Dx Rx: Brain Tumors (Dx Rx Neurology Series)

Dx/Rx: Brain Tumors Eudocia Quant, MD Center for Neuro-Oncology Dana-Farber/Brigham and Women’s Cancer Center Boston, ...

Author: Eudocia Quant

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Dx/Rx:

Brain Tumors Eudocia Quant, MD Center for Neuro-Oncology Dana-Farber/Brigham and Women’s Cancer Center Boston, MA Series Editor: Kevin N. Sheth, MD Division of Neuro-Critical Care & Stroke University of Maryland Medical Center R. Adams Cowley Shock Trauma Center Baltimore, MD

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World Headquarters Jones and Bartlett Publishers 40 Tall Pine Drive Sudbury, MA 01776 978-443-5000 [email protected] www.jbpub.com

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Jones and Bartlett’s books and products are available through most bookstores and online booksellers. To contact Jones and Bartlett Publishers directly, call 800-832-0034, fax 978-443-8000, or visit our website, www.jbpub.com. Substantial discounts on bulk quantities of Jones and Bartlett’s publications are available to corporations, professional associations, and other qualified organizations. For details and specific discount information, contact the special sales department at Jones and Bartlett via the above contact information or send an email to [email protected]. Copyright © 2011 by Jones and Bartlett Publishers, LLC All rights reserved. No part of the material protected by this copyright may be reproduced or utilized in any form, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without written permission from the copyright owner. The authors, editor, and publisher have made every effort to provide accurate information. However, they are not responsible for errors, omissions, or for any outcomes related to the use of the contents of this book and take no responsibility for the use of the products and procedures described. Treatments and side effects described in this book may not be applicable to all people; likewise, some people may require a dose or experience a side effect that is not described herein. Drugs and medical devices are discussed that may have limited availability controlled by the Food and Drug Administration (FDA) for use only in a research study or clinical trial. Research, clinical practice, and government regulations often change the accepted standard in this field. When consideration is being given to use of any drug in the clinical setting, the healthcare provider or reader is responsible for determining FDA status of the drug, reading the package insert, and reviewing prescribing information for the most up-to-date recommendations on dose, precautions, and contraindications, and determining the appropriate usage for the product. This is especially important in the case of drugs that are new or seldom used. Production Credits Senior Acquisitions Editor: Nancy Anastasi Duffy Editorial Assistant: Sara Cameron Production Director: Amy Rose Associate Production Editor: Jessica deMartin Senior Marketing Manager: Barb Bartoszek V.P., Manufacturing and Inventory Control: Therese Connell

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Library of Congress Cataloging-in-Publication Data Quant, Eudocia. Dx/Rx. Brain tumors / Eudocia Quant. p. ; cm. — (Dx/Rx neurology series) Other title: Brain tumors Includes bibliographical references and index. ISBN-13: 978-0-7637-7372-4 ISBN-10: 0-7637-7372-7 1. Brain—Tumors—Handbooks, manuals, etc. I. Title. II. Title: Brain tumors. III. Series: Jones and Bartlett Publishers Dx/Rx neurology series. [DNLM: 1. Brain Neoplasms—diagnosis—Handbooks. 2. Brain Neoplasms— therapy—Handbooks. WL 39 Q15d 2011] RC280.B7.Q83 2011 616.99'481—dc22 2010000301 6048 Printed in the United States of America 14 13 12 11 10 10 9 8 7 6 5 4 3 2 1

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Contents Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 1

Primary Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . 1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Histological Classification of Primary Brain Tumors . . . . 1 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Gliomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Meningioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Primary CNS Lymphoma (PCNSL) . . . . . . . . . . . . . . . 28 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2

Brain Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features in Parenchymal Metastases . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain Metastases from Breast Cancer . . . . . . . . . . . . . . Brain Metastases from Non-Small Cell Lung Cancer (NSCLC) . . . . . . . . . . . . . . . . . . Brain Metastases from Melanoma . . . . . . . . . . . . . . . . Brain Metastases from Renal Cell Carcinoma (RCC) . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

43 43 44 44 46 53 55 57 58 59

Spinal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extradural Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intradural Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67 68 73 80

iii

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iv Contents 4

Leptomeningeal Metastases . . . . . . . . . . . . . . . . 83 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

83 83 84 84 85 86 87 90

Neurologic Complications of Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . 93 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Radiation Effects on the Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . 94 Radiation Effects on the Peripheral Nervous System . . . . . . . . . . . . . . . . . . . . . . . 101 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

6

Neurologic Complications of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . 107 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Chemotherapy Agents . . . . . . . . . . . . . . . . . Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . Peripheral Nervous System . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

Paraneoplastic Disorders . . . . . . . . . . . . . . . . . . 127 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Paraneoplastic Disorders . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8

107 107 110 115 123

127 127 128 129 130 131 152

Cerebrovascular Complications . . . . . . . . . . . . 161 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Ischemic Strokes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

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Contents v Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thrombotic Disease (Including Small, Medium, and Large Vessel Disease) . . . . . . . . . . . . . . . . Intracranial Hemorrhages . . . . . . . . . . . . . . . . . . . . . . Cerebral Venous Thrombosis (CVT) . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

163 166 169 173 176

Medical Complications of Brain Tumor Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Venous Thromboembolism (VTE). . . . . . . . . . . . . . . . Cerebral Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cognitive Impairment . . . . . . . . . . . . . . . . . . . . . . . . . Fatigue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Complications and Their Management . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

181 186 190 192 194 195 196 202

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

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Editor’s Preface

Welcome to the Dx/Rx Neurology series. This is a new series of books focusing on common neurological disorders. This book, Dx/Rx: Brain Tumors, is a comprehensive overview of tumors of the central nervous system and complications of cancer and cancer therapy. Dr. Eudocia Quant provides a succinct and easy-to-read overview for the neurological trainee, neurologist, and practicing oncologist as well as the general internist. The additional focus on complications of nervous system tumors and their associated therapies is most useful in addressing the significant morbidity patients with brain tumors face. I believe you will find this, and the entire neurology series, an invaluable resource to you and your colleagues. Kevin N. Sheth, MD

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Preface

This book focuses on two difficult issues in neuro-oncology: brain tumors and neurologic complications of cancer. The former represents a heterogeneous group that includes benign and malignant histologies as well as primary and metastatic lesions. The latter is often a source of significant morbidity for cancer patients. While some patients may ultimately be referred to neuro-oncologists, it often falls upon general internists, neurologists, or oncologists to initially manage these issues. This book is intended for them. Eudocia Quant, MD

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C H A P T E R

1

Primary Brain Tumors Epidemiology ■

■

Central Brain Tumor Registry of the United Status (CBTRUS)1 • The overall incidence rate for 2004–2005 in the United States for primary brain and CNS tumors was 23.62 per 100,000 person-years for adults (ages 201 years). • The most frequently reported histology is meningioma (33.4%), followed by glioblastoma (17.6%). Mortality rates from nervous system tumors (including meningiomas) in North America, Western Europe, and Australia are approximately 4 to 7 per 100,000 persons per year in men and 3 to 5 per 100,000 persons per year in women.2

Histological Classification of Primary Brain Tumors ■

■

Primary brain tumors rarely metastasize outside of the CNS. Grading of primary brain tumors is as follows: • Conventional TNM grading is not used for primary brain tumors. • Several grading systems exist for primary brain tumors, but the WHO classification is the most widely adopted (Table 1-1).3 ■ Tumors are graded I to IV, which correlates with the degree of malignancy. ■ Subclassification is based on the morphologic appearance of tumor cells.

1

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2 Chapter 1 Table 1-1:

WHO Classification of Primary Brain Tumors

Classification

WHO Grade (I–IV)

Astrocytic tumors Pilocytic astrocytoma

I

Diffuse astrocytoma

II

Anaplastic astrocytoma

III

Glioblastoma

IV

Gliosarcoma

IV

Gliomatosis cerebri Oligodendroglial tumors Oligodendroglioma

II

Anaplastic oligodendroglioma

III

Oligoastrocytic tumors Oligoastrocytoma

II

Anaplastic oligoastrocytoma

III

Ependymal tumors Subependymoma

I

Myxopapillary ependymoma

I

Ependymoma

II

Anaplastic ependymoma

III

Choroid plexus tumors Choroid plexus papilloma

I

Atypical choroid plexus papilloma

II

Choroid plexus carcinoma

III

(Continues)

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Primary Brain Tumors 3 Table 1-1:

WHO Classification of Primary Brain Tumors (Continued)

Classification

WHO Grade (I–IV)

Neuronal and mixed neuronal-glial tumors Gangliocytoma

I

Ganglioglioma

I

Anaplastic ganglioglioma

III

Central neurocytoma

II

Pineal tumors Pineocytoma

I

Pineoblastoma

IV

Embryonal tumors Medulloblastoma

IV

Tumors of the cranial and peripheral nerves Schwannoma

I

Neurofibroma

I

Malignant peripheral nerve sheath tumor

II–IV

Meningeal tumors Meningioma

I

Atypical meningioma

II

Anaplastic/malignant meningioma

III

Hemangioblastoma

I

Tumors of the hematopoietic system Primary CNS lymphoma

(Continues)

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4 Chapter 1 Table 1-1:

WHO Classification of Primary Brain Tumors (Continued)

Classification

WHO Grade (I–IV)

Germ cell tumors Germinoma Teratoma Choriocarcinoma Tumors of the sellar region Craniopharyngioma

I

Data are from Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumors of the Central Nervous System, 4th ed. Lyon: International Agency for Research on Cancer; 2007.

Risk Factors4 ■

Genetic syndromes account for only a few cases. • Neurofibromatosis 1: an autosomal dominant disorder that is characterized by multiple neurofibromas, malignant peripheral nerve sheath tumors, optic nerve gliomas, café-au-lait spots, axillary/inguinal freckling, and iris hamartomas.2 • Neurofibromatosis 2: an autosomal dominant disorder that is characterized by schwannomas, meningiomas, and gliomas. • Tuberous sclerosis: an autosomal dominant disorder that is characterized by cortical tubers, facial angiofibroma, subependymal nodules, and giant cell astrocytomas. • Retinoblastoma • Li-Faumeni (TP53): an autosomal dominant disorder that is characterized by multiple primary neoplasms in children and young adults, with a predominance of soft-tissue sarcomas, osteosarcomas, and breast cancer, as well as an increased incidence of brain tumors (mostly astrocytic gliomas).2

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Primary Brain Tumors 5

■

■

■

• Turcot syndrome: an autosomal dominant disorder that is characterized by adenomatous colorectal polyps, colon carcinomas, and malignant neuroepithelial tumors.2 • Multiple hamartoma syndrome Genetic polymorphisms: several polymorphisms have been implicated, but too few studies have been conducted to assure consistency. Ionizing radiation exposure is a generally accepted cause of primary brain tumors. • This is based on data from bomb studies, nuclear test fallout data, therapeutic radiation for cancer and benign conditions, and occupational and environmental studies. • Cranial irradiation (even low doses) can increase the incidence of meningiomas by a factor of 10 and the incidence of glial tumors by a factor of 3 to 7, with a latency period of 10 years to more than 20 years.5 Nonionizing radiation exposure: the association of electromagnetic fields or radiofrequency cell phones with brain tumors remains unresolved because of inconsistency between studies.2,4

Diagnosis ■

■

MRI with gadolinium is generally the test of choice in primary brain tumors. • Imaging is useful for tumor diagnosis, preoperative planning, intraoperative imaging, postoperative care, and treatment response.6 • The appearance varies depending on histology (discussed later in this chapter). • Imaging cannot substitute for tissue diagnosis because it is difficult to differentiate between glioma histologies based on imaging alone. Pathology (obtained via surgical biopsy or resection) is often required for definitive diagnosis.

Gliomas (Table 1-2) ■

These arise from glial cells (astrocytes, oligodendrocytes, ependymal cells, etc.).

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Grade II

Peak incidence ages 30–40, slight male predominance

Well-differentiated neoplastic astrocytes on background of loosely structured matrix

Demographics

Histopathology

Diffuse Astrocytoma

Compared with diffuse astrocytoma, increased cellularity, distinct nuclear atypical, mitotic activity. Microvascular proliferation and necrosis are absent.

Mean age of diagnosis is approximately 45 years, slight male predominance

Grade III

Anaplastic Astrocytoma

Astrocytic Tumors

Astrocytic Versus Oligodendroglial Tumors

WHO grade

Table 1-2:

Poorly differentiated, often pleomorphic astrocytic tumor cells with marked nuclear atypia and high mitotic activity. Prominent microvascular proliferation and/or necrosis are essential.

Peak incidence ages 45–75, slight male predominance

Grade IV

Glioblastoma

Diffusely infiltrating gliomas of moderate cellularity, composed of monomorphic cells with uniform round nuclei and perinuclear halos on paraffin sections. Other features include microcalcifications, mucoid/cystic degeneration, and a dense network of branching capillaries.

Peak incidence ages 40–45, slight male predominance

Grade II

Oligodendroglioma

(continues)

Compared with oligodendroglioma WHO grade II, mitotic activity, prominent microvascular proliferation, or conspicuous necrosis

Peak incidence ages 45–50, slight male predominance

Grade III

Anaplastic Oligodendroglioma

Oligodendroglial Tumors

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5–10 years

Median survival

2–3 years

Irregularly shaped mass with peritumoral edema, typically contrast enhancing with necrotic center

9–12 years

Irregularly shaped, contrast-enhancing mass with necrotic center. Typically more extensive peritumoral edema than anaplastic gliomas

Heterogenous patterns due to variable presence of necrosis, cystic degeneration, intratumoral hemorrhages, and calcifications. Contrast enhancement may be patchy or homogenous.

Depends on 1p/19q status: median survival in patients with 1p/19q codeletions is more than 7 years compared with 2.8 years in patients with 1p/19q retained

Nonenhancing mass, T1-hypointense, T2-hyperintense

Oligodendroglial Tumors

Data are from Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumors of the Central Nervous System, 4th ed. Lyon: International Agency for Research on Cancer; 2007. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):494–507.

Nonenhancing mass, T1-hypointense, T2-hyperintense

Astrocytic Tumors

Astrocytic Versus Oligodendroglial Tumors (Continued)

Typical MRI appearance

Table 1-2:

Primary Brain Tumors 7

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8 Chapter 1 ■ ■

■

■

Glioblastomas account for 54% of all gliomas.1 Most low-grade gliomas undergo malignant transformation to higher grade tumors. The incidence of gliomas has increased slightly over the past 2 decades, primarily because of improved diagnostic imaging.7 They rarely spread outside of the CNS.

Astrocytoma Pilocytic Astrocytoma (WHO Grade I/IV) ■ These are mostly seen in the pediatric population. Diffuse Astrocytoma (WHO Grade II/IV) ■ Biology • p53 tumor suppressor mutations are found in more than 60% of astrocytomas.8 • The combined loss of 1p and 19q is a rare event in low-grade astrocytomas.9 ■ Clinical features • The mean age of presentation is 34 years.6 • Patients may present with generalized or focal signs/ symptoms. • There is a high rate of seizures in low-grade tumors because of frequent involvement of the cortex and slower growth than higher grade tumors. ■ MRI appearance: typically nonenhancing mass, hypointense on T1-weighted images, hyperintense on T2-weighted images ■ Treatment for low-grade gliomas • There is no standard of care, and treatment recommendations vary widely. • Studies of low-grade glioma often combine astrocytoma, oligoastrocytoma, and oligodendroglioma patient populations. • Surgery ■ Surgery is important for establishing a diagnosis. ■ It is controversial whether the extent of resection improves outcomes.

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Primary Brain Tumors 9

• Gliomas are often infiltrative, diffuse, and/or near eloquent brain regions. • There is an increasing trend among neurosurgeons toward aggressive resection. • No randomized studies are available on the extent of resection in low-grade gliomas, but several retrospective reviews show improved survival with aggressive tumor resection.10,11 ■ Benefits of more extensive resection include • Minimizing tumor burden • Reducing symptoms • Decreasing sampling error and improving diagnostic accuracy12 ■ Results from a phase II study of 111 “good-risk” patients with low-grade glioma (neurosurgeondefined gross total resection and age #40) followed with serial MRI imaging13: • Overall 5-year survival rate, 93% • Five-year progression-free survival rate, 48% • Factors associated with poorer progression-free survival in multivariate analysis: preoperative tumor diameter $4 cm, astrocytoma or oligoastrocytoma histologic type, and residual tumor $1 cm on an MRI • Radiation therapy ■ Radiation therapy is considered standard treatment for low-grade gliomas. ■ The total dose is typically 50–54 Gy. • A randomized, multicenter study of 379 patients with low-grade glioma comparing lower dose (45 Gy over 5 weeks) versus higher dose (59.4 Gy over 6.6 weeks) conventional, limited-field, external-beam radiation demonstrated no difference in overall survival or 5-year progressionfree survival.14 • A randomized, multicenter study of 211 patients with low-grade glioma comparing lower dose (50.5 Gy in 28 fractions) versus higher dose

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10 Chapter 1 (64.8 Gy in 36 fractions) conventional, limitedfield, external-beam radiation demonstrated no difference in overall survival or progression-free survival but did demonstratemore radiationinduced toxicity with higher dose.15 ■ Timing of radiation therapy • A randomized, multicenter trial of 311 patients with low-grade glioma comparing immediate radiation therapy after resection versus delayed radiation until tumor progression demonstrated a significant difference in 5-year progressionfree survival in the early radiation arm over the delayed radiation arm (55% vs. 34.6%) but no difference in overall survival and it is unclear if there is any impact on quality of life16 ■ Long-term side effects of radiation • There is concern for an effect on cognitive functioning. • Results from a longitudinal neuropsychological study of patients with radiographically and clinically stable low-grade glioma: ■ At mean of 6 years after diagnosis, results suggested that the tumor itself (not radiation) had the most deleterious effect on cognitive functioning, and only high fraction dose radiation (daily fractions .2 Gy) was associated with additional cognitive deterioration.17 ■ At mean of 12 years after diagnosis, the patients who received radiation therapy (even those with daily fractions #2 Gy) showed a progressive decline in attentional functioning, whereas those who never received radiation therapy had stable radiological and cognitive status.18 • Chemotherapy ■ There is interest in developing effective chemotherapy for low-grade glioma in an attempt to spare patients the late toxicities associated with radiation.

