer 352–353 hepatocellular carcinoma 369 leptomeningeal carcinomatosis 311–312 lung cancer 202–203 sarcomas 393 unknown primary 293–296 primary disease esophageal cancer 363 gallbladder cancer 371

Index 481 gastric cancer 366 hepatocellular carcinoma 368 lung cancer 202, 298–299 pancreatic cancer 374 clinical series, epidemiologic data 21–22 cognitive changes 439 identiﬁcation/diagnosis 435–436 treatment-induced 432–434 prophylactic cranial irradiation 135, 434 tumor-related 430–432 cognitive rehabilitation 437, 438–440 collecting duct carcinoma 268 collimation 167 colorectal cancer (carcinoma) 279–291 biology 43, 44, 45 epidemiology intracranial metastases 24 primary disease 279, 280 management 284–289 MR imaging 78 complications (incl. adverse effects and toxicity) leptomeningeal carcinomatosis therapy 322 neuropsychological see neuropsychological impairment radiation (incl. WBRT/cranial irradiation) 128–129, 433– 434 prophylactic 134–135, 434 radiosurgery 158–160, 254, 434 surgical see surgery computed tomography brain metastases 98 breast cancer 233, 234 contrast-enhanced 72 in cranial base 418 esophageal cancer 365 features on 72, 73 for fractionated stereotactic radiotherapy 178 gallbladder cancer 373 hepatocellular carcinoma 369 history 5, 6 intraneural metastases 65 leptomeningeal carcinomatosis 313 lung cancer 209 melanoma 248 renal cell carcinoma 268, 269

primary site gastric cancer 366 lung cancer 203, 299 unknown 299–300 see also single photon emission computed tomography contrast-enhanced CT 72 contrast-enhanced MR imaging 98 dynamic 83–84 in focal radiation patients pretreatment use 167 prostate cancer 354 unknown primary 298 convulsions see seizures cortical surface involvement 72, 73 surgery 112, 113 corticomedullary location, imaging 73 corticosteroids see steroids cost (economic) radiosurgery 157–158 rehabilitation 438 whole-brain radiation therapy ± surgery 158 cranial dura see dural metastases cranial irradiation see whole-brain radiation therapy cranial nerves, effects on cranial base metastases 417 leptomeningeal carcinomatosis 311 radiosurgery 160 craniotomy see surgery, brain metastases cranium/cranial bone (skull) 415–429 basal metastases 415–429 clinical ﬁndings 419–423 diagnosis 417–419 incidence 415–417 pathophysiology 417 treatment 423–427 classiﬁcation of basal tumors 415 metastases 57–58, 415–429 basal see subheadings above breast cancer see breast cancer incidence 415–417 origin of 56, 57–58, 416 creatine in MR spectroscopy 89 cutaneous tumors see melanoma; mycosis fungoides Cyberknife 167, 177–180 cyclins and cyclin-dependent kinases 188

482

Index

cyclooxygenases COX-2 447, 448, 450 inhibitors (=NSAIDs) 450 cystic metastases, imaging 81 cytarabine (ara-C), leptomeningeal carcinomatosis 316–317, 317 cytokeratins (CK) 61, 303 colorectal adenocarcinoma 284 cytological tests, leptomeningeal carcinomatosis 312 cytotoxic drugs see chemotherapy dacarbazine (DTIC), melanoma 257, 258 deaths see mortalities; survival decision-making 107–112, 461, 468–474 factors in 468–470 histopathology 111–112, 470 location of metastases 109–110, 469–470 number of lesions 108–109, 470 size 110, 469–470 systemic disease status 110–111, 469 practical case scenarios 470–474 sarcomas 394 deep venous thrombosis 100 dexamethasone 99 diagnosis 60–64, 98 cranial base metastases 417–419 differential histology in 63 imaging in 77–81 with neuropsychological manifestations 435–436 history 4–6 imaging in see imaging leptomeningeal carcinomatosis 311–314 pitfalls 60–64 sarcomas 393 unknown primary 298–301 upper gastrointestinal cancer (primaries) esophageal cancer 363 gallbladder cancer 371 gastric cancer 366 hepatocellular carcinoma 368 pancreatic cancer 374 diaziquone, leptomeningeal carcinomatosis 318 diet and renal cell carcinoma 266 differential diagnosis see diagnosis diffusion MR imaging 84–85

direct brain stimulation 116 disialoganglioside targeting in leptomeningeal carcinomatosis 319–32 0 distribution see location dose (radiation), prognosis in radiosurgery related to 153 dose–response relationship (radiation therapy) for local control 140–141 doxorubicin (Adriamycin), bladder cancer 357 drug therapy see medical management and speciﬁc (types of) drugs DTIC, melanoma 257, 258 ductal carcinoma (breast), inﬁltrating 222–223 cranial base metastases, surgery 424 ductal carcinoma in situ of breast 222 dural metastases 57–58, 72 breast cancer 231 decision-making 472, 474 imaging 73, 472, 475 origin of 56, 57–58 dynamic contrast MR imaging 83–84 dynamic susceptibility contrast (DSC) mapping 82–83, 86 economic cost see cost edema, cerebral 99 EEG, diagnostic use 5 EGF and melanoma 40 eicosanoids (arachidonic acid metabolites) 447, 450 electroencephalography, diagnostic use 5 electron microscopy and site of origin 61 endocrine cancer 381–390 endocrine therapy see hormonal therapy endometrial cancer 334–336 epidemiology of metastases 25–26 primary disease 334 endothelium (and endothelial cells) and the blood–brain barrier 185 endothelial alterations 46 epidemiology metastases 20–34 cranial base 415–417 leptomeningeal carcinomatosis 309–310 sarcomas 27, 392, 395

Index 483 primaries breast cancer 221–222 cervical cancer 331 endometrial cancer 334 esophageal cancer 362, 363, 365 genitourinary cancer 352 lung cancer 199–200 melanoma 245 ovarian carcinoma 336, 337 sarcomas 391, 395, 397, 398–399 , 399–400, 400, 401 unknown 292 epidermal growth factor and melanoma 40 epidermal growth factor receptor leptomeningeal carcinomatosis and targeting of 319 renal cell carcinoma and 268 epidural space metastases, origin of 56 Epstein–Barr virus 64 esophageal cancer 362–365 epidemiology metastases 25 primary disease 362, 363 estrogen receptors and metastatic breast cancer therapy 227, 228, 240 estrogen replacement therapy and endometrial cancer 334 etoposide, melanoma 257 evidence-based guidelines 463–464, 467–468 Ewing’s sarcoma 401–403 epidemiology metastases 25 primary 391 treatment 396, 402–403 experimental studies of biology 37–47 extracranial/extracerebral disease as prognostic factor in radiosurgery 151 unknown primary, extent and distribution 296 see also systemic disease extravasation into brain parenchyma, melanoma cells 39 eye involvement, orbital metastases 419 facial nerve paresis/paralysis, temporal bone metastases 422 females see breast cancer; gynecologic cancer; women FGF, basic, melanoma and 40

ﬁbroblast growth factor, basic, melanoma and 40 ﬁbrous histiocytoma malignant 395, 396 FIGO staging, endometrial cancer 334, 335 ﬁne needle aspiration, lung cancer 204 FLAIR imaging (ﬂuid-attenuated inversionrecovery) 75, 82 meningitis 78–79 ﬂuid-attenuated inversion-recovery see FLAIR imaging follicular thyroid cancer 381, 383 cranial base metastases, surgery 424 fossa middle, metastases involving see Gasserian ganglion syndrome posterior, origin of metastases in 56 unknown primary 297 fotemustine, melanoma 258 fractionated radiation accelerated 141, 435–436 conventional, cranial base metastases 425 stereotactic 165, 176–180, 180, 181 frequency data 20–23 frontal lobes, functional impairment 431 functional mapping, intraoperative 115–11 6 functional MR imaging 85–87 gallbladder cancer 371–373 Gamma Knife 117, 144–145, 168 breast cancer 239 history 12 multicenter review 144–145, 149 ovarian cancer 346 prognosis in 149, 155–156 randomized trials 145, 146 Gasserian ganglion syndrome (posterior fossa lesion) 420, 421–422 decision-making 471 gastric cancer (incl. carcinoma) 365–367 epidemiology metastases 24 primaries 365–366 imaging 76, 367 gastrointestinal cancer lower see colorectal cancer sex and frequency of 28 upper 362–380 epidemiology of metastases 24

484

Index

gender see sex gene therapy, leptomeningeal carcinomatosis 320–321 genetics, renal cell carcinoma 267–268 genitourinary cancer 352–361 clinical staging 353–354 epidemiology metastases 25, 28 primaries 352 imaging 354–356 laboratory markers 356 pathology 352 presentation 352–353 treatment 356–359 germ cell tumors chemotherapy 186 testicular laboratory markers 356 pathology 352 treatment 356, 357, 358 gestational trophoblastic disease 340–346 Gleason grading 353, 354 Gleevec 188 glioblastoma multiforme, MR imaging 79, 81, 90 gliomas, intraneural dissemination 65 Gowers WR 3, 4 granulomatosis, lymphomatoid see lymphomatoid granulomatosis growth metastases 71–72 primary tumor 35–36 growth factors angiogenesis and 44 melanoma and 40 see also speciﬁc factors guidelines for management see practice parameters gynecologic cancers 331–351 epidemiology 25–26 see also pelvic organs gyral lesions, surgical anatomy 112 hair loss (alopecia), radiosurgery 159 Hand–Schüller–Christian disease 59 headache leptomeningeal carcinomatosis 311 unknown primary 293 hearing loss, temporal bone metastases 422

hematogenous dissemination 35–36, 72 breast cancer 230 melanoma 247 therapeutic strategies aimed at 449 hematopoietic neoplasms, secondary CNS involvement 58–59 histology 62–64 macroscopic appearance 60 hemispheric metastases breast cancer 232 neuropsychological changes 431 surgical anatomy 112, 113 hemorrhage, intracranial 97 anticoagulant-related risk 100–101 melanoma 248, 473 heparin 100, 101 hepatic cancer see liver cancer hepatitis B and C and hepatocellular carcinoma 368 hepatoblastoma 370–371 hepatocellular carcinoma 368–370 Herceptin 229–230 herpes simplex-thymidine kinase gene in leptomeningeal carcinomatosis therapy 321 histiocytoma, malignant ﬁbrous 395, 396 histiocytosis X 59 histology/histopathology of brain metastases 60–64 breast cancer 61, 303 epidemiology related to 23–27 leptomeningeal carcinomatosis 62, 309–31 0, 323 lung cancer 61, 303 as prognostic factor in radiosurgery 152 sarcomas 393–394 in treatment decision-making 111–112, 470 unknown primary 302–303 of primaries breast cancer 222–224 cranial base 415 genitourinary cancer 352 sarcomas 392 thyroid cancer, variants of papillary forms 383 see also origin

Index 485 history 3–19 diagnosis 4–6 Hodkgin’s disease (HD) 59 histology and identiﬁcation of 64 macroscopic appearance 60 hormonal therapy leptomeningeal carcinomatosis 322 metastatic breast cancer 227–229 intracranial disease 239–240 hormone (estrogen) replacement therapy and endometrial cancer 334 HPV and cervical cancer 331–332 HSV-thymidine kinase gene in leptomeningeal carcinomatosis therapy 321 Hu, antibodies to 135 human chorionic gonadotrophin (hCG) and hydatidiform mole 342 human papillomavirus and cervical cancer 331–332 hydatidiform mole 340–342, 342 hydrocephalus, metastatic breast cancer 237 hydroxyeicosatetraenoic acids (HETEs) 451 hypertension and renal cell carcinoma 267 imaging (brain metastases) 4–6, 71–94 breast cancer (primarily carcinoma) 73, 80, 81, 233–234 , 471 colorectal cancer with pulmonary metastases 289 cranial base metastases 417–419 decision-making and 107–110 in differential diagnosis 77–81 features 72–77 for fractionated stereotactic radiotherapy 178 gastric cancer 76, 367 genitourinary cancer 354–356 hepatocellular carcinoma 369–370 intraneural metastases 65 leptomeningeal carcinomatosis 313 lung cancer 209 melanoma 248–249 renal cell carcinoma 74, 268–269, 421 sarcomas 393