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Primary Brain Tumors 11

Randomized studies evaluating chemotherapy in low-grade glioma • A randomized, multicenter trial of radiation with or without lomustine showed no difference in survival.19 • A randomized, multicenter trial of high-risk patients with low-grade glioma (defined as residual tumor or age .40) of radiation with or without six cycles of adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy.20 ■ The overall median survival and progressionfree survival were similar for both arms between the years 0 and 2. ■ Beyond 2 years, the overall survival and progression-free survival curves separated significantly, favoring PCV and radiation therapy. • Results are pending on a randomized, multicenter trial of patients with low-grade glioma comparing radiation versus temozolomide. ■ Phase II studies have demonstrated objective responses with the following regimens.9 • Procarbazine, CCNU, and vincristine (PCV) • Temozolomide Prognosis • Based on a Swiss population-based study, the median overall survival for patients with low-grade astrocytoma was 5.6 years.21 • In a study of newly diagnosed low-grade gliomas treated with temozolomide, methylated methylguaninemethytransferase (versus unmethylated MGMT) and loss of 1p/19q were associated with longer progressionfree survival.22 ■

■

Anaplastic Astrocytoma (WHO Grade III/IV) ■ Biology • They frequently arise from lower grade astrocytomas. • They frequently undergo malignant transformation into glioblastomas. • p53 mutations and platelet-derived growth factor receptor (PDGFR) overexpression are common.23

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12 Chapter 1 ■

■

■

Clinical features • Patients may present with generalized or focal signs/ symptoms. • The median age at the time of diagnosis is 40 to 50 years. MRI appearance: irregularly shaped mass with associated edema, typically contrast enhancing Treatment • Most trials to date that include anaplastic astrocytomas have lumped grade III and grade IV astrocytomas together, although ongoing trials are beginning to separate grade III from grade IV astrocytomas. • Treatment decisions are often extrapolated from glioblastoma trials. • Surgery ■ Surgery is important for establishing diagnosis. ■ Pathology should be taken from the contrastenhancing margin of the lesion rather than the necrotic core.23 ■ It is controversial whether the extent of resection improves outcomes. • Retrospective studies suggest that more aggressive resections increase survival, but such studies are prone to bias. • In a randomized study of 30 older patients (age .65) with grade III or grade IV gliomas comparing stereotactic biopsy with open craniotomy and resection, median survival was longer after resection (171 days vs. 85 days).24 • Radiation therapy ■ The role of radiation therapy is clearly established in anaplastic astrocytoma. ■ For patients with adequate performance status, a radiation therapy dose of 60 Gy in 30 fractions/day is the standard of care.25 • Chemotherapy ■ The role of chemotherapy in newly diagnosed anaplastic astrocytoma is less well established than the role of radiation therapy.

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Primary Brain Tumors 13 ■

■

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Preliminary results from a randomized, multicenter trial of patients with newly diagnosed anaplastic glioma randomized to sequential radiochemotherapy (radiation therapy upfront followed by PCV or temozolomide at first progression versus PCV or temozolomide upfront followed by radiation therapy at first progression):26 • There was no difference in time to failure (progression after radiotherapy and chemotherapy in either sequence) or median overall survival between initial radiotherapy and initial chemotherapy and between temozolomide and PCV. • Patients with anaplastic astrocytoma had a worse time to failure than those with anaplastic astrocytoma or anaplastic oligoastrocytoma. Based on data from the glioblastoma population,27 there is an increasing trend toward using radiation therapy with concurrent and adjuvant temozolomide. Results from a randomized, multicenter trial of 193 patients with newly diagnosed anaplastic astrocytoma comparing radiation therapy with concurrent and adjuvant BCNU and dibromodulcitol (DBD) versus radiation therapy alone:28 • This study demonstrated no statistically significant difference in overall survival or progressionfree survival. • The study terminated early because of decreasing accrual. • The 2-year survival rate was 56% in the combined therapy arm versus 49% in the radiation therapy-only arm. • At central pathology review, 53% of the locally diagnosed cases of anaplastic astrocytoma could not be confirmed. In a randomized multicenter trial of 290 patients with newly diagnosed anaplastic oligodendroglioma or anaplastic oligoastrocytoma comparing

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PCV chemotherapy followed by radiation therapy versus radiation therapy alone, there was no difference in overall survival or progression-free survival.29 ■ Results are pending on an ongoing randomized phase III trial in anaplastic astrocytoma of radiation therapy with temozolomide versus radiation therapy with a nitrosourea. • Recurrent disease ■ Chemotherapy is frequently given for recurrent disease. ■ Preliminary results from a multicenter, randomized phase III trial of 447 patients with chemotherapynaïve, recurrent grade III or grade IV astrocytomas or oligoastrocytomas comparing temozolomide versus PCV chemotherapy:30 • The study demonstrated no difference in overall median survival comparing temozolomide to PCV. • There was no clear evidence of differential treatment effect in either GBM or anaplastic astrocytoma. • A 5-day regimen of temozolomide was superior to a 21-day regimen of temozolomide with respect to progression-free and overall survival. ■ In a multicenter phase II trial of patients with anaplastic astrocytoma or anaplastic oligoastrocytoma who recurred after radiation therapy, temozolomide demonstrated good activity with 6-month progression-free survival rate of 46% and an objective response rate of 35%.31 ■ Several investigational agents have also been tested in phase II clinical trials for malignant glioma (i.e., grade III and grade IV gliomas), although none has become a standard therapy yet.7 Prognosis • Based on European population studies for patients diagnosed during 1990–1994, the 1-year survival was 44%, and the 5-year survival was 16%.23

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• Based on a Swiss population-based study, the median overall survival for anaplastic astrocytoma was 1.6 years.21 • Based on a phase III clinical trial of radiation with or without DBD and BCNU, the median overall survival for anaplastic astrocytoma was 2 to 2.6 years.28 • Good prognostic factors are younger age (,50 years old), good performance status, and intact neurologic function. Glioblastoma (WHO Grade IV/IV) ■ Biology • Other histologic variants include gliosarcoma, giantcell glioblastoma, small-cell glioblastoma, and glioblastoma with oligodendroglial features. • It may present de novo (primary GBM) or arise from a lower grade tumor (secondary GBM). • Genetic differences exist between primary and secondary GBMs.7 ■ Primary GBMs are characterized by epidermal growth factor receptor (EGFR) amplification and mutations, loss of heterozygosity of chromosome 10q, deletion of PTEN, and p16 deletion. ■ Secondary GBMs are characterized by p53 mutations, overexpression of PDGFR, abnormalities in p16 and retinoblastoma pathways, and loss of heterozygosity of chromosome 10q. ■ Clinical features • GBMs may present with focal or generalized signs/ symptoms. • The median age at the time of diagnosis is 64 years,7 although patients presenting with a primary GBM are generally older than patients with a secondary GBM. ■ MRI appearance • Heterogeneous enhancement with nonenhancing necrotic center, surrounding edema, and mass effect • Most commonly disseminate along white matter tracts, especially the corpus callosum, to involve the contralateral hemisphere

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16 Chapter 1 ■

Treatment • Primary and secondary GBMs are currently treated similarly despite their genetic differences, but this may change in the future. • Surgery ■ This is important for establishing a diagnosis. ■ It is somewhat controversial about whether the extent of resection improves outcomes, although recent prospective studies suggest a survival benefit for more extensive resections. • Because of the infiltrating nature of GBMs, it is not possible to remove the tumor in its entirety, and thus, the extent of resection is defined by the contrast-enhancing portion of the tumor on postoperative MRI with contrast. • Retrospective studies suggest that more aggressive resections increase survival, but such studies are prone to bias. • In a randomized study of 30 older patients (age .65) with grade III or grade IV gliomas comparing stereotactic biopsy with open craniotomy and resection, median survival was longer after resection (171 days vs. 85 days).24 • Results from a randomized study of 322 patients with grade III or IV glioma comparing the extent of resection by fluorescence-guided resection with 5-aminolevulinic acid versus conventional microsurgery: ■ Interim analysis suggested that patients without residual contrast-enhancing tumor had a higher overall median survival than those with residual-enhancing tumor (17.9 months vs. 12.9 months).32 ■ Subgroup analysis of 243 patients with GBM demonstrated treatment bias regarding complete versus incomplete resection, but when patients were stratified based on age and eloquent location, survival advantages from complete resection remained significant.33

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Primary Brain Tumors 17

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• Newly diagnosed glioblastoma ■ The current standard of care for newly diagnosed glioblastoma is radiation plus concomitant temozolomide followed by adjuvant temozolomide.27 ■ Based on a randomized phase III clinical trial, initial treatment with radiation plus concomitant temozolomide followed by adjuvant temozolomide for six cycles increased the median overall survival compared with radiation alone (15 vs. 12 months). ■ The regimen is well tolerated, with myelosuppression occurring in less than 10%. ■ There is no data showing an improvement in overall survival with prolonged adjuvant temozolomide. ■ Several studies have demonstrated correlations between treatment outcome and expression of the DNA repair enzyme methylguanine methyltransferase (MGMT).34 ■ There are several phase II trials of promising targeted molecular therapies added to the standard radiation/temozolomide regimen, but none has been adopted as a new standard of care.7 • Recurrent glioblastoma ■ There is no clear standard of care, but a bevacizumabcontaining regimen is often given to patients with recurrent GBM. ■ FDA approval of bevacizumab for recurrent glioblastoma is based on several phase II clinical trials with bevacizumab monotherapy35,36 or bevacizumab plus irinotecan36–38 demonstrating prolongation of progression-free survival and improvement in response rates compared with historical controls. ■ There are several phase II trials of other promising targeted molecular therapies,7 but none has been as widely adopted as bevacizumab. Prognosis • Based on a Swiss population-based study, the median survival for glioblastoma was 0.4 years.21

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18 Chapter 1 • Based on the phase III clinical trial of radiation with or without temozolomide, the median survival for glioblastoma was 12 to 15 months.27 Oligodendroglioma Oligodendroglioma (WHO Grade II/IV) ■ Biology • Loss of heterozygosity of 1p and 19q chromosomes is associated with response to treatment and good prognosis but is studied less extensively in low-grade oligodendrogliomas than in anaplastic oligodendrogliomas.9 • Other less common genetic abnormalities in low-grade oligodendroglioma include overexpression of plateletderived growth factor or receptor, epidermal growth factor receptor, or vascular endothelial growth factor.39 • They arise in white matter, commonly in the frontal lobes. ■ Clinical features • Oligodendrogliomas may present with generalized or focal signs/symptoms. • There is a high rate of seizures in low-grade tumors because of the frequent involvement of the cortex and slower growth than higher grade tumors. • The median age of presentation is 35 to 40 years. ■ MRI appearance • MRI typically shows a nonenhancing mass, hyperintense on T2-weighted imaging. • Calcifications may be present and may be more conspicuous on gradient echo sequences.6 • Features that favor oligodendroglioma over astrocytoma include cortical involvement, the presence of calcifications, and a heterogeneous signal.6 ■ Treatment • No standard of care exists for low-grade oligodendroglioma, and treatment recommendations vary widely. • Treatment options are similar to low-grade astrocytoma (discussed previously in this chapter).

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Primary Brain Tumors 19 ■

Prognosis • Low-grade oligodendrogliomas have a better prognosis than low-grade astrocytomas. • Based on a Swiss population-based study, the median overall survival for a low-grade oligodendroglioma was 11.6 years.21

Anaplastic Oligodendroglioma (WHO Grade III/IV) Biology • Loss of heterozygosity of 1p and 19q chromosomes is associated with an increased response to treatment and good prognosis.39 ■ The incidence of either 1p or 19q deletions in oligodendrogliomas is approximately 75%.40 ■ The incidence of combined 1p 19q loss in oligodendrogliomas is 60% to 70%.40 ■ The combined loss of 1p 19q is mediated by translocation of 1 and 19q.41,42 • Other less common genetic changes include amplification of CDK4 or MYC, mutations of CDKN2A or CDKN2C, and deletions on chromosome 10.39 • Progression from low-grade oligodendroglioma to anaplastic oligodendroglioma is associated with defects in PTEN, retinoblastoma, p53, and cell cycle pathways.7 ■ Clinical features: generalized or focal signs/symptoms ■ MRI appearance6 • Marked enhancement is associated with anaplastic grades. • Calcifications may be present and may be more conspicuous on gradient echo sequences. • Features that favor oligodendroglioma over astrocytoma include cortical involvement, the presence of calcifications, and a heterogeneous signal. ■ Treatment • No standard of care is set for anaplastic oligodendroglioma. • The best treatment regimen is unknown, and treatment recommendations vary widely. • Surgery

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20 Chapter 1 This is important for establishing a diagnosis. Pathology should be taken from the contrastenhancing margin of the lesion rather than the necrotic core.23 ■ It is controversial whether the extent of resection improves outcomes. • Radiation therapy ■ Randomized trials in malignant gliomas demonstrate a survival advantage with adjuvant radiation therapy, but no trials have specifically addressed radiation therapy in the anaplastic oligodendroglioma.40 • Chemotherapy ■ Two large multicenter randomized phase III trials of newly diagnosed anaplastic oligodendroglioma showed that the addition of PCV chemotherapy to radiation does not prolong overall survival but does increase progression-free survival. • One study included 368 patients with anaplastic oligoastrocytoma and oligodendroglioma randomized to standard radiation therapy alone or radiation therapy followed by six cycles of adjuvant PCV (procarbazine, lomustine, vincristine).43 • The other study included 289 patients with anaplastic oligodendroglioma randomized to standard radiation therapy alone or four cycles of neoadjuvant dose-intensive PCV followed by radiation therapy.29 • In both trials, 80% of patients assigned to radiation therapy alone were treated with chemotherapy at progression. • There was no effect of treatment on survival even in the subgroup with 1p 19q codeletion. • The subgroup with 1p 19q codeletion had a longer median survival than those with 1p 19q retained. • The addition of PCV to radiation was associated with greater toxicity than radiation therapy alone. ■ ■

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Primary Brain Tumors 21

Temozolomide is effective in newly diagnosed anaplastic oligodendroglioma (based on phase II trials44–46) and is less toxic than PCV chemotherapy,26 but it is unclear whether temozolomide is equivalent, inferior, or superior to PCV chemotherapy. ■ Results are pending in several ongoing randomized phase III trials in anaplastic oligodendroglioma. • CATNON: radiation plus temozolomide versus radiation alone in anaplastic glioma without 1p 19q loss. • Codeleted trial: radiation alone versus temozolomide alone versus radiation plus temozolomide in newly diagnosed anaplastic oligodendroglioma or anaplastic oligoastrocytoma with 1p 19q codeletions. • Recurrent anaplastic oligodendroglioma ■ 1p 19q codeleted tumors that previously responded to chemotherapy will often respond again, although for a shorter period. ■ Procarbazine, CCNU, and vincristine chemotherapy (PCV) produced favorable responses in several phase II studies of recurrent anaplastic oligodendroglioma.47,48 • Radiographic response rates were 62% to 73%. • Median time to progression was 12 to 24 months. • Toxicities, including hematologic and gastrointestinal side effects, limit the duration of PCV administration. ■ Temozolomide produced favorable responses in several phase II studies of recurrent anaplastic oligodendroglioma. • Response rates were 25% to 44% following progression on PCV chemotherapy.49,50 • The response rate was 53% after progression on surgery and radiation.51 Prognosis • Anaplastic oligodendrogliomas have a better prognosis than anaplastic astrocytomas. ■

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22 Chapter 1 • Based on a Swiss population-based study, median overall survival for anaplastic oligodendroglioma was 3.5 years.21 • Based on randomized phase III trials of radiation therapy with or without PCV chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma, median overall survival was 2.6 to 4.9 years.29,43 ■ The difference in overall survival between two trials may be explained by stricter selection criteria in one trial resulting in a larger number of patients with 1p 19q codeletions and with fewer anaplastic features.

Meningioma ■ ■

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Tumors arising from arachnoid (meningothelial) cap cells Most common type of primary brain tumor, accounting for 33.4% of all primary brain tumors, with an annual incidence rate of 6.03 per 100,000 person-years1 Twice as common in women than men1

Risk Factors Ionizing radiation52 • Cranial radiotherapy for gliomas, leukemias, lymphomas, or cerebral metastases is associated with the development of meningiomas within the previous radiation field after a median latency period of 24 years. • Most meningiomas associated with radiotherapy are higher grade with a high proliferation index. ■ Hereditary syndromes, including neurofibromatosis type 2, Gorlin syndrome, and Cowden syndrome ■ Other suspected factors with insufficient evidence to determine definitively whether they increase the risk for meningiomas include cellular phones and head injury. ■

Clinical Features ■ The most common locations (in descending order) are the convexities, parasagittal areas, sphenoid and middle cranial fossa, frontal base, posterior fossa, cerebellar

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Primary Brain Tumors 23

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convexity, cerebellopontine angle, intraventricular, and clivus.53 Spinal meningiomas are most often found in the thoracic spine. Symptoms depend on location (Table 1-3). • Parasagittal meningiomas occur most frequently in the frontal lobe and can grow to a large size before causing symptoms such as seizures or papilledema. • Frontal skull base meningiomas may present with vision changes, headache, anosmia, mental status changes, and seizures.