unknown primary 298 see also speciﬁc modalities imaging (primary site) gallbladder cancer 371 gastric cancer 366 liver cancer 368 lung cancer 203–204, 299 unknown primary 299 see also speciﬁc modalities immunohistochemistry 61 leptomeningeal carcinomatosis 313 unknown primary 302–303 immunotherapy leptomeningeal carcinomatosis 318–320 melanoma 189, 258 renal cell carcinoma 270 see also biological agents incidence data 20–23 see also epidemiology inﬂammatory carcinoma of breast 226 infratentorial metastases, colorectal cancer 282–283 interferon alpha 188 melanoma 257 renal cell carcinoma 270 interleukin-2 leptomeningeal carcinomatosis 320 melanoma 189, 258 renal cell carcinoma 270 International Federation of Gynecology and Obstetrics (FIGO) staging, endometrial cancer 334, 335 interstitial radiation 165, 167–176, 180 methods 167–168 implants/seeds see brachytherapy intra-arterial chemotherapy 190 melanoma 257 intracellular signalling, drugs targeting 188 intracranial pressure, increased 99–100 bone sarcoma 400 intraepithelial neoplasia, cervical 331, 332 intraneural dissemination 64–65 intrathecal chemotherapy breast cancer 237–238 Ewing’s sarcoma 402 leptomeningeal carcinomatosis 315–318 toxicity 322

486

Index

intrathecal immunotherapy, leptomeningeal carcinomatosis 320 intratumoral delivery of chemotherapy 190 invasion see spreading iodine, radioactive monoclonal antibodies labelled with I-131, leptomeningeal carcinomatosis therapy 319–320 thyroid cancer therapy 382 irradiation see radiation therapy Joint Tumor Section (JTS/AANS) guidelines 464, 467–468 jugular foramen metastases 422–423 manifestations 420, 422–423 K-1735 melanoma cells 38, 38–40, 42 Karnofsky Performance Scale 102–103, 186–187 postoperative complications and 122 radiosurgery and 146 prognosis in 148, 151 kidney see renal cancer c-KIT and melanoma 247 laboratory/biochemical tests breast cancer metastases 234 genitourinary cancer 356 leptomeningeal carcinomatosis 312–313 lung cancer 204 unknown primary 299 lactate dehydrogenase levels and transitional cell carcinoma of urinary tract 356 LAK cells, leptomeningeal carcinomatosis 320 Langerhans’ cell histiocytosis 59 large bowel cancer see colorectal cancer large cell cancer/carcinoma, lung 201–202 large pink-cell tumor, histology and differential diagnosis 63 leiomyosarcoma 397–398 cranial base metastases, surgery 424 leptomeninges see meninges letrozole, metastatic breast cancer 228 leukemia 58 histology and identiﬁcation of 62 macroscopic appearance 60 MR images 80

light microscopy, brain metastases of unknown primary 302–303 see also histology linear accelerator/LINAC (for radiosurgery) 117, 166–167 history 12 prognostic factors 147–148, 156 randomized trials 146 survival 146, 147–148, 149 lipoxygenases 447, 448, 451 inhibitors 451 liver cancer 368–371 secondary, from colorectal cancer 281–282 liver transplantation with hepatocellular carcinoma 369 lobular carcinoma (breast), inﬁltrating 223–224 lobular carcinoma in situ (breast) 223 local control (with radiation therapy) dose–response relationship for 140–141 radiosurgery in 141–143, 147–156 local drug delivery (intracranial) 190 breast cancer 240 location (site) in bowel of colorectal cancer 280, 281 of brain metastases 71–72, 446 colorectal cancer 282–283 in decision-making 109–110, 469–470 gastric cancer 367 hepatocellular carcinoma 370 imaging see imaging melanoma 247–248 neuropsychological changes related to 431–432 unknown primaries 296–297 see also speciﬁc locations of extracranial metastases with unknown primaries 296 of origin of brain metastases see origin lomustine, melanoma 15 lung cancer 199–219 biology 43, 44, 45 chemotherapy 185, 186, 187, 210 chemotherapy + radiotherapy 189 clinical presentation (primary and intracranial metastases) 202–203, 298–299

Index 487 epidemiology of intracranial metastases related to histology 23 men vs women 28 epidemiology of primary 199–200 histology and identiﬁcation of 61, 303 imaging metastases 73, 77, 209 primary disease 203–204, 299 leptomeningeal carcinomatosis 309–310 management (principles) decision-making 471, 472 intracranial metastases 208–213 primary disease 206–208 risk factors 199–200 secondary, from colorectal cancer 281, 282 neuroimaging 289 resection 288 staging 205–206 stereotactic radiation brachytherapy 171 photonic radiosurgery source 175 radiosurgery 209, 210 as unknown primary 297, 298, 303 whole-brain (cranial) radiation therapy 128, 209, 210, 212–213 prophylactic 131–135, 210–211, 434 lymph nodes metastases breast cancer 226 metastasis of 42–43 in TNM staging see N removal in renal cell carcinoma 269 lymphoblastic leukemia, acute, MR images 80 lymphoid neoplasms, secondary CNS involvement 58–59 histology and differential diagnosis 63 lymphokine-activated killer cells, leptomeningeal carcinomatosis 320 lymphoma (of CNS) primary, steroid therapy 8 secondary/invasive 58–59 histology and identiﬁcation of 62–64 macroscopic appearance 60 lymphomatoid granulomatosis 58 macroscopic appearance 60

macroscopic appearance 59–60 mafosfamide, leptomeningeal carcinomatosis 317–318 magnetic resonance imaging brain metastases 6, 72–90, 98 advanced techniques 82–90 breast cancer 73, 80, 81, 233–234 , 471 in cranial base 418, 421 and decision-making in practical case scenarios 471, 472, 473, 475 in differential diagnosis 77–81 dural lesions 73, 472, 475 features 72–77 in focal radiation patients, pretreatment use 167 gastric cancer 76, 367 hepatocellular carcinoma 369–370 history 6 intraneural metastases 65 leptomeningeal carcinomatosis 313 lung cancer 73, 77, 209, 471 melanoma 248–249 pancreatic cancer 375 postoperative 120 prostate cancer 354 renal cell carcinoma 268, 269 unknown primary 298 disseminated disease (in general), prostate cancer 353 primary disease, lung cancer 203–204 see also FLAIR imaging magnetic resonance spectroscopic techniques, in vivo 87–89 males see men mammography, occult tumor 299 management (treatment) 95–155 complications of see complications decision-making see decision-making goals 106–107 guidelines see practice parameters history 6–8 principles 97–195 see also speciﬁc modes of treatment and sites of origin mannitol 189–190 marimastat 188 mass effect, urgency of relieving 469 matrix metalloproteinases 184 inhibitor 188

488

Index

maxillary sinus metastases, incidence 417 MCAM 246–247 MCF-7 breast carcinoma cell line 43 M. D. Anderson Cancer Center, surgery cranial base metastases 423–424 multiple metastases 108 neuropsychological assessment 436 outcomes 121, 123 mediastinoscopy, lung cancer 204 medical condition of patient in decisionmaking 470 medical management metastatic disease 98–102 melanoma 257–259 neurobehavioral problems 440 see also speciﬁc (types of) drugs medullary thyroid cancer 383 medulloblastoma histology and identiﬁcation of 64 intraneural dissemination 64–65 melanoma (primarily cutaneous) biology 246–247 experimental studies 37–41, 42–43, 44–45, 446 pathogenesis 36, 246–247 epidemiology of metastatic disease 24 age and 28 children and 27 epidemiology of primary disease 245 histology and identiﬁcation of 61–62 imaging 248–249 location in brain 247–248 macroscopic appearance 59 survival 250 melanoma, therapy of intracranial metastases 245–265 chemotherapy 15, 257–258 decision-making 473 immunotherapy 189, 258 medical therapies 257–259 stereotactic radiation/radiosurgery 254–255, 256 photonic radiosurgery source 175 prognosis 152 surgery 252–254, 424 whole-brain radiation therapy 250–252, 253 postoperative/adjuvant 117, 251

melanoma cell adhesive molecule 246–247 memory deﬁcits radiation-related 433 rehabilitation 439 men breast cancer 221 incidence of metastases 28 renal cell carcinoma 266 see also sex meninges 58 carcinoma in (=leptomeningeal carcinomatosis) 58, 309–330 breast cancer 231–232, 237–238 diagnosis 311–314 epidemiology 309–310 histology 62, 309–310, 323 macroscopic appearance 60 management 314–324 meningitis and, imaging in differentiation of 78 pathophysiology 310 prognosis 322–324 side-effects of treatment 322 sources 58, 309–310 symptoms and signs 311–312 metastasis of murine melanoma to 38 origin of metastases in 56, 58 meningiomas MR images 79 multiple 65 mesenchymal tumors, classiﬁcation 392 metalloproteinases see matrix metalloproteinases metastasis of metastases to brain 42–43 methotrexate (MTX) in leptomeningeal carcinomatosis 321 intrathecal 316 toxicity 322 methylphenidate 440 mice see mouse microglia, response to metastatic invasion 447, 448 microinvasive breast carcinoma 226 microscopic appearance see histology middle fossa (Gasserian ganglion) syndrome 420, 421–422 Mini-Mental Status Exam 435–436 models see animal studies; experimental studies

Index 489 monoclonal antibodies scanning of renal cell carcinoma 269 therapeutic use leptomeningeal carcinomatosis 318–320 metastatic breast cancer 229–230 mood changes 431–432 morbidity, surgical 121–122 mortalities/deaths gestational trophoblastic disease 344–345 surgical 120–121 prevention 130 see also survival motor cortex lesion, decision-making 471 mouse, experimental studies of melanoma 37–40 human melanoma cells in nude mice 40–41 multiple endocrine neoplasia type 2a/2b, medullary thyroid cancer in 383 multiple metastases radiological assessment 108–109 treatment breast cancer 236–237 decision-making 108–109 melanoma 253 see also number multiple myeloma see myeloma multiple simultaneous primaries, breast cancer 226 murine studies see mouse M-VAC regimen, bladder cancer 357 mycosis fungoides (cutaneous T cell lymphoma) 58 histology and identiﬁcation of 62 macroscopic appearance 60 myeloma, multiple 59 histology and identiﬁcation of 64 macroscopic appearance 60 N (in TNM staging) breast cancer 224, 225 lung cancer 205–206 necrosis of brain, radiation-induced 76–77 radiosurgery 159–160 neovascularization, pathologic see angiogenesis nephrectomy, renal cell carcinoma 269

nerve, dissemination within 64–65 see also cranial nerves neuroimaging see imaging neurological complications, postoperative 121–122 neurological status in decision-making 111 as prognostic factor 103 radiosurgery and its impact on 146, 159 neurological symptoms gastric cancer 367 hepatocellular carcinoma 369 leptomeningeal carcinomatosis 311 unknown primary 293–296 neuropsychological impairment 430–441 diagnosis 435–436 intervention/management strategies 436–437 metastasis-related 430–432 treatment-related 432–434 prophylactic cranial irradiation 134 –135 , 434 neurosurgery see surgery neurotrophin receptor p75NTR 446, 447 nimustine, leptomeningeal carcinomatosis 318 non-Hodkgin’s lymphoma, secondary CNS involvement 58 histology and identiﬁcation of 62–64 macroscopic appearance 60 non-small cell lung cancer (NSCLC) 200, 208–21 2 chemotherapy 186, 187, 210 histological types 201–202 see also speciﬁc types imaging 77 leptomeningeal carcinomatosis 310 management (principles) intracranial metastases 208–212 primary disease 206–207 prophylactic cranial irradiation 134, 434 staging 205–206 stereotactic radiation brachytherapy 171 photonic radiosurgery source 175 nonsteroidal anti-inﬂammatory drugs (NSAIDs) 450 nude mice, human melanoma cells in 40–41