Pathology ■ WHO grades • Benign meningiomas (WHO grade I/IV) ■ Most common grade ■ Subtypes: meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte rich, and metaplastic • Atypical meningiomas (WHO grade II/IV) ■ Represent 5% to 7% of all meningiomas ■ Subtypes: atypical, clear cell, and choroid ■ Compared with benign meningiomas, increased mitotic activity, increased cellularity, small cells with high nucleus:cytoplasm ratio, prominent nucleoli, pattern-less or sheet-like growth, or foci of spontaneous or geographic necrosis • Anaplastic/malignant meningiomas (WHO grade III/IV) ■ Less common ■ Subtypes: rhabdoid, papillary, and anaplastic (malignant) ■ Other pathologic changes • Genetic changes ■ Deletion of chromosome 22q, which contains the NF2 gene • Sex hormones54 ■ Progesterone receptors are found in 76% of meningiomas, mostly benign meningiomas.

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Olfactory groove

Hemiparesis, dysphagia Visual acuity/field disturbance due to optic nerve compression, proptosis, cranial nerve dysfunction (III, IV, V, VI)

Middle one third (alar)

Medial (clinoidal)

(continues)

Foster Kennedy syndrome (anosmia, ipsilateral optic atrophy with contralateral papilledema), frontal lobe syndromes, mental status changes, urinary incontinence, seizure

Similar to convexity tumors

Headache, visual symptoms, seizures, mental status changes

Posterior one third

Lateral/pterional

Jacksonian seizures, progressive hemiparesis

Middle one third

Sphenoid wing

Headache, mental status changes

Anterior one third

Parasagittal and falcine

Clinical Presentation

Location

Meningioma Location and Associated Typical Clinical Presentations

Meningioma

Table 1-3:

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Cranial nerve deficits (III, IV, V, VI) Hearing loss, facial pain/numbness/weakness/spasms, headaches, cerebellar signs Unilateral cervical pain, extremity motor and sensory loss (clockwise involvement), cold and clumsy hands with intrinsic hand atrophy Hearing loss, vertigo, tinnitus, facial pain, cranial nerve deficits (V, VI, VIII, VIII)

Cavernous sinus

Cerebellopontine angle

Foramen magnum

Petroclival

Adapted from Asthagiri AR, Helm GA, Sheehan JP. Current concepts in management of meningiomas and schwannomas. Neurol Clin. 2007; 25(4):1209–1230.

Visual acuity/field disturbance, anosmia, hydrocephalus, endocrinologic syndromes

Clinical Presentation

Tuberculum sella/ suprasellar

Location

Meningioma Location and Associated Typical Clinical Presentations (Continued)

Meningioma

Table 1-3:

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26 Chapter 1 ■

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More aggressive meningiomas are associated with low numbers or absence of progesterone receptors. Estrogen receptors are found in 19% of meningiomas.

Imaging Characteristic findings on MRI with gadolinium include the following6: • Sessile or pedunculated mass that homogeneously and intensely enhances • CSF cleft sign between the tumor and the brain • Involvement of the dura with a dural tail sign in 40% to 60% • Intratumoral calcification may be present • Presence of peritumoral edema is variable ■ Staging for metastatic disease • There are no consensus guidelines regarding systemic staging but meningioma metastases are uncommon; thus, further staging is unnecessary in most cases. • The most common sites of metastases are lung, bone, liver, and lymph nodes. • If lung metastases are suspected, then staging should include chest CT with contrast. ■

Treatment ■ Surgery • Approximately 80% of meningiomas (mostly grade I meningiomas) can be cured by surgery.52 • The goal is for complete resection, including the dural attachment and infiltrated bone. • The extent of resection is associated with the recurrence rate.53 • Complete resection is not achievable in some patients because of inaccessibility or proximity to vital structures, such as the cavernous sinus and clivus. • Preoperative embolization may facilitate removal and improve surgical outcomes by reducing vascularity and operative blood loss, but embolization is associated with a risk of ischemic and hemorrhagic complications.

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Primary Brain Tumors 27 ■

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Radiation therapy • Focal external beam radiation therapy is considered standard treatment for recurrent meningiomas and after surgery for atypical and malignant meningiomas. • Stereotactic radiosurgery can also be considered for small lesions (,3 cm) and/or for locations not amenable to surgery (i.e., cavernous sinus). • The use and timing of radiation after resection of a benign meningioma are controversial. ■ Some centers withhold radiation, even after subtotal resection of benign meningioma, until the time of progression. ■ In patients with WHO grade I meningiomas, radiation in single daily doses of 1.8–2.0 Gy to total doses of 45–60 Gy after subtotal resection produces comparable 5-year progression-free survival rates to rates after complete surgical resection.52 • Radiation is often provided after resection, even after total resection, in atypical and anaplastic meningiomas. Medical therapy52,55 • Mostly used as investigational agents or after progression despite multiple surgeries and/or radiation treatments • Agents with possible benefit (mostly based on pilot studies and phase II studies) include the following: ■ Interferon-a ■ Somatostatin analogues ■ Hydroxyurea Observation • There are no clear guidelines on observation versus treatment. • The decision for treatment depends on clinical history, severity of symptoms, rate of growth, amenability of the tumor to surgery, and the estimated benefit of treatment. ■ Patients with small asymptomatic meningiomas can be followed with serial imaging. ■ Atypical or anaplastic meningiomas should be treated.

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28 Chapter 1 Prognosis The overall 5-year survival ranges from 69% to 90% depending on the study.52 ■ Atypical and anaplastic meningiomas • Poorer prognosis than benign meningiomas • Usually demonstrate recurrence and aggressive growth rates regardless of treatment modality (extirpation, radiosurgery, or external beam radiation therapy)53 ■ Unfavorable prognostic factors include old age, male gender, and significant comorbidities56 ■ Tumor growth rates based on volumetric analysis57 • In study of patients with WHO grade I meningiomas who underwent subtotal resection, doubling time was 5.2 years. • Growth rates were higher in young patients. • Growth rates were lower in meningiomas with calcifications and in asymptomatic meningiomas. ■ Recurrences • High recurrence rates are associated with high histological grading, papillary and hemangiopericytic morphology, large tumor size, and high mitotic index.52 • In one series of 936 meningiomas, the 5-year recurrence rate after complete resection was 3% in benign meningiomas, 38% in atypical meningiomas, and 78% in anaplastic meningiomas. ■

Primary CNS Lymphoma (PCNSL) ■

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Rare form of extranodal non-Hodgkin lymphoma confined to the brain, leptomeninges, spinal cord, and eyes Accounted for 2.5% of all primary brain and CNS tumors diagnosed in the United States between 2004 and 20051

Risk Factors Congenital or acquired immunodeficiency (discussed later in this chapter) is a risk factor. ■ HIV infection is associated with a 3,600-fold increased risk of developing PCNSL.58 ■

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Primary Brain Tumors 29

Pathology Ninety percent of PCNSL are diffuse large B-cell lymphoma (DLBCL), with the remaining 10% poorly characterized low-grade lymphomas, Burkitt lymphomas, and T-cell lymphomas.59 ■ The DLBCL type is composed of immunoblasts or centroblasts with a predilection for blood vessels, resulting in lymphoid clustering around small cerebral vessels.60 ■ They are classified as stage I disease according to the Ann Arbor staging system, but the prognostic significance of the Ann Arbor staging system does not apply to PCNSL. ■

Clinical Features ■ The median age of diagnosis in immunocompetent patients is 53 to 57 years.60 ■ Patients present with neurologic signs and symptoms depending on the location of the tumor, including focal deficits, neuropsychiatric symptoms, increased intracranial pressure, seizures, and ocular symptoms. ■ Sixteen percent to 42% of patients with PCNSL have leptomeningeal involvement at diagnosis, but most do not show clinical signs of leptomeningeal disease.60 ■ Twenty percent have ocular involvement, presenting as floaters, blurred vision, diminished visual acuity, and painful red eyes.60 ■ Systemic B symptoms (fever, weight loss, night sweats) are less common, unlike systemic DLBCL. ■ Occult systemic disease has been reported in up to 8% of patients initially thought to have isolated PCNSL.61 Diagnosis61 ■ A definitive diagnosis usually requires a stereotactic biopsy. ■ MRI with gadolinium of the entire neuroaxis • Lesions appear clearly delineated and are isointense to hypointense on T2-weighted MRI because of high cell density and scant cytoplasm.

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• Lesions are typically homogeneously enhancing on postcontrast T1-weighted MRI in immunocompetent patients. • Lesions are solitary in 65% of patients and multifocal in 35%.60 • Locations include cerebral hemispheres (38%), thalamus/basal ganglia (16%), corpus callosum (14%), ventricular region (12%), and cerebellum (9%).60 • Lesions may appear to vanish with steroids because steroids reduce swelling and cause tumor lysis. Lumbar puncture with cytology, flow cytometry, and immunoglobulin heavy-chain gene rearrangement studies • CSF typically demonstrates increased WBC count, high protein concentrations, and low glucose. Complete ophthalmologic examination, including dilated fundus and slip-lamp examinations Other recommended studies to look for systemic disease • Chest, abdomen, and pelvic CT scan with contrast • Bone marrow biopsy • Clinical and ultrasound testicular examination in men • Clinical examination of peripheral lymph nodes • Routine blood work including HIV testing, CBC, LDH • Possibly PET scan

Treatment ■ PCNSLs are sensitive to corticosteroids, but responses are not durable. ■ There is no standard treatment. ■ There are no randomized, controlled phase III trials in PCNSL. ■ Treatment options are based on the results from phase II clinical trials.62 • Newly diagnosed PCNSL ■ Surgery • Stereotactic biopsy is indicated for diagnosis. • Gross total resection or tumor debulking confers no survival benefit over surgery alone.60

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Primary Brain Tumors 31 ■

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High-dose methotrexate monotherapy • CNS penetration of methotrexate is poor at conventional doses. • High doses (3 to 8 g/m2) can achieve cytocidal concentrations of methotrexate in cerebrospinal fluid.63 • High-dose methotrexate monotherapy is associated with response rates of 35% to 74% and with median progression-free survival of 12.8–13.7 months. • High doses $3 g/m2 require intensive inpatient management and good renal function. Methotrexate-based multidrug regimens • The incremental benefit from additional chemotherapy beyond high-dose methotrexate is unclear. ■ Preliminary results from a randomized phase II study of high-dose methotrexate (followed by whole brain radiation) with or without high-dose cytarabine found that the addition of cytarabine increased response rates from 40% to 69%.64 • Radiographic response rates and disease-free survival may be slightly higher in trials with methotrexate-based multidrug regimens compared with trials with methotrexate monotherapy, but rates often overlap.62 • Multidrug regimens may be associated with higher toxicity than methotrexate monotherapy. • Common regimens include methotrexate, procarbazine, and vincristine (MPV); high-dose cytarabine and methotrexate; and temozolomide and methotrexate in older patients (age .60).62 Intrathecal chemotherapy • Intrathecal chemotherapy is standard treatment for patients with proven leptomeningeal disease. • However, the use of adjuvant intrathecal chemotherapy with high-dose methotrexate-based regimens is controversial because methotrexate

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32 Chapter 1

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doses $3 g/m2 can achieve adequate concentrations in the CSF.62 Adjuvant corticosteroids • Corticosteroids are useful for edema and symptomatic management. • Incorporation of corticosteroids into multidrug regimens has not increased response rates compared with non-steroid-containing regimens and is associated with side effects. High-dose chemotherapy with autologous stem-cell transplantation • Based on results from several phase II clinical trials, this approach is feasible in a selected population (younger and chemotherapy sensitive). • It is unclear whether patients in transplantation trials would have done as well with standard high-dose methotrexate-based chemotherapy regimens. • Studies show that transplantation is associated with higher mortality and morbidity than chemotherapy regimens without transplantation. Whole-brain radiation (WBRT) • WBRT was historically the standard of care in PCNSL but has been replaced by high-dose methotrexate-based regimens. • WBRT is often deferred, especially in patients older than 60 years of age and depending on response to chemotherapy. ■ WBRT alone does not produce durable remissions in most patients.65 ■ It is associated with neurotoxicity, including dementia, gait disturbance, and urinary incontinence (see Chapter 5 for additional information regarding radiation-related toxicities). Adjuvant rituximab • Rituximab is a humanized monoclonal antibody to CD20, a cell surface protein found on mature B cells. • It may be incorporated into treatment regimens for patients with DLBCL, which express CD20.

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• Response rates with rituximab monotherapy in PCNSL are modest. • Rituximab combined with methotrexate, procarbazine, vincristine, and cytarabine produced a high response rate of 93% in a phase II clinical trial.66 • There are several ongoing trials of rituximab in PCNSL. Recurrent or refractory PCNSL • Up to 50% of patients with PCNSL will relapse, and 10% to 15% of patients have primary refractory PCNSL.62 • Optimal management is unclear because of limited data. • Options include whole-brain radiation (for patients who had this treatment option initially deferred), reinduction with high-dose methotrexate, single agent topotecan, and single agent temozolomide. Ocular lymphoma • Ocular lymphoma may occur in isolation or in combination with parenchymal PCNSL. • Symptoms are similar to a nonspecific uveitis but eventually become refractory to topical steroids. • Definitive diagnosis is made with vitreal cytology. • For those with isolated ocular lymphoma, the risk of developing brain involvement is as high as 80%.62 • Treatment may include the following: ■ Primary intraocular lymphoma: directed ocular treatment with ocular radiotherapy or intraocular methotrexate. ■ Parenchymal brain and ocular lymphoma: the addition of directed ocular treatment may improve disease control, but a methotrexate dose of 8 g/m2 can also produce cytocidal concentrations in the vitreous body.

Prognosis ■ Durable complete responses and long-term survival are possible with treatment. ■ Outcomes are worse compared with patients with a similarly staged systemic non-Hodgkin lymphoma.

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34 Chapter 1 Table 1-4:

Prognostic Factors in PCNSL and Estimated 2-Year Overall Survival Rates

Poor Prognostic Factors

• Age .60 years • Performance status of 1 on the Eastern Cooperative Oncology Group (ECOG) performance status scale • Elevated serum LDH • High CSF protein concentration • Tumor location in the deep brain regions (periventricular regions, basal ganglia, brainstem and/or cerebellum)

Number of Poor Prognostic Factors

Two-Year Overall Survival Rates

0–1

80%

2–3

48%

4–5

15%

Data are from Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003;21(2):266–272.

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Poor prognostic factors in PCNSL and 2-year survival rates are listed in Table 1-4.67

HIV-Related PCNSL Nearly 6% of the AIDS population will be afflicted with PCNSL.6 ■ The disease incidence has decreased during the highly active antiretroviral therapy (HAART) era.68 ■ MRI with gadolinium in HIV-related PCNSL • This may demonstrate ring enhancing lesions, which makes it difficult to differentiate from toxoplasmosis. • Compared with PCNSL in immunocompetent patients, there is a higher frequency of multiple lesions, cortical-based lesions, lesions with irregular margins, heterogeneity, and hemorrhage.6 ■

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Primary Brain Tumors 35 ■ ■

Pathophysiology involves Epstein-Bar virus (EBV). Optimal management is unclear, but high-dose methotrexate, whole-brain radiation, and/or HAART may be used.62

References 1.

2. 3.

4.

5. 6. 7. 8.

9. 10.

11.

12.

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CBTRUS. Statistical report: primary brain and central nervous system tumors diagnosed in the United Status in 2004–2005. Hinsdale, IL: Central Brain Tumor Registry of the United States; 2009. http://www.cbtrus.org/reports// 2007–2008/2007report.pdf. Accessed August 15, 2009. Ohgaki H. Epidemiology of brain tumors. Methods Mol Biol. 2009;472:323–342. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System, 4th ed. Lyon: International Agency for Research on Cancer; 2007. Bondy ML, Scheurer ME, Malmer B, et al. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer. 2008;113(7 Suppl):1953–1968. DeAngelis LM. Brain tumors. N Engl J Med. 2001;344(2): 114–123. Mechtler L. Neuroimaging in neuro-oncology. Neurol Clin. 2009;27(1):171–201, ix. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507. Okamoto Y, Di Patre PL, Burkhard C, et al. Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas. Acta Neuropathol. 2004;108(1):49–56. Lang FF, Gilbert MR. Diffusely infiltrative low-grade gliomas in adults. J Clin Oncol. 2006;24(8):1236–1245. Claus EB, Horlacher A, Hsu L, et al. Survival rates in patients with low-grade glioma after intraoperative magnetic resonance image guidance. Cancer. 2005;103(6):1227–1233. Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008;26(8):1338–1345. Jackson RJ, Fuller GN, Abi-Said D, et al. Limitations of stereotactic biopsy in the initial management of gliomas. Neuro Oncol. 2001;3(3):193–200. Shaw EG, Berkey B, Coons SW, et al. Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg. 2008;109(5):835–841.

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Karim AB, Maat B, Hatlevoll R, et al. A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys. 1996;36(3):549–556. Shaw E, Arusell R, Scheithauer B, et al. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol. 2002;20(9):2267–2276. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985–990. Klein M, Heimans JJ, Aaronson NK, et al. Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet. 2002;360(9343):1361–1368. Douw L, Klein M, Fagel SS, et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol. 2009;8(9):810–818. Eyre HJ, Crowley JJ, Townsend JJ, et al. A randomized trial of radiotherapy versus radiotherapy plus CCNU for incompletely resected low-grade gliomas: a Southwest Oncology Group study. J Neurosurg. 1993;78(6):909–914. Shaw E, Wang M, Coons SW, et al. Final report of Radiation Therapy Oncology Group (RTOG) protocol 9802: Radiation therapy (RT) versus RT + procarbazine, CCNU, and vincristine (PCV) chemotherapy for adult low-grade glioma (LGG). J Clin Oncol. 2008;26(Suppl):abstr 2006. Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64(6):479–489. Everhard S, Kaloshi G, Criniere E, et al. MGMT methylation: a marker of response to temozolomide in low-grade gliomas. Ann Neurol. 2006;60(6):740–743. Stupp R, Reni M, Gatta G, Mazza E, Vecht C. Anaplastic astrocytoma in adults. Crit Rev Oncol Hematol. 2007;63(1): 72–80. Vuorinen V, Hinkka S, Farkkila M, Jaaskelainen J. Debulking or biopsy of malignant glioma in elderly people - a randomised study. Acta Neurochir (Wien). 2003;145(1):5–10.