490

Index

number of lesions/metastases in decision-making 108–109, 470 prognosis in radiosurgery related to 149 radiological assessment 108–109 obesity and renal cell carcinoma 267 occipital condyle metastases 423 manifestations 420, 423 occupational (vocational) rehabilitation 438 ocular involvement, orbital metastases 419 Ommaya reservoir breast cancer 237, 238 leptomeningeal carcinomatosis 315 toxicity problems with 322 oophorectomy in metastatic breast cancer 227 ophthalmological involvement, orbital metastases 419 options in patient management 462 orbital metastases clinical ﬁndings 419 incidence 416 origin (source) of metastases 42–43 anatomic location of metastases related to 56 cranial base metastases 56, 57–58, 416 epidemiology related to 23–27 identifying 60–64 in leptomeningeal carcinomatosis 58, 309–310 unknown primary 297–298 see also histology osteosarcomas 400–401 incidence 391 treatment 396, 400–401 otological symptoms, temporal bone metastases 422 ovarian cancer (carcinoma) 336–340 epidemiology metastases 26, 28 primary disease 336, 337 radiosurgery 346 ovariectomy (oophorectomy) in metastatic breast cancer 227 P-glycoprotein and drugs and the bloodbrain barrier 185 p75NTR 446, 447 pachymeningitis interna hemorrhagica 58

Paget’s “seed and soil hypothesis” 36–37, 184 palliative therapy colorectal cancer 285 esophageal cancer 364 gallbladder cancer 372 leptomeningeal carcinomatosis 315 lung cancer 206, 207 pancreatic cancer 374–375 papillary carcinoma breast 224 renal cell 268 thyroid 381 variant forms 383 papillary neoplasms, histology and differential diagnosis 63 paraganglioma 385 paranasal sinus metastases, incidence 416–41 7 paraneoplastic syndrome cognitive deﬁciency related to 135 lung cancer 203 renal cell carcinoma 268 parasellar syndrome 420–421 parathyroid carcinoma 385 parathyroid hormone-related protein and metastatic breast cancer 231 parenchyma, brain breast cancer metastases 232 melanoma (murine) metastasizing to 38 origin of metastases in 56–57 unknown primary metastases 296 parotid gland adenocarcinoma, imaging 76 pathogenesis 35–37 PDGF and melanoma 40 pediatric patients see children pelvic organs, unknown primaries from 297 see also gynecologic cancers percutaneous stereotactic implantation of radioactive seeds 168 performance status in decision-making 470 see also Karnofsky Performance Scale perfusion MR imaging 82–83 peripheral primitive neuroectodermal tumor 64 petrous apex metastases 420 pharmacological therapy see medical management and speciﬁc (types of) drugs

Index 491 phase reversal 115–116, 116 phenytoin 100 pheochromocytoma 385 photonic radiosurgery source (PRS) 172–176, 180 pink-cell tumor, large, histology and differential diagnosis 63 pituitary cancer 385 placental site trophoblastic tumor 342 plasma cells, atypical 64 platelet-derived growth factor and melanoma 40 polymer wafers for drug delivery 190 population-based epidemiologic studies 20–21 positron emission tomography brain metastases 6 melanoma 249 renal cell carcinoma 269 primary and regional disease lung cancer 204 unknown primary 300 posterior fossa see fossa postmenopausal women, aromatase inhibitors in metastatic breast cancer 228–229 post-mortem (autopsy) series, epidemiologic data 22–23 practice parameters (guidelines) for management 461–468 clinical research literature and 462–464 types 462–463 premotor cortex lesion, decision-making 471 presenting features see clinical presentation prevention see prophylaxis primitive neuroectodermal tumor (PNET) 64 procarbazine, melanoma 257 progesterone receptors and metastatic breast cancer therapy 227, 228, 240 prognosis and prognostic factors (metastatic disease) breast cancer 226–227 in intracranial metastatic disease 102–103 colorectal cancer 285 Ewing’s sarcoma 403–404 leptomeningeal carcinomatosis 322–324

radiation therapy and 102, 186–187 radiosurgery and 147–156 with unknown primary 303–305 see also survival prognosis and prognostic factors (primary disease) breast cancer 222–223 , 223–224 renal cell carcinoma 269 prophylaxis/prevention of brain metastases 448–45 1 adjuvant strategies 448–451 radiation therapy in see radiation therapy prostaglandin synthase inhibitors (=NSAIDs) 450 prostate cancer (carcinoma) clinical staging 353 epidemiology metastases 25 primaries 352 imaging 353, 354 pathology 352–353 presentation 353 treatment 358–359 prostate-speciﬁc antigen 353, 356 psychiatric illness 432 psychological impact see neuropsychological impairment psychometric tests 436 psychostimulant drugs 440 PTK787 188 pulmonary cancer see lung cancer quality of life, radiosurgery and 146 radiation therapy (brain metastases) 8–11, 126–18 2 adjuvant/postoperative see surgery plus radiation breast cancer 9, 235–236 chemotherapy and see chemoradiation for brain metastases complications see complications cranial base metastases 425 focal 165–182 indications 167 principles 166–167 fractionated 165, 177–180, 180, 181 history 8–11

492

Index

radiation therapy (brain metastases) (cont.): imaging features following 75–77 leiomyosarcoma 398 leptomeningeal carcinomatosis 315 side-effects 322 ovarian carcinoma 338–339 prognostic factors 186–187 prophylactic cranial 131–135, 185 lung cancer 131–135, 210–215, 434 renal cell carcinoma 271–272 sarcomas 404 sensitivity to (=radiosensitivity) in decision-making 469 histology in determination of 111 stereotactic see stereotactic radiation whole-brain see whole-brain radiation therapy radiation therapy (primary tumor), lung cancer 206–207 Radiation Therapy Oncology Group (RTOG) neuropsychological changes assessed 435–436 prognostic factors studied by 102, 186 whole-brain (cranial) radiation therapy 126–128 accelerated fractionation/ hyperfractionation 141, 435–436 melanoma 252 prophylactic 134 ± radiosurgery 146 radioactive seeds, implanted see brachytherapy radiography (X-rays) intracranial cranial base metastases 417 history 4–5 leptomeningeal carcinomatosis 313 primary tumor lung cancer 203 unknown 299 radiolabelled monoclonal antibodies, leptomeningeal carcinomatosis therapy 319–320 radiology see imaging and speciﬁc modalities radionecrosis see necrosis radionuclide scans, cranial base metastases 418

radiosurgery (stereotactic; SRS) 11–13, 117–120, 139–16 4, 465–466 , 467 breast cancer 236, 239 colorectal cancer 286 complications 158–160, 254, 434 cost considerations 157–158 cranial base metastases 426–427 fractionated (FRS) 165, 177–180, 180, 181 genitourinary cancer 356–357 history 11–13 local control and effects of 141–143, 147–156 lung cancer 209, 210, 212–213 melanoma see melanoma multicenter reviews 143–145, 147–149 ovarian cancer 346 photonic radiosurgery source (PRS) 172–176, 180 prognostic factors 147–156 rationale 139–141 recommended uses 119–120 renal cell carcinoma 118, 273 sarcomas 406–407 surgery compared with or complementary to see surgery brain metastases survival and effects of 143–156, 465 trials/studies addressing role of 145–147, 465–466, 467 radiosurgery plus whole-brain radiation therapy 119, 130–131, 154–155 genitourinary cancer 356–357 Joint Tumor Section guidelines 468 lung cancer 212–213 melanoma 254–255 renal cell carcinoma 273 unknown primary 301 radiotherapy see radiation therapy rapamycin derivative 188 rectal cancer see colorectal cancer recurrence of metastases brachytherapy for 171–172 breast cancer, treatment 238 decision-making 470 melanoma, management 253 postoperative 122–123 sarcoma, management 406 recursive partitioning analysis (RPA) 102–103, 144, 186–187

Index 493 rehabilitation problems 437–440 renal cancer (renal cell carcinoma/ adenocarcinoma) 266–278 biology 43–44, 44–45 classiﬁcation 267 epidemiology of metastases 24 primary disease 266 imaging 74, 268–269, 421 management of metastases in brain 271–273 radiosurgery 118, 273 surgery + adjuvant whole brain radiation therapy 117, 272–273, 273 management of metastases in general 270–271 management of primary/localized disease 269 molecular biology 267–268 skull base metastases 421, 424 rhabdomyosarcoma 395–397 epidemiology of metastases 25, 395 treatment 396, 397 ricin, leptomeningeal carcinomatosis 319 RTOG see Radiation Therapy Oncology Group sarcomas 391–411 childhood 391, 395–397, 401–403 epidemiology of metastases 25 histology and identiﬁcation of 64 classiﬁcation 392 clinical decision-making 394 diagnosis 393 management 394–403 natural history 404–405 pathology 393–394 uterine 335–336, 397 scintigraphy (radionuclide scans), cranial base metastases 418 screening for intracranial metastases colorectal cancer 289 esophageal cancer 365 lung cancer 208–209 “seed and soil hypothesis” 36–37, 184 seizures (convulsions) 97 breast cancer 233 drug management see anticonvulsants melanoma 259

sella turcica metastases 420 sex (gender) 28 and prognosis in radiosurgery 153 and renal cell carcinoma 266 see also men; women sex steroid receptors (ER/PR) and metastatic breast cancer therapy 227, 228, 240 side-effects of treatment see complications signal transduction inhibitors 188 signs see clinical presentation single and solitary metastases 293 distinction of single vs solitary 293 treatment breast cancer 235–236 melanoma 253 prognosis in radiosurgery 149 radiological assessment and decisions on 108 see also speciﬁc methods single photon emission computed tomography, cranial base metastases 419 single voxel technique 87 sinuses (paranasal), incidence of metastases 416–41 7 site see location; origin size intracranial lesion in decision-making 110, 470 radiosurgery prognosis related to 153–154 in TNM staging see T skin tumors see melanoma; mycosis fungoides skull see cranium small blue-cell tumors, histology and differential diagnosis 63 small cell lung cancer (SCLC) 200, 200–201 chemotherapy 185, 186, 210 chemotherapy + radiotherapy 189 epidemiology 23 leptomeningeal carcinomatosis 309–310 management (principles) intracranial metastases 208–212 primary disease 207–208 staging 205 whole-brain (cranial) radiation therapy 128 prophylactic 131–134, 210–211, 434

494

Index

small round blue-cell tumors of childhood, histology and identiﬁcation of 64 smoking lung cancer and 199–200 renal cell carcinoma and 266 soft-tissue sarcomas classiﬁcation 392 incidence 391 management 395–399 soft-tissue tumors, benign, classiﬁcation 392 solar radiation and melanoma 245 solitary metastases see single and solitary metastases somatostatinoma, pancreatic 375 source of metastases see origin spectral data analysis in magnetic resonance spectroscopy 88 spectroscopic imaging technique 87 sphenocavernous syndrome 420–421 sphenoidal sinus metastases 417 spinal symptoms and signs, leptomeningeal carcinomatosis 311 spreading/invasion (of primary) 55, 183–184 blood-brain barrier and see blood-brain barrier brain’s response to invasion 447–448 cervical cancer 332 colorectal cancer 281–282 endometrial cancer 335 esophageal cancer 363 gastric cancer 366 to generalizing site 42 hepatocellular carcinoma 369 mechanisms 35–36, 72 melanoma 246–247 ovarian carcinoma 337 sarcomas 392, 394 see also metastasis sputum samples, lung cancer 204 squamous cell lung cancer 201 epidemiology 23 staging breast cancer 224–226 endometrial cancer 334, 335 genitourinary cancer 353–354 lung cancer 205–206 standards in management 462 stereotactic devices aiding surgery 114–115

stereotactic radiation therapy (in general) 11–12, 165–18 2 history 11–12 lung cancer see lung cancer steroids (corticosteroids) 6–8, 99 alveolar soft-part sarcoma 399 breast cancer 234 colorectal cancer 285 gastric cancer 367 history 6–8, 11 neuropsychological effects 432 radiation therapy and 11 in radiosurgery patients chronic dependency 160 reinstitution 159 stomach cancer see gastric cancer subarachnoid space, spreading to 74–75 FLAIR imaging 80 subinsular cortex, surgical anatomy 112, 113 sulcal lesions, surgical anatomy 112 sun exposure and melanoma 245 supratentorial metastases origin 56 surgical anatomy 112 of unknown primary, differential diagnosis 300 surgery, brain metastases (incl. craniotomy) 13–14, 106–12 5, 464 –465 advantages 106–107 anatomic location 112–114 bladder cancer 357–358 breast cancer 13, 238–239 cervical cancer 334 colorectal cancer 285, 286, 287–288 complications 121–122 neuropsychological 432 cranial base metastases 423–424 epidemiologic data 21 esophageal cancer 364–365, 365 gallbladder cancer 372–373 gastric cancer 367 gestational trophoblastic disease 345–346 history 13–14 liver cancer 370 lung cancer 209, 211–212 melanoma 252–254, 424 outcomes 120–123 ovarian carcinoma 338–339