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Primary Brain Tumors 37 25.

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Bleehen NM, Stenning SP. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. Br J Cancer. 1991;64(4):769–774. Wick W, Weller M, Neurooncology Working Group of the German Cancer Society. Randomized phase III study of sequential radiochemotherapy of oligoastrocytic tumors of WHO-grade III with PCV or temozolomide: NOA-04. J Clin Oncol. 2008;26(Suppl):abstr LBA 2007. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. Hildebrand J, Gorlia T, Kros JM, et al. Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882). Eur J Cancer. 2008;44(9):1210–1216. Cairncross G, Berkey B, Shaw E, et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006;24(18):2707–2714. Brada M, Gabe R, Stenning S, Thompson L, Lee SM. A randomised trial of temozolomide vs PCV chemotherapy for recurrent malignant glioma (MRC BR12). Paper presented at the 33rd European Society for Medical Oncology (ESMO) Congress; September 12–16, 2008; Stockholm, Sweden. Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999;17(9): 2762–2771. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392–401. Stummer W, Reulen HJ, Meinel T, et al. Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery. 2008;62(3): 564–576. Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol. 2007;25(26):4127–4136.

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Kreisl TN, Kim L, Moore K, et al. Phase II trial of singleagent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740–745. Cloughesy TF, Prados MD, Wen PY, et al. A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol (Meeting Abstracts). 2008;26(Suppl):abstr 2010b. Vredenburgh JJ, Desjardins A, Herndon JE II, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253–1259. Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25(30):4722–4729. Cairncross G, Jenkins R. Gliomas with 1p/19q codeletion: a.k.a. oligodendroglioma. Cancer J. 2008;14(6):352–357. van den Bent MJ, Reni M, Gatta G, Vecht C. Oligodendroglioma. Crit Rev Oncol Hematol. 2008;66(3):262–272. Griffin CA, Burger P, Morsberger L, et al. Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol. 2006;65(10):988–994. Jenkins RB, Blair H, Ballman KV, et al. At (1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006;66(20):9852–9861. van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progressionfree survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006;24(18): 2715–2722. Taliansky-Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treatment for newly diagnosed anaplastic oligodendrogliomas: a clinical efficacy trial. J Neurooncol. 2006;79(2): 153–157. Vogelbaum MA, Berkey B, Peereboom D, et al. Phase II trial of preirradiation and concurrent temozolomide in patients

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Primary Brain Tumors 39

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with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: RTOG BR0131. Neuro Oncol. 2009;11(2):167–175. Mikkelsen T, Doyle T, Anderson J, et al. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009;92(1):57–63. Soffietti R, Ruda R, Bradac GB, Schiffer D. PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery. 1998;43(5):1066–1073. Cairncross G, Macdonald D, Ludwin S, et al. Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994;12(10): 2013–2021. Chinot OL, Honore S, Dufour H, et al. Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy. J Clin Oncol. 2001;19(9):2449–2455. van den Bent MJ, Chinot O, Boogerd W, et al. Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. Ann Oncol. 2003;14(4):599–602. van den Bent MJ, Taphoorn MJ, Brandes AA, et al. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol. 2003;21(13):2525–2528. Marosi C, Hassler M, Roessler K, et al. Meningioma. Crit Rev Oncol Hematol. 2008;67(2):153–171. Asthagiri AR, Helm GA, Sheehan JP. Current concepts in management of meningiomas and schwannomas. Neurol Clin. 2007;25(4):1209–1230, xi. Huisman TW, Tanghe HL, Koper JW, et al. Progesterone, oestradiol, somatostatin and epidermal growth factor receptors on human meningiomas and their CT characteristics. Eur J Cancer. 1991;27(11):1453–1457. Sioka C, Kyritsis AP. Chemotherapy, hormonal therapy, and immunotherapy for recurrent meningiomas. J Neurooncol. 2009;92(1):1–6. Sankila R, Kallio M, Jaaskelainen J, Hakulinen T. Long-term survival of 1986 patients with intracranial meningioma

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diagnosed from 1953 to 1984 in Finland. Comparison of the observed and expected survival rates in a population-based series. Cancer. 1992;70(6):1568–1576. Nakamura M, Roser F, Michel J, Jacobs C, Samii M. Volumetric analysis of the growth rate of incompletely resected intracranial meningiomas. Zentralbl Neurochir. 2005;66(1):17–23. Cote TR, Manns A, Hardy CR, Yellin FJ, Hartge P. Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. AIDS/Cancer Study Group. J Natl Cancer Inst. 1996;88(10):675–679. Miller DC, Hochberg FH, Harris NL, Gruber ML, Louis DN, Cohen H. Pathology with clinical correlations of primary central nervous system non-Hodgkin’s lymphoma. The Massachusetts General Hospital experience 1958–1989. Cancer. 1994;74(4):1383–1397. Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol. 2006;24(8):1281–1288. Abrey LE, Batchelor TT, Ferreri AJ, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):5034–5043. Morris PG, Abrey LE. Therapeutic challenges in primary CNS lymphoma. Lancet Neurol. 2009;8(6):581–592. Lippens RJ, Winograd B. Methotrexate concentration levels in the cerebrospinal fluid during high-dose methotrexate infusions: an unreliable prediction. Pediatr Hematol Oncol. 1988;5(2):115–124. Ferreri AJ, Reni M, Martelli M, et al. Randomized phase II trial on primary chemotherapy with high-dose methotrexate (HD-MTX) alone or associated with high-dose cytarabine (HD-araC) for patients with primary CNS lymphoma (I.E.L.S.G. #20 Trial): Tolerability, activity, and survival analyses. J Clin Oncol (Meeting Abstracts). 2009;27(Suppl): abstr 8545. Nelson DF, Martz KL, Bonner H, et al. Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys. 1992;23(1):9–17. Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25(30):4730–4735.

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Primary Brain Tumors 41 67.

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Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003; 21(2):266–272. Marti-Carvajal AJ, Cardona AF, Lawrence A. Interventions for previously untreated patients with AIDS-associated nonHodgkin’s lymphoma. Cochrane Database Syst Rev. 2009(3): CD005419.

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C H A P T E R

2

Brain Metastases Epidemiology ■

■

■

■

■

■

Brain metastases are the most common intracranial neoplasm in adults.1 The exact incidence is unknown, but it is estimated to be as high as 200,000 cases per year in the United States.2 The incidence of CNS metastases appears to be rising because of more effective systemic treatments resulting in longer survival, earlier detection, and better imaging modalities. Most brain metastases originate from the following primary malignancies.1 • Lung cancer (40% to 50%) • Breast cancer (15% to 25%) • Melanoma (5% to 20%) Most brain metastases occur through hematogenous and spread with a predilection for vascular border zones and gray-white matter junction. The distribution parallels blood flow: 80% in cerebral hemispheres, 15% in cerebellum, and 5% in brainstem.3

Clinical Features in Parenchymal Metastases ■ ■

■ ■

Headache Neurologic deficits depending on location of lesion (i.e., ataxia with cerebellar lesions, motor deficits with corticospinal tract involvement) Cognitive and mental status changes Seizures

43

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44 Chapter 2

Diagnosis ■

■

■

Brain MRI with gadolinium is the preferred imaging modality for evaluation of brain metastases. • Lesions typically are well circumscribed and enhance with gadolinium because of an impaired blood–brain barrier. • A brain MRI should not be used in emergency situations if the patient is too unstable. • Posterior fossa and leptomeninges are better visualized on MRI than CT. In an acute presentation, head CT without contrast is appropriate to identify life-threatening pathology, including intracranial hemorrhage, acute hydrocephalus, or herniation. Brain biopsy is indicated if the diagnosis is in question. • Multiple, widespread brain metastases in a patient with cancer are strongly suggestive of brain metastases, but brain abscesses can have a similar appearance, especially in immunosuppressed or septic patients. • Single or solitary brain lesions may be more difficult to diagnose. ■ In one study, 11% of patients with cancer undergoing surgery for a single brain lesion had pathology consistent with a primary brain tumor, an infectious disease, or an inflammatory disease.4

Prognosis ■

Important prognostic factors include age, Karnofsky performance status (KPS) (Table 2-1), number of brain metastases (single or multiple), primary tumor type, systemic tumor activity (controlled or uncontrolled), and time since primary tumor diagnosis.5,6

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Brain Metastases 45 Table 2-1: Karnofsky Performance Status Scale Percentage

Description

100

Normal, no complaints, no evidence of disease

90

Able to carry on normal activity; minor signs or symptoms of disease

80

Normal activity with effort; some signs or symptoms of disease

70

Cares for self, unable to carry on normal activity or to do active work

60

Requires occasional assistance but is able to care for most of his or her needs

50

Requires considerable assistance and frequent medical care

40

Disabled, requires special care and assistance

30

Severely disabled, hospitalization indicated; death not imminent

20

Very sick, hospitalization indicated; death not imminent

10

Moribund, fatal processes progressing rapidly

0

Dead

■

Recursive partitioning analysis (RPA) classes (Table 2-2)5 • Patients can be divided into subgroups based on prognosis. • Subgroups are based on a review of 1,200 patients in the Radiation Therapy Oncology Group (RTOG) database who received whole-brain radiation therapy.

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46 Chapter 2 Table 2-2: Recursive Partitioning Analysis (RPA) Classes in Patients with Brain Metastases Class I KPS

$70

Age

,65

Extent of disease

Controlled primary tumor, no extracranial metastases

Median overall survival

7.1 months

Class II

Class III ,70

Any patient not in class I or class III

Any

4.2 months

2.3 months

Any

Modified from 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(4):745–751.

Treatment ■

■

■

The treatment approach often depends on tumor histology, number of brain metastases, the control of systemic disease, and the status of neurologic function. Main treatment options include whole-brain radiation, surgical resection, radiosurgery, and systemic treatments. Fifty percent of patients with CNS metastasis have a single brain metastasis.

Whole-Brain Radiation Therapy (WBRT) ■ This is the mainstay of treatment for patients with brain metastases. ■ Indications for WBRT are as follows: • Curative intent • Palliation • Consolidation to reduce neurological morbidity • Prophylaxis in specific patients with SCLC, NSCLC, or breast cancer with curative intent

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Brain Metastases 47 ■

■

■

■

Nonrandomized studies suggest that WBRT increases median survival by 3 to 4 months over no treatment (the median survival is approximately 1 month with no treatment).1 Radiographic response rate (complete responses or partial responses) to WBRT is approximately 60% in RTOG randomized controlled trials.7 Symptom stabilization or improvement is achieved in approximately 60% of patients, although this may be overestimated because corticosteroids are often administered with WBRT.8 Neurologic complications from radiation therapy are further discussed in Chapter 5.

WBRT Treatment Regimens The most common regimen used is 35 Gy delivered in 2.5 Gy fractions over 14 treatment days. ■ Fractions of .3 Gy increase the risk of neurotoxicity. ■ Differences in dose, timing, and fractionation do not alter the median survival of patients receiving WBRT for brain metastases.9 ■

WBRT 1 Radiation Sensitizers ■ Most radiosensitizers (lonidamine, metronidazole, misonidazole, gadolinium, or bromodeoxyuridine) have demonstrated no benefit over WBRT alone in terms of local brain tumor control or overall survival. ■ In a randomized phase III study of WBRT with or without motexafin gadolinium for treatment of brain metastases from solid tumors, there were no significant differences between the two arms in terms of survival or time to neurologic progression.10 • In the follow-up trial in patients with NSCLC, the motexafin arm exhibited a nonsignificant trend toward improved neurologic outcomes (time to neurologic progression 10.0 months for WBRT vs. 15.4 months for WBRT 1 motexafin, P 5 0.122).11 ■ In a randomized phase III study of WBRT and supplemental oxygen with or without efaproxiral for treatment of brain

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48 Chapter 2 metastases from solid tumors, there was no significant difference between the two arms for survival.12 • In subgroup analysis of patients with breast cancer, the efaproxiral arm had significantly reduced death rates by 46% and improved quality of life.13 • Preliminary results from the follow-up phase III openlabel trial in patients with breast cancer, however, suggest no difference in overall survival, response rate, performance status, or neurologic signs/symptoms.14 WBRT 1 Chemotherapy ■ Several chemotherapeutic agents yield higher response rates at the expense of greater toxicity and no benefit in overall survival, including chloroethylnitrosoureas, tegafur, fotemustine, and teniposide. ■ Efficacy and safety of temozolomide and radiation in brain metastases have been evaluated in several phase II trials, but the combination does not seem to improve survival. • Antonadou et al. reported significant improvement in the response rate with temozolomide 1 WBRT compared with WBRT alone (96% vs. 67%) but survival data were not evaluated.15 • In a randomized phase II trial of temozolomide 1 WBRT versus WBRT alone, overall survival and response rates were similar in both arms, but the percentage of patients with progression-free survival of brain metastases at 90 days was significantly higher for the temozolomide 1 WBRT arm (72% vs. 54%).16 Stereotactic Radiosurgery (SRS) ■ SRS uses multiple convergent beams to deliver a single high dose of focal radiation to a small target volume. ■ This is a common treatment modality for newly diagnosed brain metastases, alone or in combination with WBRT, and as salvage therapy after WBRT. ■ The most common delivery systems include linear accelerator, gamma knife, and cyclotron.

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Brain Metastases 49 ■

■

■

■ ■

Maximum tolerated doses are based on the RTOG 90-05 protocol.17 • Tumors 31 to 40 mm: 15 Gy • Tumors 21 to 30 mm: 18 Gy • Tumors less than or equal to 20 mm: 24 Gy but subsequent retrospective analysis suggested that doses .20 Gy increase neurotoxicity and do not improve local control.18 One-year actuarial local control rates for single and multiple brain metastases with SRS alone are 71% to 79%.18–21 Based on a small series, SRS at recurrence is an acceptable treatment for patients with good functional status and controlled/indolent extracranial disease with local control rates of 57% to 100% and overall brain control rates of 65% to 78%.17,22–25 SRS does not prevent distant failure. The complications from SRS are the following: • Early treatment-induced cerebral edema (4% to 6% patients within 1 to 2 weeks of treatment) • Seizures (2% to 6% patients within the first 24 to 48 hours) • Delayed radiation necrosis (2% to 17%) ■ There is a higher risk for radiation necrosis with larger tumor volume, higher radiation dose, and prior radiotherapy.

WBRT with or without SRS ■ Based on three randomized controlled trials and two retrospective studies, SRS boost after WBRT improves survival in select patients with single brain metastases.1 ■ In patients with two to three brain metastases, the role of SRS boost is less clear. • Based on subgroup analysis of a large randomized controlled trial, SRS boost after WBRT did not improve survival or local control.26 • Based on a smaller randomized study 27 and retrospective series,28 SRS boost did improve survival.

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50 Chapter 2 SRS with or without WBRT It is controversial whether patients can be treated with SRS alone in order to spare the risk for late neurotoxicity from WBRT. ■ Based on a randomized controlled trial, SRS alone as compared with WBRT 1 SRS results in worse local control and worse distant intracranial disease control with no difference in overall survival.19 ■ Preliminary results from the SRS arm of the European Organization for Research and Treatment of Cancer (EORTC) study 22952-26001 (patients with good performance status and 1–3 brain metastases with stable systemic cancer or asymptomatic synchronous primary tumor without metastases outside the CNS)29: • No difference in overall survival between SRS alone versus SRS 1 WBRT • Significant reduction of intracranial progression after WBRT in both arms of the study ■ There is a risk of distant brain failure in patients who receive SRS alone.30 • The low-risk (median time to distant brain failure 47.9 weeks) group had three or fewer metastases, an absence of extracranial disease, and nonmelanoma histologic characteristics. • The median time to distant brain failure for all other possible groupings ranged from 12.3 to 28.7 weeks. ■

Surgery ■ The benefits of surgery include pathology for definitive diagnosis, rapid relief of neurologic symptoms caused by mass effect, and local control. ■ Resection of single brain metastasis is a standard option in patients with good, functional status and controlled or indolent extracranial disease.31 ■ The in-hospital mortality for resection of brain metastases in high-volume centers is as low as 1.8%.31

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Brain Metastases 51

Surgery for a Single Brain Metastasis Three randomized controlled trials have compared surgical resection 1 WBRT versus WBRT alone in patients with a single brain metastasis (Table 2-3).4,32,33 • Patchell et al. 1990: resection 1 WBRT versus biopsy 1 WBRT associated with longer median survival time, better local control rate, longer duration of functional independence (KPS $ 70) and longer freedom from death due to neurologic causes. • Vetch et al. 1993: resection 1 WBRT associated with longer median survival time as compared with WBRT alone. • Mintz et al. 1996: no survival difference between two groups but patients had a poorer functional status and more active extracranial disease than other studies.

■

Table 2-3: Results from Randomized Controlled Trials of Patients with a Single Brain Metastasis Comparing Surgical Resection ⴙ WBRT Versus WBRT Alone

Study

Resection ⴙ WBRT Median Overall Survival

WBRT Median Overall Survival

Patchell et al., 1990

9.2 months

3.4 months

Vecht et al., 1993

10.0 months

6.0 months

Mintz et al., 1996

5.6 months

6.3 months

Data are from 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(8):494–500. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33(6):583–590. 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(7):1470–1476.