Index 495 radiosurgery and 118–120 comparisons/relative efﬁcacy 118–119, 156–158 complementary use 119–120 sarcomas 396, 404 –406 alveolar soft-part sarcoma 399 Ewing’s sarcoma 403 ﬁbrous histiocytoma (malignant) 395 osteosarcoma 401 in recurrent disease 406 techniques 112–116 testicular germ cell tumors 357 trials/studies addressing role of 464–465, 466, 467 unknown primary 301–302 surgery, primary tumor cervical cancer 332 esophageal cancer 363–364 gallbladder cancer 371 gastric cancer 366 hepatocellular carcinoma 369 lung cancer 206 ovarian carcinoma 337 pancreatic cancer 374 surgery plus chemotherapy see adjuvant chemotherapy; surgery plus radiation plus chemotherapy surgery plus radiation, brain metastases (incl. whole-brain radiation therapy and adjuvant use) 108, 116–117, 129–13 0, 140, 180, 464–465 bladder cancer 357–358 breast cancer 236 costs 158 endometrial cancer 335 Joint Tumor Section guidelines 467 melanoma 117, 251 ovarian carcinoma 338–339 recurrence rate 123 renal cell carcinoma 117, 272–273, 273 sarcomas 396, 407 alveolar soft-part sarcoma 399 Ewing’s sarcoma 403 ﬁbrous histiocytoma (malignant) 395 leiomyosarcoma 398 osteosarcoma 401

trials/studies addressing role of 464 –465 , 466 unknown primary 301 surgery plus radiation plus chemotherapy, sarcomas 396, 407 Ewing’s sarcoma 403 leiomyosarcoma 398 survival 102 brachytherapy 466 with cerebellar metastases of colorectal cancer 288 choriocarcinoma 342–343 genitourinary tract tumors 358 leptomeningeal carcinomatosis 322, 323 melanoma 250 postoperative 123, 464–465 with colorectal cancer 288 with unknown primary 301 radiosurgery and its effects on 143–156, 465 steroids prolonging 8 with unknown primary 288, 303–304 whole-brain radiation therapy 464–465 see also mortalities; prognosis symptoms see clinical presentation systemic disease status in decision-making 110–111, 469 with unknown primary, outcome and adjuvant treatment 303–305 see also extracranial disease T (size in TNM staging) breast cancer 224, 225, 226 lung cancer 205–206 T cell lymphoma, cutaneous see mycosis fungoides tamoxifen (in metastatic disease) breast cancer 227–228 melanoma 257 temozolomide 187 leptomeningeal carcinomatosis 321 intrathecal 317 melanoma 187–188, 258 non-small cell lung cancer 187 temporal bone metastases 422 incidence 416 manifestations 420, 422

496

Index

teniposide 189 teratoma, imaging 355 testicular cancer clinical staging 353 epidemiology metastases 25, 28 primaries 352 imaging 353, 354, 355 laboratory markers 356 pathology 352 presentation 352 treatment 356, 357 TGF-ß and melanoma 40, 41 thalidomide, melanoma 187–188 thiotepa, leptomeningeal carcinomatosis 316, 317 thrombosis, deep venous 100 thymidine kinase in leptomeningeal carcinomatosis gene therapy 321 thymus gland cancer 385 thyroid cancer 381–384 cranial base metastases, surgery 424 differentiated 381–383 epidemiology of metastases 27 TTF-1 marker 61, 303 TNM staging breast cancer 224, 225, 226 lung cancer 205, 205–206 tobacco smoke see smoking topotecan, leptomeningeal carcinomatosis 317 toxicity of treatment see complications toxins coupled to monoclonal antibodies, leptomeningeal carcinomatosis 318–319 transforming growth factor beta and melanoma 40, 41 transitional cell carcinoma of urinary tract LDH levels 356 treatment 358 trastuzumab 229–230 treatment see management trigeminal ganglion syndrome see Gasserian ganglion syndrome trophic support of brain colonization 446–447 trophoblastic disease, gestational 340–346 TTF-1 61, 303 tumor boards 474

ultrasound, intraoperative 114, 115 ultraviolet radiation and melanoma 245 undifferentiated tumor, histology and differential diagnosis 63 unknown primaries 292–308 clinical presentation 293–296 diagnostic evaluation 298–301 epidemiology 292 of metastases 26–27 extent and distribution of metastatic disease 296–297 histopathology 302–303 management 301–302 outcome/prognosis 303–305 relationship with speciﬁc systemic cancers 297–298 urgency of condition in decision-making 468–469 urinary tract/urothelial cancer imaging 355 laboratory markers 356 presentation 352–353 see also bladder cancer uterine cancer 334–336, 397 see also endometrial cancer UV radiation and melanoma 245 vaccines, melanoma 258 vascular endothelial growth factor (VEGF) angiogenesis and 44, 45 drugs targeting (and its receptor) 188 vascularization see angiogenesis VEGF see vascular endothelial growth factor venous drainage and colorectal cancer 281 venous thrombosis, deep 100 ventricular metastases, surgical anatomy 112, 113 VHL gene and renal cell carcinoma 268 video-assisted thoracoscopic surgery, lung cancer 204 vinblastine, bladder cancer 357 vincristine, melanoma 257 viral etiology cervical cancer 331–332 hepatocellular carcinoma 368 visual effects, orbital metastases 419 vocational rehabilitation 438 von Hippel–Lindau disease (VHL) gene and renal cell carcinoma 268

Index 497 warfarin 100–101 water diffusion and MR imaging 85 weight, body, and renal cell carcinoma 267 white matter adverse effects of radiation 433 lesions, surgical anatomy 112, 113 WHO classiﬁcation, lung cancer 201, 202 whole-brain radiation therapy/cranial irradiation (WBRT) 126–138, 466–467 alone (compared with other treatments or combinations of treatments) compared with radiosurgery + WBRT 119, 145 compared with surgery + WBRT 108, 119, 140 breast cancer 235–236 in recurrent disease 238 colorectal cancer 285–286 complications see complications genitourinary cancer 356 gestational trophoblastic disease 344–345 for gross metastasis 126–129 history 9–11 lung cancer see lung cancer melanoma see melanoma, therapy of intracranial metastases ovarian cancer 338, 340, 346 prophylactic see radiation therapy radiosurgery compared with, in local control 143

renal cell carcinoma 272 sarcomas 396, 404 Ewing’s sarcoma 402 leiomyosarcoma 398 osteosarcoma 401 trials addressing role of 464–465 see also radiation therapy whole-brain radiation therapy/cranial irradiation (WBRT) plus other treatments brachytherapy + WBRT 170, 466 chemotherapy + WBRT see chemoradiation for brain metastases chemotherapy + WBRT + surgery see surgery plus radiation plus chemotherapy focal therapy (in general) + WBRT 180 radiosurgery + WBRT see radiosurgery plus whole-brain radiation therapy surgery + WBRT see surgery plus radiation women incidence of intracranial metastases 28 renal cell carcinoma 267 see also breast cancer; gynecologic cancer; sex World Health Organization classiﬁcation, lung cancer 201, 202 X-rays see radiation therapy; radiography

A

B

Plate 5.1 Patient with recurrent cerebral metastatic breast carcinoma. (A) FLAIR image. (B) Dynamic susceptibility contrast (DSC) regional cerebral blood volume (rCBV) map showing normal gray-white matter perfusion contrast and well-demarcated increased rCBV in a recurrent metastasis (arrow). (C) Vascular endothelial transfer coefﬁcient (permeability) parametric map. In the parametric map, dark blue represents low permeability and red represents high permeability.

C

A

B

C

Plate 5.2 Blood-oxygen-level-dependent (BOLD) contrast fMRI data. (A) A left hand ﬁnger-thumb tapping task is performed by a patient with multiple brain metastases. Regions of primary sensorimotor and supplementary motor area activation are noted. (B) A bilateral ﬁnger-thumb tapping task results in a patient with anaplastic astrocytoma demonstrating an anterior shift of the left hemisphere sensorimotor strip due to mass effect of the tumor. (C) fMRI data are overlaid on three-dimensionally rendered data for surgical planning.

Plate 5.3 Patient with recurrent cerebral metastatic breast carcinoma. (Left) FLAIR image with choline-to-creatine ratio "metabolite map" (red: high choline-to-creatine ratio, blue: low ratio values). (Right) Spectra from volumes of interest shown in pink in the FLAIR image. Note in spectra 18 and 19 (*) the high levels of choline, low levels of creatine and NAA, and elevated lipid levels that are common spectral traits for metastatic lesions. Spectra 22 and 23 are representative of normal brain tissue for the acquisition parameters used for this study (PRESS-spectroscopic imaging, TE = 144 ms, TR = 1000 ms).

Plate 7.1 Surgical approaches to supratentorial metastases. 1. Transcortical and transsulcal approaches to subcortical metastasis arising near gray-white junction below top of gyrus. 2. Transcortical and transsulcal approaches to lobar metastasis located entirely within white matter; transsulcal approach reduces brain injury. 3. Transcallosal approach via interhemispheric ﬁssure permits access to metastases within the cingulate gyrus or within a ventricle (shown); intraventricular lesions may also be resected by transcortical approach. 4. Sylvian ﬁssure approach to insular metastasis. (Reprinted from Lang FF, Chang EL, Suki D, et al. Metastatic brain tumors. In Winn HR (ed): Youmans Neurological Surgery. 5th ed (in press). Copyright 2003, with permission from Elsevier).

Plate 16.1 Venous vascular drainage patterns that provide hematogenous routes for the metastasis of colorectal cancer to the brain: A – via the rectal plexus of veins into the inferior vena cava, bypassing the liver; B – via Batson's vertebral plexus, bypassing the liver and lungs; C – via the portal veins to the liver and lungs and then to the brain. (A) Possible route for hematogenous metastasis of proximal colon cancers. (B) Possible route for hematogenous metastasis of distal colon and rectal cancers. Plate 26.1 The blood-brain barrier (BBB) is an obstacle to the invasion of metastatic tumor cells. The vascular components of the BBB consist of a tightly organized lining of specialized vascular endothelial cells. Endothelial cells contain pinocytotic vesicles and large numbers of mitochondria and are linked tightly together by junction strictures. Specialized pericytes encircle the endothelial cells residing on the abluminal side of the microvessels. A thick basal lamina separates the pericytes from the endothelial cells and astrocyte footpads. These footpads envelop the capillary structures and are interconnected to a web of astroglial cells, providing a boundary that is highly responsive to injury. Pericytes send out cellular projections that inﬁltrate the basal lamina and cover a large portion of the microvascular surface. There is no stromal connective tissue matrix surrounding the vessel or in the brain parenchyma.

Plate 26.2 Interactions between invading cancer cells and normal cells in the brain microenvironment. Tumor cells release growth factors: acidic ﬁbroblast growth factor (aFGF), basic ﬁbroblast growth factor (bFGF), and transforming growth factor alpha (TGFa); cytokines: tumor necrosis factor alpha (TNF-a) and interleukin-1 (IL-1); and fatty acid metabolites: prostaglandins (PGs), leukotrienes (LTs), and hydroxy eicosa tetraenoic acids (HETEs) that can affect host cells, such as parenchymal cells, endothelial cells, glial cells, oligodendrocytes, astrocytes, and host tissue extracellular matrix. Reactive astrocyte formation can be stimulated by blood-derived vasogenic factors, factors released by brain-invading cancer cells, and factors released from other brain cells. In turn, the host cells release factors that stimulate or inhibit tumor-cell motility and proliferation. Astrocytes, oligodendrocytes, and neurons can release neurotrophins in response to brain-invading cancer cells. Astrocytes and microglial cells can release PGs, LTs, and HETEs in response to tumor-cell-induced inﬂammation.