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52 Chapter 2 Surgery for Multiple Brain Metastases Patients with good prognostic features and two to three metastases may benefit from resection of the dominant lesion.34,35 ■ A highly selected subset of patients with multiple metastases may benefit from resection of all lesions.36 ■

Surgery with or without WBRT ■ Based on a randomized controlled trial, resection of a single brain metastasis 1 WBRT versus resection alone is associated with better local, distant, and overall intracranial control rates.37 ■ No benefit is seen in overall survival from combined therapy, although the patients who received WBRT were less likely to die from neurologic causes. ■ Preliminary results from the surgery arm of EORTC 22952-26001 (patients with one to three brain metastases with stable systemic cancer or asymptomatic synchronous primary tumor without metastases outside of the CNS)29: • No difference in overall survival between surgery alone versus surgery 1 WBRT • Significant reduction of intracranial progression with WBRT Surgery Versus SRS ■ There are no prospective studies directly comparing surgery versus SRS. ■ Most retrospective studies demonstrate no difference in survival between surgery and SRS.38 ■ Surgery is probably better for larger tumors with extensive edema and mass effect or tumors requiring rapid relief of neurologic symptoms. ■ SRS is noninvasive and can treat tumors that are not amenable to surgery. Chemotherapy This is traditionally reserved for patients who have failed other treatment modalities or tumors that are

■

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Brain Metastases 53

■

■

■

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chemosensitive (lymphoma, SCLC, germ cell tumors more chemosensitive than breast cancer). Because brain metastases represent a late event in the natural history of most cancers, tumors may have acquired resistance to many drugs. For patients with active systemic disease and brain metastases, chemotherapy provides an opportunity to treat both compartments.39 Delivery to the CNS is limited by the blood–brain barrier, efflux by P-glycoprotein, nonuniform drug distribution in the tumor (preferential concentration in necrotic areas), and poor drug accumulation (due to tumor interstitial fluid gradients).40 This is discussed further later in this chapter.

Brain Metastases from Breast Cancer Epidemiology Breast cancer is the second most frequent cause of brain metastasis.41 ■ Up to 30% patients with breast cancer will develop CNS metastases.42–44 ■ Breast cancer is the solid tumor most commonly associated with leptomeningeal metastases.44 ■ Leptomeningeal involvement is found at autopsy in 5% to 16% of breast cancer patients.44 ■ In the majority of breast cancer patients, metastases to the CNS develop following extracranial metastases, although the CNS may be the first site of recurrence in 20% to 39% of patients.45 ■

Incidence in Patients Receiving Trastuzumab ■ Trastuzumab is a monoclonal antibody against the HER2/ neu oncoprotein used to treat HER2/neu-positive breast cancer. ■ Some studies report a higher incidence of CNS metastases in patients who received trastuzumab-based regimens for HER2 overexpressing metastatic breast cancer,46–49 whereas other studies did not find a higher incidence.

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The proposed causes for possible higher incidence are as follows: • Trastuzumab does not cross the blood–brain barrier, and therefore, the CNS may act as a sanctuary site for metastatic disease. • There is prolonged survival in HER2-positive metastatic breast cancer due to trastuzumab, resulting in an increased risk for CNS relapse. • There is an inherent biology of HER2-positive breast cancer (which may be associated with higher risk for CNS metastases). Continued use of trastuzumab in patients with brain metastases may improve overall survival compared with discontinuation of trastuzumab, possibly because of better control of systemic disease.50

Risk Factors for the Development of CNS Metastases in Breast Cancer44,45,51 ■ Young age ■ Negative hormone receptor status ■ Invasive ductal carcinoma Treatment Options for Brain Metastases from Breast Cancer ■ Treatment recommendations are similar to brain metastases from other primary tumors. Surgery This is indicated for urgent decompression and solitary brain metastasis. ■ Surgery is typically reserved for patients with a single brain lesion, minimal extracranial disease, and/or better performance status. ■ Surgical resection for single brain metastases followed by WBRT is superior to WBRT alone with stable/absent extracranial disease.4 ■

SRS ■ SRS is typically recommended for #3 brain metastases, with each lesion measuring #3 cm, but the failure rate outside the SRS field is 37%.

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There are no randomized trials comparing SRS with surgery for treatment of single brain metastasis. Combining SRS 1 WBRT is better than WBRT alone.44

WBRT ■ Seventy-five percent to 85% of patients who receive WBRT experience improvement or stabilization of symptoms (seizures and headaches most effectively palliated).44 ■ Postoperative WBRT does not extend survival but does reduce brain recurrences.37 Systemic Treatments ■ This is generally recommended after failure with surgery and radiation. ■ Selected chemotherapy agents such as capecitabine, 5-fluorouracil, platinum analogues, temozolomide, methotrexate, topotecan, bendamustine have known activity in the CNS.40,51 ■ Lapatinib has modest antitumor activity against CNS metastases in HER2-positive breast cancer patients.52 ■ Capecitabine in combination with temozolomide or lapatinib may have activity in new and recurrent brain metastases, but larger studies are needed.50

Brain Metastases from Non-Small Cell Lung Cancer (NSCLC) Epidemiology ■ Brain metastases may develop in 20% to 40% of patients with NSCLC.53 ■ NSCLC is usually chemoresistant, and thus, patients who develop brain metastases usually have been heavily pretreated. ■ RPA classification scheme (Table 2-2) was based on a study in which lung cancer accounted for 61% of the patients studied (almost all had NSCLC).5 ■ Although survival times are short for patients with brain metastases, patients with brain metastases from NSCLC may have a worse prognosis than patients with brain metastases from other solid tumors.54

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56 Chapter 2 Risk Factors for Development of CNS Metastases in NSCLC ■ Age5 ■ Clinical stage (later stage)55 ■ Adenocarcinoma histology56 ■ CEA serum levels $40 ng/mL56 Treatment Options for Brain Metastases from NSCLC ■ Treatment decisions in NSCLC are often based on the extent of disease characterized as follows: • Single brain metastasis with controlled or controllable primary disease • Oligometastatic disease (primary disease and less than three distant metastases) • Multiple metastases ■ Carefully selected patients with resectable N0,1 primary NSCLC and an isolated brain metastasis as the only site of metastatic disease may benefit from aggressive therapy of the primary site and brain lesion (surgery or SRS) to prolong survival.57 ■ In patients with a single brain metastasis and previously resected primary NSCLC, surgical resection or SRS of the isolated brain metastasis should be considered.57 ■ Select patients with oligometastatic disease may be treated with surgical resection or radiosurgery followed by WBRT.58 ■ Patients with multiple brain metastases from NSCLC are generally treated with WBRT. Systemic Treatments For patients with brain metastases, chemotherapy and targeted therapies have a greater role for patients with active systemic disease or contraindications to other treatment modalities.53 ■ For patients with brain metastases but controlled or stable systemic disease, surgery and radiation are more commonly used. ■ Chemotherapy-naïve patients with brain metastases may benefit from cisplatin alone (radiographic response rates ■

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30%)59 or in combination with other agents (radiographic response rates 28% to 45%).60–64 Patients with recurrent brain metastases may benefit from TMZ alone (RR 0% to 20%)65–68 or in combination with vinorelbine (higher RR but more toxicity).69 Data on the response of brain metastases to small molecular epidural growth factor receptor (EGFR) inhibitors (erlotinib, gefitinib) is limited, but responses to these agents likely depend on the presence of EGFR mutations.70

Brain Metastases from Melanoma Epidemiology ■ CNS metastases detectable on imaging develop in nearly 50% of patients with metastatic melanoma.71 ■ Patients with metastatic melanoma to the brain have a medial survival of 4 to 6 months.72 ■ Brain metastases from melanoma tend to be hemorrhagic. Imaging ■ The typical melanotic pattern on MRI consists of high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. • The MRI appearance is attributed to free radicals in melanin as well as blood products. ■ An amelanotic pattern is also frequently described consisting of a hypointense/isointense appearance on T1-weighted images and hyperintense/isointense appearance on T2-weighted images. ■ Dural involvement by malignant melanoma is rare. Treatment Options for Brain Metastases from Melanoma ■ Whole brain radiation therapy is moderately effective for the control of melanoma metastatic to the brain (a complete response rate of less than 20% and a partial response rate of approximately 50%).72

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Select patients with limited disease may benefit from stereotactic surgery for local control. Chemotherapy does not significantly increase the local control rate. • Fotemustine (response rate 5% to 25%) and temozolomide (response rate of 6% to 10%) are the most active agents.38 A select subset of patients achieve disease stabilization with aggressive local control 1 WBRT.1

Brain Metastases from Renal Cell Carcinoma (RCC) Epidemiology Only 4% to 11% of patients with RCC develop brain metastases.73 ■ Over 90% of patients with brain metastases from RCC are symptomatic (headaches, mental status changes, confusion, and seizures).74 ■ Development of brain metastases suggests late-stage disease, and patients frequently have extracranial disease. ■ Brain metastases from RCC tend to be hemorrhagic. ■

Treatment Options for Brain Metastases from RCC ■ A select subset of patients, particularly those with one to two brain metastases and an absence of extracranial disease, can achieve long-term survival with surgical resection 1 radiation.75 ■ Brain metastases from RCC are considered “radioresistant,” although in a published case series of patients with up to five lesions, SRS with or without WBRT has produced good local control and prolonged survival.76 Prospective studies are needed to confirm these results and to characterize better which patients would benefit most from SRS treatment. ■ The role of vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in brain metastases from RCC is unclear because most published phase II and phase III clinical trials of systemic disease excluded patients with brain metastases.

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review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery. 2005;56(5):1021–1034. Stark AM, Tscheslog H, Buhl R, Held-Feindt J, Mehdorn HM. Surgical treatment for brain metastases: prognostic factors and survival in 177 patients. Neurosurg Rev. 2005;28(2):115–119. Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg. 1993;79(2):210–216. 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(17):1485–1489. Soffietti R, Ruda R, Trevisan E. Brain metastases: current management and new developments. Curr Opin Oncol. 2008;20(6):676–684. Nguyen TD, DeAngelis LM. Brain metastases. Neurol Clin. 2007;25(4):1173–1192, x–xi. Tosoni A, Franceschi E, Brandes AA. Chemotherapy in breast cancer patients with brain metastases: have new chemotherapic agents changed the clinical outcome? Crit Rev Oncol Hematol. 2008;68(3):212–221. Lee YT. Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol. 1983;23(3):175–180. Boogerd W. Central nervous system metastasis in breast cancer. Radiother Oncol. 1996;40(1):5–22. Boogerd W, Vos VW, Hart AA, Baris G. Brain metastases in breast cancer; natural history, prognostic factors and outcome. J Neurooncol. 1993;15(2):165–174. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 2004;22(17):3608–3617. Tham YL, Sexton K, Kramer R, Hilsenbeck S, Elledge R. Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer. 2006; 107(4):696–704. Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumabbased therapy for metastatic breast carcinoma. Cancer. 2003;97(12):2972–2977. Clayton AJ, Danson S, Jolly S, et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer. 2004;91(4):639–643. Shmueli E, Wigler N, Inbar M. Central nervous system progression among patients with metastatic breast cancer

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responding to trastuzumab treatment. Eur J Cancer. 2004; 40(3):379–382. Stemmler HJ, Kahlert S, Siekiera W, Untch M, Heinrich B, Heinemann V. Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. Breast. 2006;15(2):219–225. Barrett-Lee P, Bidard FC, Pierga JY. Contemporary issues and the potential uses of capecitabine in metastatic breast cancer. Cancer Treat Rev. 2009;35(7):582–589. Stemmler HJ, Heinemann V. Central nervous system metastases in HER-2-overexpressing metastatic breast cancer: a treatment challenge. Oncologist. 2008;13(7):739–750. Lin NU, Dieras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009; 15(4):1452–1459. Adamo V, Franchina T, Adamo B, Scandurra G, Scimone A. Brain metastases in patients with non-small cell lung cancer: focus on the role of chemotherapy. Ann Oncol. 2006; 17(Suppl 2):ii73–ii75. Barton R. Inoperable brain metastases from non-small cell lung cancer: what part does whole brain radiotherapy play in standard treatment? Thorax. 2008;63(1):1–2. Robnett TJ, Machtay M, Stevenson JP, Algazy KM, Hahn SM. Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma. J Clin Oncol. 2001;19(5):1344–1349. Arrieta O, Saavedra-Perez D, Kuri R, et al. Brain metastasis development and poor survival associated with carcinoembryonic antigen (CEA) level in advanced non-small cell lung cancer: a prospective analysis. BMC Cancer. 2009;9:119. Shen KR, Meyers BF, Larner JM, Jones DR. Special treatment issues in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl): 290S–305S. Kvale PA, Selecky PA, Prakash UB. Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):368S–403S. Kleisbauer JP, Guerin JC, Arnaud A, Poirier R, Vesco D. [Chemotherapy with high-dose cisplatin in brain metastasis of lung cancers]. Bull Cancer. 1990;77(7):661–665. Bernardo G, Cuzzoni Q, Strada MR, et al. First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the

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treatment of brain metastases from non-small-cell lung cancer: a phase II study. Cancer Invest. 2002;20(3):293–302. Cortes J, Rodriguez J, Aramendia JM, et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology. 2003;64(1):28–35. Cotto C, Berille J, Souquet PJ, et al. A phase II trial of fotemustine and cisplatin in central nervous system metastases from non-small cell lung cancer. Eur J Cancer. 1996;32A(1): 69–71. 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(7):1599–1605. Minotti V, Crino L, Meacci ML, et al. Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer. Lung Cancer. 1998;20(2):93–98. Abrey LE, Olson JD, Raizer JJ, et al. A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol. 2001;53(3):259–265. Christodoulou C, Bafaloukos D, Kosmidis P, et al. Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol. 2001;12(2):249–254. Dziadziuszko R, Ardizzoni A, Postmus PE, et al. Temozolomide in patients with advanced non-small cell lung cancer with and without brain metastases. a phase II study of the EORTC Lung Cancer Group (08965). Eur J Cancer. 2003;39(9):1271–1276. Giorgio CG, Giuffrida D, Pappalardo A, et al. Oral temozolomide in heavily pre-treated brain metastases from nonsmall cell lung cancer: phase II study. Lung Cancer. 2005; 50(2):247–254. Omuro AM, Raizer JJ, Demopoulos A, Malkin MG, Abrey LE. Vinorelbine combined with a protracted course of temozolomide for recurrent brain metastases: a phase I trial. J Neurooncol. 2006;78(3):277–280. Shimato S, Mitsudomi T, Kosaka T, et al. EGFR mutations in patients with brain metastases from lung cancer: association with the efficacy of gefitinib. Neuro Oncol. 2006;8(2): 137–144. Amer MH, Al-Sarraf M, Baker LH, Vaitkevicius VK. Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer. 1978;42(2):660–668.

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McLoughlin JM, Zager JS, Sondak VK, Berk LB. Treatment options for limited or symptomatic metastatic melanoma. Cancer Control. 2008;15(3):239–247. Muacevic A, Siebels M, Tonn JC, Wowra B. Treatment of brain metastases in renal cell carcinoma: radiotherapy, radiosurgery, or surgery? World J Urol. 2005;23(3):180–184. Klatte T, Lam JS, Shuch B, Belldegrun AS, Pantuck AJ. Surveillance for renal cell carcinoma: why and how? When and how often? Urol Oncol. 2008;26(5):550–554. Harada Y, Nonomura N, Kondo M, et al. Clinical study of brain metastasis of renal cell carcinoma. Eur Urol. 1999; 36(3):230–235. Samlowski WE, Majer M, Boucher KM, et al. Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating stereotactic radiosurgery. Cancer. 2008;113(9):2539–2548.

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C H A P T E R

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Spinal Tumors Introduction ■

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Spinal tumors are uncommon but can cause significant neurologic morbidity. Early diagnosis and adequate treatment are critical for functional outcomes and long-term prognosis.

Spinal Cord Anatomy (Figure 3-1) ■ Bone: the spinal cord is housed within a canal formed by vertebral bodies and neural arches. • The vertebral body lies on the ventral (anterior) side of the spinal cord. • The neural arch lies on the dorsal (posterior) side of the spinal cord. • The spinal ner ves pass through an opening between the vertebrae called the inter vertebral foramen.

Figure 3-1: Spinal cord anatomy

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Meninges: the spinal cord is covered by three membranes known together as the meninges. • Dura mater • Arachnoid mater • Pia mater Potential spaces between meningeal layers • Epidural space: between the bone and the dura mater, contains fat and vertebral veins • Subdural space: between the dura mater and the arachnoid mater • Subarachnoid space: between the arachnoid mater and the pia mater, contains cerebrospinal fluid Spinal cord tumors are classified according to their anatomical location. • Extradural: between bone and the dura mater • Intradural: inside the dura mater ■ Extramedullary: between the dura mater and the pia mater ■ Intramedullary: within the spinal cord parenchyma

Extradural Tumors ■

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The extradural space is the most common site for spinal tumors, with 60% of all spinal cord neoplasms located in the extradural space and another 10% spanning the extradural and intradural spaces.1 • Most tumors in the extradural space are metastatic, such as epidural metastases (discussed later in this chapter). • Some extradural tumors may arise in the vertebra, such as osteosarcomas, hemangiomas, lymphoma, and plasmacytoma. Some extradural tumors may undermine the structural stability of the vertebrae, leading to painful vertebral fractures.

Metastatic Epidural Spinal Cord Compression (MESCC) Epidemiology ■ MESCC is second only to brain metastasis as the cause of neurological dysfunction caused by metastasis.2

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In patients with cancer, approximately 2% to 5% will develop MESCC.2 MESCC most frequently occurs in patients with known cancer but can be the presenting manifestation in 20% of patients.3

Pathophysiology ■ Compression of the dural sac and its contents (spinal cord and/or cauda equina) is caused by an extradural tumor mass. ■ Common causes of MESCC include prostate cancer, breast cancer, lung cancer, non-Hodgkin lymphoma, renal cell cancer, and multiple myeloma.2 ■ The site(s) of compression in the spinal column is proportional to the relative bone mass and blood flow for each part of the spine.2 • 15% in the cervical spine • 60% in the thoracic spine • 25% in the lumbosacral spine ■ Methods of metastatic spread to the epidural space are as follows: • Hematogenous spread to the vertebral body followed by extension into the epidural space • Direct extension into the spinal canal through intervertebral foramen, most commonly associated with lymphoma and neuroblastomas4 ■ Spinal cord damage is caused by direct spinal cord compression and secondary vascular damage. • Acute compression causes stenosis and occlusion of the epidural venous plexus, resulting in breakdown of the blood–spinal cord barrier and vasogenic edema. • Prolonged compression causes arterial flow obstruction, resulting in spinal cord ischemia. Clinical Features ■ Worsening back pain: often localized ■ Radicular pain: often worse at night, lying down, with Valsalva ■ Weakness: may be upper motor neuron or lower motor neuron, depending on location of compression

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Sensory deficits: usually follow pain and weakness Bladder or bowel dysfunction Inability to walk

Diagnosis ■ A whole-spine MRI with gadolinium is the imaging modality of choice to evaluate for MESCC. • The minimum radiologic evidence for cord compression is indentation of the thecal sac at the level of clinical features.5 • If patient is not able to undergo an MRI, the CT or conventional myelogram is an alternative but suboptimal choice. ■ Definitive diagnosis is based on pathology, but a presumptive diagnosis may be made on imaging in a patient with cancer. Treatment ■ MESCC is a medical emergency causing paraplegia if left untreated. ■ Early diagnosis and appropriate treatment can prevent or reverse paraplegia in most patients.6 ■ Corticosteroids • Corticosteroids are first-line treatment to reduce edema for all tumor types and to induce tumor lysis for leukemias and lymphomas. • The addition of steroids to radiation may improve ambulatory outcomes.7 ■ In patients with MESCC from solid tumors, treatment with dexamethasone followed by radiation improved ambulatory rates at 3 and 6 months compared with radiation alone. ■ Dexamethasone was given as 96 mg IV followed by 96 mg/day PO 3 3 days followed by a 10-day taper. • The optimal dosing regimen of corticosteroids is unknown. ■ Randomized studies of high boluses of dexamethasone 96–100 mg versus moderate doses 10–16 mg show no differences in pain or ambulation outcomes.8,9

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Animal studies suggest that steroids have a dose–response effect on spinal cord compression, and thus, some advocate the use of highdose dexamethasone for patients who cannot walk at diagnosis or have rapidly progressive motor symptoms.2 ■ Based on a small phase II study of 20 patients with MESCC but no neurologic deficits or massive invasion of the spine, radiation therapy without steroids is a feasible regimen.10 Radiation therapy • There are no randomized studies comparing external beam radiation to supportive care, but multiple retrospective studies demonstrate improvement or stabilization in function with radiation.2 • This is most effective for radiosensitive tumors and for patients who are ambulatory prior to treatment. • Nonambulant patients have only an 18% to 29% chance of regaining ambulation with radiotherapy.5 • In a randomized phase III study of MESCC patients with short life expectancies, #6 months, or unfavorable histologies (NSCLC, colorectal, kidney, gastric, head and neck, liver, bladder, sarcoma, melanoma, uterine carcinoma), there is no difference in ability to walk, pain relief, survival, or toxicity between short-course (16 Gy in two fractions) versus split-course (30 Gy in eight fractions) radiotherapy.11 • The optimal dose, schedule, or technique for patients with good prognosis are unknown.5 • Data on newer radiation techniques such as stereotactic radiosurgery in MESCC are sparse. Surgery2 • This may be beneficial in selected groups of patients. ■ Unknown primary tumor ■ Relapse after radiation therapy ■ Progression while on radiation therapy ■ Unstable spine or pathological features ■ Less radiosensitive primary tumors with single area of cord compression, paraplegia ,48 hours, and a predicted survival .3 months ■

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• An anterior surgical approach is often preferred over laminectomy because most epidural metastases extend from the vertebral body. ■ An anterior approach allows direct decompression and spine reconstruction. ■ Laminectomy does not remove the tumor and may result in spine destabilization. • The benefit from surgery was demonstrated in a randomized study of patients with less radiosensitive tumors, a single area of MESCC, paraplegia ,48 hours, and a predicted survival .3 months comparing direct decompressive surgery plus radiation therapy versus radiation therapy alone.12 ■ The study was terminated after interim analysis because of positive results. ■ The surgical arm had higher ambulatory rates (84% versus 57%) and retained ability to ambulate longer (median 122 days vs. 13 days). ■ For those unable to walk prior to treatment, more patients regained the ability to ambulate (10 versus 3 patients). ■ The median overall survival was longer in the surgical arm (126 days vs. 100 days). • The benefit of direct decompressive surgery in patients with good neurological function and stable spines is unclear.5 Chemotherapy • Chemotherapy is rarely used to treat MESCC even in chemosensitive tumors because the response is too slow and unpredictable. • Chemotherapy may be used as salvage therapy for patients who are no longer candidates for radiation therapy or surgery. Recurrent MESCC • The recurrence rate after successful initial treatment is 7% to 14%.2 • If the recurrence is within the original radiation field, then reirradiation is not recommended because of possible adverse events such as radiation-induced myelopathy.

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Prognosis The median survival for patients with MESCC (based on retrospective studies) is 3 to 6 months.2 ■ Good prognostic factors associated with prolonged survival include the ability to ambulate before and after treatment, radiosensitive tumors (multiple myeloma, germ cell tumors, lymphomas, small cell carcinomas), no visceral or brain metastases, and a single site of epidural cord compression (as opposed to multiple sites).2 ■ Poor prognostic factors for treatment with radiation include bony compression and spinal instability.5 ■

Intradural Tumors ■

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Thirty percent of all spinal cord tumors are contained within the intradural space, with an additional 10% spanning the extradural and intradural spaces.1 Intradural tumors can be further subdivided into extramedullary (outside the spinal cord parenchyma) and intramedullary (within the spinal cord parenchyma).

Extramedullary Tumors These account for more than 70% of intradural tumors in adults.1

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Nerve Sheath Tumors ■ Arise from nerve sheath cells covering the spinal nerve roots ■ Most commonly arise in the lumbosacral region13 ■ Histology • Schwannomas ■ Typically round or oval, lobulated, encapsulated tumors that contain Schwann cells without invasion of nerve fibers ■ Generally considered benign ■ Most commonly seen in patients with neurofibromatosis type 2 ■ Represent 25% to 30% of all intraspinal masses14

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74 Chapter 3 Intradural in 70% to 75%, extradural in 15%, combined intradural–extradural (dumbbell) in 15%14 ■ Commonly arises from the dorsal sensory roots of the cervical and lumbar spine • Neurofibromas ■ Contain Schwann cells, fibroblasts, and nerve fibers ■ Generally considered benign ■ Rare intraspinal tumors except in patients with neurofibromatosis type 2 • Malignant peripheral nerve-sheath tumors (MPNSTs) ■ Uncommon primary tumor of nerve sheath origin ■ More than 50% of MPNSTs associated with neurofibromatosis type 115 ■ Prognosis generally poor despite treatment Diagnosis • MRI with contrast is the imaging modality of choice. ■ Nerve sheath tumors are isointense on T1-weighted images and hyperintense on T2-weighted images. ■ Schwannomas and neurofibromas are indistinguishable on MRIs. ■ Enhancement may be seen with benign or malignant tumors. ■ They may contain both intradural and extradural components, creating a dumbbell-shaped appearance. ■ Imaging features suggestive of MPNST include larger size (.5 cm), heterogeneity, indistinct margins, and a lack of a pseudocapsule.14 • Definitive diagnosis is made on the basis of histology. Treatment • Observation ■ Benign, asymptomatic schwannomas, or neurofibromas could be followed with serial imaging. ■ Definitive diagnosis requires pathology, however. • Surgery ■ Total resection is the primary treatment for nerve sheath tumors. ■ Total resection often requires removal of the involved ventral or dorsal nerve root and is usually ■

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not associated with pronounced postoperative motor or sensory deficit.16 • Radiation and/or chemotherapy ■ These treatment modalities are used primarily for MPNSTs. • Radiation therapy may provide local control and delay recurrence in MPNSTs but has little effect on long-term survival.17 • The role of chemotherapy is controversial in MPNSTs because they are traditionally considered chemotherapy insensitive.17 ■ These treatment modalities are not indicated for completely resected schwannomas or neurofibromas. ■ Partially resected or unresectable schwannomas or neurofibromas • The role of radiation is controversial. • Because tumors are benign and slow growing, tumors could be monitored with serial imaging and undergo further resection if necessary. • Patients with neurofibromatosis may be at higher risk for secondary malignancies from radiation. Spinal Meningioma ■ These arise from meningeal cells along the spinal cord surface. ■ Ninety percent of spinal meningiomas are intradural, whereas the remaining 10% are extradural or dumbbell tumors.18 ■ Epidemiology is as follows: • Most occur between the fifth and seventh decades of life and are more common in women than men.18 • They account for 25% to 46% of all primary intraspinal neoplasms.19 • They are most commonly located in the thoracic region, lateral or posterior to the spinal cord. • They are usually solitary lesions, although patients with neurofibromatosis type 2 may have multiple spinal meningiomas.

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Clinical features • The most common presenting symptom is focal pain. • Myelopathy may be present. • Neurologic deficits depend on tumor location. Pathology • Psammomatous meningiomas is the most common histology, followed by meningothelial and transitional.18 • Atypical or anaplastic meningiomas are rare. Diagnosis • Spine MRI with contrast is the imaging modality of choice. ■ Meningiomas are well-circumscribed lesions, are hypointense to isointense on T1-weighted images, are hyperintense on T2-weighted images, and display homogeneous enhancement. ■ Dural tail and calcification may be seen but less commonly than with intracranial meningiomas. • Presumptive diagnosis can often be made with imaging, although definitive diagnosis is based on pathology. Treatment • Surgery ■ Gross total resection is the primary treatment and is feasible as meningiomas are usually well circumscribed. ■ Recurrence rates with total or subtotal resection is 3% to 7% in WHO grade I meningomas.1 • Radiation therapy ■ Not indicated for completely resected low-grade meningiomas ■ Indications • Adjuvant therapy after subtotal resection • Treatment after recurrence

My xopapillary Ependymoma ■ Typically benign ■ Account for 40% to 50% of spinal ependymomas1 ■ Arise from the conus medullaris and filum terminalis ■ Clinical features: may present with features suggestive of conus medullaris or cauda equina syndrome, including radicular pain, lower extremity numbness or weakness, bowel or bladder dysfunction

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Imaging: circumscribed mass with homogeneous enhancement, hypointense on T1-weighted images and hyperintense on T2-weighted images Treatment • Gross total resection is the primary treatment, but entrapment of nerve roots may limit resectability. • Adjuvant radiation may be considered after subtotal resection or for disseminated tumors.

Extramedullary Leptomeningeal Metastasis (see Chapter 4) Intramedullary Tumors ■ Account for 20% to 30% of intradural tumors in adults1 ■ Clinical features • May present with slowly progressive myelopathy • Midline back pain with or without radicular pain at the level of the tumor • Leg weakness and sensory changes • Bowel/ bladder dysfunction are late symptoms Ependymoma ■ They account for 40% to 60% of intramedullary spinal cord tumors in adults.1 ■ They can occur anywhere in the central nervous system, but nearly 50% of all ependymomas arise within the spinal canal.20 ■ Most arise in the cervical or cervicothoracic regions. ■ Most are benign, slow growing, and tend to compress rather than infiltrate normal adjacent tissue.21 ■ The diagnosis is as follows: • Spine MRI with contrast is the imaging modality of choice. ■ Homogeneously enhancing mass ■ Hypointense on T1-weighted images and hyperintense on T2-weighted images • Definitive diagnosis requires pathology. • All patients with spinal ependymomas should undergo screening of the entire neuroaxis with brain MRI with contrast, whole-spine MRI with contrast, and CSF cytology.

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Treatment • Surgery ■ Gross total resection is the primary treatment and is achieved in 50% to 65% of patients.21 ■ The extent of resection is the strongest predictor of survival.21 • Radiation therapy ■ Not indicated after gross total resection in lowgrade tumors ■ May increase tumor-free survival rates in patients with high-grade ependymomas or after subtotal resection1 • The role of chemotherapy is controversial. • Five-year survival rates for low-grade intramedullary ependymomas are 83% to 100%.1

Astrocytoma ■ These can occur anywhere in the CNS, with approximately 3% originating in the spinal cord.20 ■ The most common locations are the cervical and cervicothoracic regions. ■ Astrocytomas usually extend multiple levels at the time of diagnosis. ■ The pathology is as follows: • They are graded according to the same WHO criteria as intracranial astrocytomas. • Almost two-thirds of intramedullary astrocytomas are pilocytic astrocytoma or fibrillary astrocytoma.1 • Approximately 10% of intramedullary astrocytomas are anaplastic astrocytoma and glioblastoma.1 • Except for pilocytic astrocytomas, most spinal cord astrocytomas typically grow in a diffuse manner, infiltrating surrounding normal neural tissue. • Thirty percent to 60% of the tumors are associated with rostral, caudal, or intratumoral cysts or syringomelias.1 ■ Diagnosis • Spine MRI with contrast is the imaging modality of choice.

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Low-grade tumors • Focal fusiform expansions of the spinal cord, hypointense to isointense on T1-weighted images, hyperintense on T2-weighted images • Little or no cord edema • May enhance with contrast • Calcifications are rare ■ High-grade tumors • Appear heterogeneous because of intratumor cysts, necrosis, and surrounding edema22 • Heterogeneous enhancement with contrast • A definitive diagnosis requires pathology. Treatment • Treatment depends on tumor histology. • Surgery ■ Gross total resection is feasible in pilocytic astrocytomas, but may not be feasible in higher grade tumors because of their infiltrative nature. ■ Electrophysiological monitoring of the spinal cord during surgery may help with resection. • Radiation ■ Recommended as adjuvant therapy for high-grade astrocytomas ■ Could be considered for progressive disease or for unresectable tumors • Chemotherapy ■ The role in spinal cord astrocytomas is unknown. ■ Based on its role in intracranial glioblastomas, temozolomide and other chemotherapies could be considered in patients with intramedullary glioblastomas. ■

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Intramedullary Metastasis ■ These are extremely rare and suggest advanced metastatic disease. ■ The most common tumors causing intramedullary metastases are lung and breast cancer.20

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References 1.

2. 3.

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Traul DE, Shaffrey ME, Schiff D. Part I: spinal-cord neoplasms-intradural neoplasms. Lancet Oncol. 2007;8(1): 35–45. Cole JS, Patchell RA. Metastatic epidural spinal cord compression. Lancet Neurol. 2008;7(5):459–466. Schiff D, O’Neill BP, Suman VJ. Spinal epidural metastasis as the initial manifestation of malignancy: clinical features and diagnostic approach. Neurology. 1997;49(2):452–456. Sioutos PJ, Arbit E, Meshulam CF, Galicich JH. Spinal metastases from solid tumors. Analysis of factors affecting survival. Cancer. 1995;76(8):1453–1459. George R, Jeba J, Ramkumar G, Chacko AG, Leng M, Tharyan P. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database Syst Rev. 2008(4):CD006716. Abrahm JL, Banffy MB, Harris MB. Spinal cord compression in patients with advanced metastatic cancer: “all I care about is walking and living my life.” JAMA. 2008;299(8): 937–946. Sorensen S, Helweg-Larsen S, Mouridsen H, Hansen HH. Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial. Eur J Cancer. 1994;30A(1):22–27. Graham PH, Capp A, Delaney G, et al. A pilot randomised comparison of dexamethasone 96 mg vs 16 mg per day for malignant spinal-cord compression treated by radiotherapy: TROG 01.05 Superdex study. Clin Oncol (R Coll Radiol). 2006;18(1):70–76. Vecht CJ, Haaxma-Reiche H, van Putten WL, de Visser M, Vries EP, Twijnstra A. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology. 1989;39(9):1255–1257. Maranzano E, Latini P, Beneventi S, et al. Radiotherapy without steroids in selected metastatic spinal cord compression patients. A phase II trial. Am J Clin Oncol. 1996;19(2): 179–183. Maranzano E, Bellavita R, Rossi R, et al. Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial. J Clin Oncol. 2005;23(15):3358–3365.

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Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643–648. Conti P, Pansini G, Mouchaty H, Capuano C, Conti R. Spinal neurinomas: retrospective analysis and long-term outcome of 179 consecutively operated cases and review of the literature. Surg Neurol. 2004;61(1):34–43; discussion 44. Parmar HA, Ibrahim M, Castillo M, Mukherji SK. Pictorial essay: diverse imaging features of spinal schwannomas. J Comput Assist Tomogr. 2007;31(3):329–334. Acharya R, Bhalla S, Sehgal AD. Malignant peripheral nerve sheath tumor of the cauda equina. Neurol Sci. 2001;22(3): 267–270. Jinnai T, Koyama T. Clinical characteristics of spinal nerve sheath tumors: analysis of 149 cases. Neurosurgery. 2005; 56(3):510–515. Gupta G, Maniker A. Malignant peripheral nerve sheath tumors. Neurosurg Focus. 2007;22(6):E12. Saraceni C, Harrop JS. Spinal meningioma: chronicles of contemporary neurosurgical diagnosis and management. Clin Neurol Neurosurg. 2009;111(3):221–226. Albanese V, Platania N. Spinal intradural extramedullary tumors. Personal experience. J Neurosurg Sci. 2002;46(1): 18–24. Parsa AT, Lee J, Parney IF, Weinstein P, McCormick PC, Ames C. Spinal cord and intradural-extraparenchymal spinal tumors: current best care practices and strategies. J Neurooncol. 2004;69(1–3):291–318. Ruda R, Gilbert M, Soffietti R. Ependymomas of the adult: molecular biology and treatment. Curr Opin Neurol. 2008; 21(6):754–761. Runge VM, Muroff LR, Jinkins JR. Central nervous system: review of clinical use of contrast media. Top Magn Reson Imaging. 2001;12(4):231–263.

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C H A P T E R

4

Leptomeningeal Metastases Introduction ■

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Neoplastic meningitis: spread of malignant cells to the leptomeninges and subarachnoid space Carcinomatous meningitis or leptomeningeal carcinomatosis: neoplastic meningitis in patients with solid tumors Leukemic meningitis: neoplastic meningitis in patients with leukemia Lymphomatous meningitis: neoplastic meningitis in patients with lymphoma

Epidemiology ■

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The number of patients diagnosed with neoplastic meningitis varies according to the type of tumor.1,2 • Solid tumors: breast cancer 3%, small cell lung cancer 6%, non-small cell lung cancer 1%, and melanoma 1% to 5% • Leukemia 5% to 15% • Diffuse high-grade non-Hodgkin lymphoma 5% to 15% ■ Risk factors include high serum LDH, low serum albumin, age ,60, involvement of testis, breast, bone marrow or more than two extranodal sites • Non-Hodgkin lymphomas with aggressive clinical course (e.g., Burkitt lymphoma, lymphoblastic lymphoma) have a .25% risk of meningeal relapse without CNS-directed therapy.3 • Primary brain tumors 1% to 2% Based on autopsy studies, 19% of cancer patients with neurologic signs/symptoms have evidence of neoplastic meningitis.4

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Carcinomas of unknown primary account for 1% to 7% of patients with neoplastic meningitis.5 Presentation may occur in the following circumstances6: • Widely disseminated and progressive systemic cancer (60% to 70%)5,7 • Following a disease-free interval (20%) • First manifestation of cancer (5% to 10%)8 • Synchronous with intraparenchymal brain metastases (11% to 31%)5,9

Pathogenesis ■

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Routes of metastasis are as follows6: • Hematogenous (arterial or venous plexus of Batson) • Direct extension from a tumor adjacent to the CSF space • Migration along perineural or perivascular spaces Dissemination occurs throughout the CSF to the entire neuroaxis. Tumor infiltration is most prominent at the skull base, dorsal surface of spinal cord, and cauda equina.1,10

Clinical Features ■

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Clinical features depend on the location of tumor deposits and may be multifocal. • Cerebral hemispheres: headache, mental status changes, seizures • Skull base: cranial nerve deficits with diplopia (CN IV more commonly affected than III, VI), sensory loss (CN V), facial weakness (CN VII), cochlear dysfunction (CN VIII), and optic neuropathy (CN II) • Spine: weakness (lower extremities more than upper extremities), sensory loss in a dermatomal pattern, pain in neck or back, radiculopathy, cauda equina syndrome Nuchal rigidity is present in only 15% of cases.6 Raised intracranial pressure or hydrocephalus may occur from obstruction of CSF outflow by tumor deposits. Thirty percent to 40% of patients with leptomeningeal disease may also have parenchymal brain metastases.6

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Diagnosis ■

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Diagnosis in early stages is important to prevent progressive neurologic dysfunction, as fixed neurologic deficits rarely respond to treatment. Three methods are used to diagnose leptomeningeal metastases and should be used in combination: clinical presentation, cerebrospinal fluid (CSF) cytology, and neuroimaging. CSF studies • Increased opening pressure (.200 mm H2O) • Elevated WBC (.4 per mm3) • Elevated protein (.50 mg/dL) • Decreased glucose (,60 mg/dL) • Positive cytology is diagnostic ■ A volume .10.5 mL is recommended.11 ■ A normal CSF cytology does not exclude the diagnosis of leptomeningeal metastases. ■ If the first cytology is negative but suspicion for neoplastic meningitis remains high, CSF studies should be repeated. • Up to 45% of patients eventually found to have positive cytology had a negative cytology on first examination.4 • Diagnostic yield increases to 80% with second CSF cytology.5 • Up to 40% of patients with clinically suspected leptomeningeal disease and negative CSF cytology had pathologically proven disease at autopsy.4 ■ Factors associated with false negative cytology include the following11: • Not collecting CSF from a site of symptomatic or radiographic involvement • Small CSF volumes (,10.5 mL) • Delayed processing of samples • Obtaining fewer than two samples • In leukemia and lymphoma, positive flow cytometry or cytogenetic studies may be more sensitive than CSF cytology.6

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Meningeal biopsy may be considered if no primary cancer is found and CSF studies are not diagnostic. Radiographic imaging • A brain and spine MRI with gadolinium is the radiographic test of choice, but findings are nonspecific. ■ Enhancement of leptomeninges (occurring in the gyri and superficial sulci), ventricles, cranial nerves, or intradural extramedullary nodules may be seen. ■ Imaging should be performed prior to lumbar puncture because the procedure can cause a meningeal reaction resulting in dural-arachnoidal enhancement.12 ■ A normal MRI does not exclude diagnosis, as the false-negative rate is $30%.6 • Radionuclide studies (111indium-diethylenetriamine pentaacetic acid or 99tecnetium macroaggregated albumin) ■ These may be used to evaluate CSF flow dynamics but are not routinely done in many centers. ■ Patients with CSF flow obstruction (as demonstrated on radionuclide studies) have decreased survival times compared with patients with normal CSF flow.13–15 ■ Involved field radiation to sites of CSF flow obstruction restores flow in 30% of patients with spinal disease and 50% of patients with intracranial disease.16,17 ■ Reestablishment of CSF flow with radiation 1 intrathecal chemotherapy is associated with longer survival and lower rates of treatment-related morbidity compared with patients with persistent CSF flow obstruction.13,14

Prognosis ■

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The median survival without treatment is 4 to 6 weeks; death is usually related to neurologic dysfunction.5 Treatment may prolong survival to 4 to 6 months,18 but responses depend on the primary tumor type.

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• Breast cancer is the best responder among solid tumors, with a median survival of 6 months and 1-year survival rates of 11% to 25%.11,19 • Favorable responses are also seen in patients with lymphoma. • Less than 15% survive longer than 12 months and have a complete treatment response.2 Treatment may improve or stabilize neurologic symptoms but generally does not improve fixed neurologic deficits. The following are poor prognostic factors for survival and response to treatment6: • Poor performance status • Multiple fixed neurologic deficits • Bulky CNS disease • Coexistent carcinomatous encephalopathy • CSF flow abnormalities on radionuclide ventriculography • Widely metastatic and aggressive cancers that do not respond well to systemic therapies

Treatment ■

Important for palliation and may prolong survival • There is no standard treatment. • Most treatment studies are small, nonrandomized, and retrospective. • Conversion of a positive CSF cytology/flow into a negative result suggests response and continuation of therapy. • More aggressive treatments are generally reserved for patients with a life expectancy of more than 3 months and a Karnofsky performance status score of more than 60%.

Surgery Placement of an intraventricular catheter with a subgaleal reservoir (e.g., Ommaya reservoir) for intrathecal chemotherapy and CSF sampling

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• Often preferred to repeated lumbar punctures, as drug distribution in CSF is more uniform through a reservoir20–22 • Complications include malposition, obstruction, and infection Ventriculoperitoneal (VP) shunt for symptomatic hydrocephalus • Does not appear to result in peritoneal dissemination of cancer23 • May include an in-line on/off valve to allow chemotherapy administration in the off position, although it is unclear whether this improves outcomes

Radiation Therapy ■ Decreasing bulky disease because intrathecal chemotherapy is unable to penetrate further than 2 to 3 mm into a tumor nodule6 ■ Palliation of symptoms regardless of presence of bulky disease or not, including symptoms related to cauda equina or cranial nerve involvement ■ Restore CSF flow due to obstruction (see the previous section on radionuclide imaging) ■ Radiation to the entire CNS axis not feasible because of systemic toxicity Chemotherapy Intrathecal (IT) Chemotherapy ■ Agents include methotrexate, liposomal cytarabine, and thiotepa. ■ This may be administered via lumbar puncture or ventricular reservoir (Ommaya). ■ Complications include the following: • CSF infection with Ommaya reservoir ■ This occurs in 2% to 13% of patients on IT chemotherapy.6 ■ Signs/symptoms include headache, mental status change, fever, and reservoir malfunction. ■ These are most frequently caused by Staphylococcus epidermidis.

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Treatment includes intravenous antibiotics 6 oral/ intraventricular antibiotics and possibly removal of the ventricular reservoir. Myelosuppression Chemical aseptic meningitis ■ Occurs in almost 50% of patients on IT chemotherapy6 ■ Usually caused by an inflammatory reaction ■ Signs/symptoms: fever, headache, nausea, vomiting, meningismus, and photophobia ■ May be managed as an outpatient with antipyretics, antiemetics, and corticosteroids Chemotherapy-related neurotoxicity, including subacute leukoencephalopathy or myelopathy, is rare. The combination of radiation and chemotherapy (especially methotrexate) may result in late leukoencephalopathy.6 ■

• •

• •

Systemic Chemotherapy ■ Some agents are able to penetrate the blood–brain barrier, resulting in cytotoxic CSF levels, including high-dose methotrexate, cytarabine, and thiotepa. ■ Some studies suggest that certain systemic chemotherapies are associated with better outcomes than IT chemotherapies while sparing the complications of IT treatments.24–26 ■ In patients with methotrexate sensitive cancers (i.e., lymphoma and breast cancer), high-dose methotrexate may be used to treat parenchymal and leptomeningeal metastases.26 ■ Hormone therapy is occasionally useful in breast cancer.27,28 Supportive Care ■ Should be offered to all patients with neoplastic meningitis regardless of treatment plan ■ Anticonvulsants for seizures ■ Analgesia and pain control ■ Corticosteroids for vasogenic edema from intraparenchymal or epidural metastases

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Antiemetics for nausea and vomiting Psychostimulants for decreased attention and somnolence

References 1. 2. 3.

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Chamberlain MC. Carcinomatous meningitis. Arch Neurol. 1997;54(1):16–17. Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol. 2006;5(5):443–452. Gokbuget N, Hoelzer D. Meningeosis leukaemica in adult acute lymphoblastic leukaemia. J Neurooncol. 1998;38 (2–3):167–180. Glass JP, Melamed M, Chernik NL, Posner JB. Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology. 1979;29(10):1369–1375. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer. 1982;49(4):759–772. Chamberlain MC. Neoplastic meningitis. Oncologist. 2008;13(9):967–977. Balm M, Hammack J. Leptomeningeal carcinomatosis. Presenting features and prognostic factors. Arch Neurol. 1996;53(7):626–632. Yap HY, Yap BS, Tashima CK, DiStefano A, Blumenschein GR. Meningeal carcinomatosis in breast cancer. Cancer. 1978;42(1):283–286. Freilich RJ, Krol G, DeAngelis LM. Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis. Ann Neurol. 1995;38(1):51–57. Little JR, Dale AJ, Okazaki H. Meningeal carcinomatosis. Clinical manifestations. Arch Neurol. 1974;30(2):138–143. Glantz MJ, Cole BF, Glantz LK, et al. Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer. 1998;82(4):733–739. Mittl RL, Jr., Yousem DM. Frequency of unexplained meningeal enhancement in the brain after lumbar puncture. AJNR Am J Neuroradiol. 1994;15(4):633–638. Chamberlain MC, Kormanik PA. Prognostic significance of 111 indium-DTPA CSF flow studies in leptomeningeal metastases. Neurology. 1996;46(6):1674–1677. Glantz MJ, Hall WA, Cole BF, et al. Diagnosis, management, and survival of patients with leptomeningeal cancer based

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on cerebrospinal fluid-flow status. Cancer. 1995;75(12): 2919–2931. Mason WP, Yeh SD, DeAngelis LM. 111Indium-diethylenetriamine pentaacetic acid cerebrospinal fluid flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases. Neurology. 1998;50(2):438–444. Chamberlain MC, Corey-Bloom J. Leptomeningeal metastases: 111indium-DTPA CSF flow studies. Neurology. 1991; 41(11):1765–1769. Chamberlain MC, Kormanik P, Jaeckle KA, Glantz M. 111 Indium-diethylenetriamine pentaacetic acid CSF flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases. Neurology. 1999;52(1):216–217. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev. 1999;25(2):103–119. Hildebrand J. Prophylaxis and treatment of leptomeningeal carcinomatosis in solid tumors of adulthood. J Neurooncol. 1998;38(2–3):193–198. Berweiler U, Krone A, Tonn JC. Reservoir systems for intraventricular chemotherapy. J Neurooncol. 1998;38(2–3): 141–143. Sandberg DI, Bilsky MH, Souweidane MM, Bzdil J, Gutin PH. Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery. 2000;47(1):49–54; discussion 54–55. Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med. 1975;293(4):161–166. Omuro AM, Lallana EC, Bilsky MH, DeAngelis LM. Ventriculoperitoneal shunt in patients with leptomeningeal metastasis. Neurology. 2005;64(9):1625–1627. Bokstein F, Lossos A, Siegal T. Leptomeningeal metastases from solid tumors: a comparison of two prospective series treated with and without intra-cerebrospinal fluid chemotherapy. Cancer. 1998;82(9):1756–1763. Boogerd W, van den Bent MJ, Koehler PJ, et al. The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. Eur J Cancer. 2004;40(18):2726–2733. Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal

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cancer: is intrathecal chemotherapy necessary? J Clin Oncol. 1998;16(4):1561–1567. Boogerd W, Dorresteijn LD, van Der Sande JJ, de Gast GC, Bruning PF. Response of leptomeningeal metastases from breast cancer to hormonal therapy. Neurology. 2000; 55(1):117–119. Ozdogan M, Samur M, Bozcuk HS, et al. Durable remission of leptomeningeal metastasis of breast cancer with letrozole: a case report and implications of biomarkers on treatment selection. Jpn J Clin Oncol. 2003;33(5):229–231.

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Neurologic Complications of Radiation Therapy Introduction ■

■

Ionizing radiation damages DNA to create permanent cell injury or death but can also damage other intracellular molecules such as lipids or proteins. Radiation is nonspecifically toxic and therefore can damage surrounding normal neural tissue.

Description of Radiation Terms ■ Fractionation: administration of radiation therapy in divided doses • Equally efficacious and better tolerated than a single dose • Spares normal tissues by allowing time to repair and repopulation of normal cells between fractions ■ Gray (Gy): absorption of 1 joule per kilogram ■ External beam therapy (EBRT): uses a focused beam of high-energy rays generated outside the patient ■ Intensity-modulated radiation therapy (IMRT): assigns nonuniform intensities to individual rays within each beam to better control dose distributions ■ Stereotactic radiosurgery (SRS): technique used to precisely deliver a single, high-dose fraction of external beam radiation to a small intracranial volume. Methods of delivery include charged particle beams, modified linear accelerators, and gamma knife units. ■ Stereotactic radiotherapy (SRT): delivery of multiple fractions using the stereotactic process ■ Brachytherapy: a form of radiation therapy where a radioactive source is placed inside or next to the tumor

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Whole-brain radiation therapy (WBRT): a form of external radiation that treats the entire brain Prophylactic cranial irradiation (PCI): radiation therapy provided to the head to reduce the risk of brain metastases

Radiation Effects on the Central Nervous System ■

■

Cranial irradiation is used as a treatment modality in many primary brain tumors, metastatic disease to the brain, CNS involvement of leukemia/lymphomas, and head/neck cancers. The radiation field may include healthy brain tissue, resulting in radiation toxicity.

Timing of Radiation Toxicity Acute Effects ■ Acute radiation toxicity occurs during or shortly after radiation. ■ Symptoms include the following: • The most common symptom is progressive fatigue, which may persist for several weeks after the completion of radiation, but is generally reversible. • A less common, more severe acute radiation encephalopathy (dizziness, signs of increased intracranial pressure, or focal neurologic deficits) may occur. ■ Symptoms may be secondary to edema and disruption of the blood–brain barrier. ■ Steroid treatment results in clinical improvement of progressive fatigue and other mild symptoms, but increased intracranial pressure requires more aggressive intervention. Early-Delayed Effects Early-delayed radiation toxicity occurs 6 to 12 weeks after radiation. ■ Symptoms after cranial radiation include generalized weakness, fatigue, somnolence, and cognitive dysfunction. ■

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Manifestations are mostly transient and reversible. These are secondary to transient demyelination, edema, and disruption of the blood–brain barrier.

Late-Delayed Effects Late delayed radiation toxicity occurs months to years after radiation. ■ Clinical manifestations may include • Minor to severe neurocognitive dysfunction (discussed further later in this chapter) • Focal radiation necrosis of brain parenchyma (discussed further later in this chapter) • Diffuse radiation necrosis of brain parenchyma • Chronic progressive myelopathy due to spinal cord injury • Endocrine dysfunction, usually due to hypothalamic injury • Radiation-induced brain tumors (discussed further later in this chapter) • Accelerated atherosclerosis affecting the carotid arteries, after neck irradiation (see Chapter 8) ■ Manifestations are often irreversible. ■ Hippocampal dysfunction may account for some of the neurocognitive changes. ■ The pathophysiology is not completely understood, but the following have been implicated: • Excessive generation of reactive oxygen species from injured and/or proinflammatory cells • Vascular endothelial damage • Long-term damage to neural cell types ■

Risk Factors for Radiation Toxicity Total radiation dose (.50 Gy) ■ Fraction size (.2 Gy) ■ Volume of tissue being irradiated ■ Administration of radiation with chemotherapy1 ■ Novel radiation delivery technique (e.g., stereotactic radiosurgery) ■ Young children, especially during developmental stages of neural tissue ■

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Old age (.60 years) Vascular risk factors Genetic instability syndromes (e.g., neurofibromatosis) Close proximity to nervous system structures Tumors compatible with long survival

Pathology Pathological changes are not specific to radiation and include the following: • Parenchymal cell loss, including white matter demyelination, encephalomalacia, gliosis, and neural cell loss • Vascular changes, including endothelial damage and fibrinoid necrosis in vessels, resulting in vascular occlusion and tissue necrosis ■ Brain damage can be focal or diffuse. ■

Imaging Abnormalities Following Radiation Therapy ■ White matter changes • White matter abnormalities may be present in some patients as early as 2 to 6 months after completion of radiation therapy, likely representing early-delayed radiation-induced injury.2 • Periventricular white matter changes occur 12 to 18 months after radiation therapy.2,3 • White matter changes are more severe in older patients.4,5 • The data are conflicting on whether white matter changes correlate with neurologic dysfunction. ■ Lacunar lesions ■ Cerebral atrophy Neurocognitive Dysfunction Radiation may have long-term detrimental effects on neurocognitive function. ■ Radiation may also have short-term beneficial effects on neurocognitive function because of improved tumor control. ■

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It is often difficult to determine whether the decline in cognitive function is attributable to therapy or another etiology such as • Disease progression • Radiation • Surgery • Chemotherapy • Medications (including corticosteroids) • Paraneoplastic disorder

Clinical Features 6 ■ Short-term memory deficits ■ Difficulty with spatial relations ■ Difficulty with visual motor processing ■ Difficulty with quantitative skills ■ Deficits in attention ■ Subcortical dementia with gait disturbance and incontinence Pathophysiology ■ Early memory impairment after WBRT may be related to hippocampus damage.7–9 Clinical Studies Radiation is an important cause of neurocognitive dysfunction based on data from retrospective studies10,11 and nonrandomized prospective studies12 in brain metastases and primary brain tumors. ■ Progression of cognitive deficits may only become apparent after several years. • In a longitudinal study of patients with low-grade glioma at a mean 12 years after diagnosis, patients who received radiation therapy had more deficits in attentional functioning, executive functioning, and information processing speed than patients who did not have radiation therapy (no differences seen between groups at a mean 6 years after diagnosis).13 • Data on late cognitive effects in patients with brain metastases are sparse because of death in all studies.12 ■

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Studies on neurocognitive function, however, may also be confounded by other factors such as tumor progression and baseline cognitive dysfunction. • Several prospective studies report cognitive impairment in cancer patients even before radiation therapy.14,15 • Results from other prospective studies suggest that tumor control is strongly associated with neurocognitive stability.15 Some data suggest that radiation does not significantly affect cognition in patients with brain metastases based on short-term (1–2 years) follow-up. • A prospective study of 208 patients with brain metastases treated with WBRT showed stable neurocognitive function on formal testing in long-term survivors at 15 months compared with baseline.16 • Randomized studies of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer suggest that patients have substantial levels of impairments at randomization (even before PCI)17 and show no differences in neuropsychological testing between the PCI group and the no PCI group.17,18 One should consider the likelihood of radiation-induced neurocognitive decline versus tumor progression when considering whether to provide or delay brain radiation.

Treatment • Donepezil may improve cognition and quality of life in irradiated brain tumor patients.19 • VP shunting is an option for radiation-induced hydrocephalus. • Other interventions used in the treatment of cognitive impairment (such as cognitive rehabilitation) may also be considered but have not been tested specifically in the irradiated brain tumor population. Focal Radiation Necrosis ■ This is a severe form of radiation-induced injury, mostly affecting white matter, although lesions may extend into cortex or deep gray matter.

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Epidemiology The incidence after conventional therapy is unknown because most studies were performed prior to modern imaging, but ranges from 3% to 24% have been reported.1

■

Clinical Features Best characterized following conventional external beam radiation, although may be relatively more common after stereotactic radiosurgery or brachytherapy ■ Rarely occurs with cumulative doses of standard fractionated radiation less than 50–60 Gy to the brain or 45 Gy to the spinal cord20 ■ Uncommon in patients who receive WBRT for brain metastases, although radiation necrosis after WBRT has been reported ■ Generally occurs as a late complication of radiation, as early as 2 months and as late as 47 months after radiation therapy1 • The mean interval from the end of radiation therapy is approximately 12 months. • The latency period is approximately five times shorter in patients with glioma than other types of tumors. ■ Nonspecific presenting signs and symptoms such as focal neurologic deficits, seizures, confusion, or headaches ■

Pathophysiology Poorly understood ■ Pathologically characterized by necrosis with hypocellular edges and dystrophic calcifications, vasculopathy (telangiectatic, hyalinized, angionecrotic blood vessels), hemorrhage, edema, and gliosis ■ Potential causes21 • Vascular damage: radiation-induced endothelial damage leading to microvasculopathy, vascular insufficiency, and infarction followed by gray and/or white matter necrosis • Glial damage: radiation-induced glial damage leading to ablation of glial precursors and demyelinative necrosis ■

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100 Chapter 5 Diagnosis Radiation necrosis is difficult to distinguish from tumor recurrence. ■ Specific patterns of enhancement on MRI (“soap bubbles” or “Swiss cheese”) have been associated with radiation necrosis as opposed to tumor recurrence.22 ■ Radiation necrosis is typically hypometabolic on PET, whereas tumor recurrence may be hypermetabolic. ■ A definitive diagnosis requires pathology. ■

Treatment ■ Surgery is not always necessary but may be an option for symptomatic control in the setting of raised intracranial pressure or progression despite conservative management. ■ Resolution of radionecrosis is reported in cases or case series with the following treatments, but efficacy has not been established. • Corticosteroids1 • Bevacizumab ■ A retrospective review of six glioma patients with biopsy-confirmed radiation necrosis demonstrated radiographic response in six of six patients and clinical improvements in three of six patients.23 ■ A retrospective review of eight glioma patients (two with biopsy-confirmed radiation necrosis) demonstrated radiographic improvements in postcontrast and FLAIR images.24 • Anticoagulation ■ In a small study of eight patients with biopsyconfirmed radiation necrosis treated with heparin followed by warfarin for 3–6 months, clinical improvement were noted in five of eight patients, but symptoms reemerged after stopping anticoagulation.25 • Hyperbaric oxygen therapy ■ Typical regimen: oxygen was delivered at 20–24 atmospheres for 20–30 sessions, with each session lasting 90–120 minutes. ■ In a study of 10 patients (8 with biopsy-confirmed radiation necrosis), clinical improvements were

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noted in 6 of 10 patients, with three documented radiographic responses, but many of these patients also received high-dose steroids.26 Radiation-Induced Brain Tumors ■ The most common secondary tumors in the CNS are meningiomas, nerve sheath tumors, pituitary adenomas, gliomas, sarcomas, and embryonal neoplasms. ■ Radiation-induced brain tumors tend to be more aggressive and higher grade. Epidemiology ■ Based on a retrospective review of 10,080 children treated with low-dose scalp irradiation (mean 1.4–1.8 Gy) for tinea capitis, relative risks as compared with matched nonirradiated controls for meningiomas were 9.5 and for gliomas were 2.6.27 ■ In a study of 9,720 children treated for prophylactic or therapeutic CNS irradiation for ALL, these patients suffered a 22-fold excess of neoplasms, mostly gliomas and primitive neuroectodermal tumors (PNET).28 ■ The latency period after radiation varies but typically presents years to decades after therapy.29 Risk Factors Radiation during childhood ■ Higher radiation doses ■

Treatment ■ Treatment options are similar to analogous non– radiation-induced tumors but are rarely successful.30

Radiation Effects on the Peripheral Nervous System ■

Most effects on the peripheral nervous system occur in a late-delayed fashion.

Postradiation Optic Neuropathy ■ This is caused by injury to the optic nerve and apparatus.

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It is most often associated with radiation to the optic pathways but can occur with radiation to tumors in close proximity to the optic pathways. It occurs 3 months to 8 years after radiation therapy.31 It presents with painless, progressive, monocular vision loss and constriction of visual fields.30 It is usually irreversible. Optimal management is unknown.31

Radiation Plexopathy ■ It may occur in the brachial plexus after radiation for lung or breast cancer or the lumbosacral plexus following radiation for pelvic or lower abdominal tumors. Clinical Features Most occur 5 to 30 months after radiation therapy. ■ Predominating symptoms are gradually progressive weakness and paresthesias. ■ Ipsilateral lymphedema is common in radiation-induced brachial plexopathy. ■ Bilateral plexus involvement (although asymmetric) is common in radiation-induced lumbosacral plexopathy. ■ Pain is uncommon, which distinguishes radiation plexopathy from tumor infiltration or compression. ■

Diagnosis It is based on clinical diagnosis. ■ Electromyography may demonstrate myokymias, which is seen only in radiation plexopathy.22 ■ MRI of the plexus may be used to exclude tumor infiltration or compression. ■

Treatment ■ Pain can be managed with NSAIDs or opioids. ■ For severe plexopathy, surgical exploration may be considered to release neural elements from fibrotic tissues.32 Radiation-Induced Peripheral Nerve Tumors ■ Includes schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs)

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Epidemiology This is a rare complication from radiation, but the true incidence is unknown. ■ The association between radiation and peripheral nerve tumors has been demonstrated in several large retrospective studies.33 ■ Based on a retrospective review of 10,080 children treated with low-dose scalp irradiation for tinea capitis, the relative risk of developing cranial nerve schwannomas compared with matched nonirradiated controls was 18.8.27 ■

Risk Factors Clinical risk factors for development of radiation-induced neurofibromas include radiation at a young age, heavy use of radiation, and long-term survival (owing to the long latency between radiation and diagnosis of a peripheral nerve sheath tumor).34 ■ Patients with neurofibromatosis are at elevated risk of developing peripheral nerve tumors after radiation therapy.35 ■

References 1.

2.

3.

4.

5.

Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65(2): 499–508. Constine LS, Konski A, Ekholm S, McDonald S, Rubin P. Adverse effects of brain irradiation correlated with MR and CT imaging. Int J Radiat Oncol Biol Phys. 1988;15(2): 319–330. Packer RJ, Zimmerman RA, Bilaniuk LT. Magnetic resonance imaging in the evaluation of treatment-related central nervous system damage. Cancer. 1986;58(3):635–640. Johannesen TB, Lien HH, Hole KH, Lote K. Radiological and clinical assessment of long-term brain tumour survivors after radiotherapy. Radiother Oncol. 2003;69(2):169–176. Tsuruda JS, Kortman KE, Bradley WG, Wheeler DC, Van Dalsem W, Bradley TP. Radiation effects on cerebral white

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matter: MR evaluation. AJR Am J Roentgenol. 1987;149(1): 165–171. Akyurek S, Senturk V, Oncu B, Ozyigit G, Yilmaz S, Gokce SC. The effect of tianeptine in the prevention of radiation-induced neurocognitive impairment. Med Hypotheses. 2008;71(6): 930–932. Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res. 2003;63(14):4021–4027. Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8(9):955–962. Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol. 2003;16(2):129–134. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39(6):789–796. Frytak S, Shaw JN, O’Neill BP, et al. Leukoencephalopathy in small cell lung cancer patients receiving prophylactic cranial irradiation. Am J Clin Oncol. 1989;12(1):27–33. Ricard D, Taillia H, Renard JL. Brain damage from anticancer treatments in adults. Curr Opin Oncol. 2009. Douw L, Klein M, Fagel SS, et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol. 2009;8(9):810–818. Welzel G, Fleckenstein K, Schaefer J, et al. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys. 2008;72(5):1311–1318. Brown PD, Kee AY, Eshleman JS, Fiveash JB. Adjuvant whole brain radiotherapy: strong emotions decide but rationale studies are needed: in regard to Brown et al. (Int J Radiat Oncol Biol Phys 2008;70:1305–1309). In reply to Drs. Larson and Sahgal. Int J Radiat Oncol Biol Phys. 2009; 75(1):316–317. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol. 2007;25(10):1260–1266. 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 randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and

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the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer. 1997; 33(11): 1752–1758. 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(3): 183–190. Shaw EG, Rosdhal R, D’Agostino RB, Jr., et al. Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol. 2006;24(9):1415–1420. Schultheiss TE, Kun LE, Ang KK, Stephens LC. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys. 1995;31(5):1093–1112. Yoshii Y. Pathological review of late cerebral radionecrosis. Brain Tumor Pathol. 2008;25(2):51–58. Kumar AJ, Leeds NE, Fuller GN, et al. Malignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapyinduced necrosis of the brain after treatment. Radiology. 2000;217(2):377–384. Torcuator R, Zuniga R, Mohan YS, et al. Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis. J Neurooncol. 2009;94(1):63–68. Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys. 2007;67(2):323–326. Glantz MJ, Burger PC, Friedman AH, Radtke RA, Massey EW, Schold SC, Jr. Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology. 1994;44(11):2020–2027. Chuba PJ, Aronin P, Bhambhani K, et al. Hyperbaric oxygen therapy for radiation-induced brain injury in children. Cancer. 1997;80(10):2005–2012. Ron E, Modan B, Boice JD, Jr., et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med. 1988;319(16):1033–1039. Neglia JP, Meadows AT, Robison LL, et al. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;325(19):1330–1336. Perry A, Schmidt RE. Cancer therapy-associated CNS neuropathology: an update and review of the literature. Acta Neuropathol. 2006;111(3):197–212. Cross NE, Glantz MJ. Neurologic complications of radiation therapy. Neurol Clin. 2003;21(1):249–277.

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Durkin SR, Roos D, Higgs B, Casson RJ, Selva D. Ophthalmic and adnexal complications of radiotherapy. Acta Ophthalmol Scand. 2007;85(3):240–250. Gosk J, Rutowski R, Reichert P, Rabczynski J. Radiationinduced brachial plexus neuropathy-aetiopathogenesis, risk factors, differential diagnostics, symptoms and treatment. Folia Neuropathol. 2007;45(1):26–30. Zadeh G, Buckle C, Shannon P, Massicotte EM, Wong S, Guha A. Radiation induced peripheral nerve tumors: case series and review of the literature. J Neurooncol. 2007;83(2): 205–212. Donohue WL, Jaffe FA, Rewcastle NB. Radiation induced neurofibromata. Cancer. 1967;20(4):589–595. Sznajder L, Abrahams C, Parry DM, Gierlowski TC, Shore-Freedman E, Schneider AB. Multiple schwannomas and meningiomas associated with irradiation in childhood. Arch Intern Med. 1996;156(16):1873–1878.

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Neurologic Complications of Chemotherapy Introduction ■

Chemotherapy: the use of chemical agents in the treatment or control of disease such as cancer

Common Chemotherapy Agents (Table 6-1) Table 6-1:

Common Chemotherapy Agents

Class of Agent Alkylating agents

Mechanism of Action Add alkyl groups to DNA, resulting in cross-linking, miscoding, or DNA strand breakage

Examples Cisplatin Carboplatin Oxaliplatin Busulfan Carmustine (BCNU) Lomustine (CCNU) Temozolomide Cyclophosphamide

Antimetabolites

Inhibits DNA synthesis

5-Fluorouracil (5-FU) Capecitabine Cytarabine Gemcitabine Fludarabine

(Continues)

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Common Chemotherapy Agents (Continued)

Class of Agent

Mechanism of Action

Examples

Antifolates

Inhibits multiple enzymatic sites leading to the depletion of intracellular folates and direct blockage of purine and pyrimidine biosynthesis

Methotrexate

Vinca alkaloids

Bind to tubulin and inhibit the assembly of tubulin into microtubules, thereby preventing mitosis and cell division

Vincristine

Stabilize microtubules, resulting in inhibition of mitosis and cell division

Paclitaxel

Inhibit topoisomerase I or II, enzymes which promote DNA strand unwinding essential for DNA synthesis and repair

Irinotecan

Taxanes

Topoisomerase inhibitors

Vinblastine Vinorelbine

Docetaxel

Topotecan Etoposide Teniposide Doxorubicin Epirubicin

Thalidomide and its analogues

Immunomodulatory, anti-inflammatory and antiangiogenic properties due to downregulation of certain signaling molecules

Thalidomide Revlimid

(Continues)

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Neurologic Complications of Chemotherapy 109 Table 6-1:

Common Chemotherapy Agents (Continued)

Class of Agent Molecular targeted agents

Mechanism of Action Mechanism varies, target specific molecules associated with tumorigenesis, tumor growth and/or progression

Examples Trastuzumab (monoclonal antibody of HER2/neu) Rituximab (monoclonal antibody of CD20) Bevacizumab (monoclonal antibody of VEGF) Imatinib (tyrosine kinase inhibitor of BCR-Abl) Erlonitib (ATP pocket binding inhibitor of EGFR) Bortezomib (proteosome inhibitor)

Antiestrogens

Bind the estrogen receptor and exert either estrogenic or antiestrogenic effects depending on the specific organ

Tamoxifen

Data are from Chabner BA, Lynch TJ, Longo DL, eds. Harrison’s Manual of Oncology. New York: McGraw Hill Companies; 2008.

Treatment Schemes Treatment Modalities ■ Neoadjuvant: chemotherapy prior to surgery or radiotherapy designed to shrink the tumor ■ Concomitant: chemotherapy given during radiation ■ Adjuvant: chemotherapy after surgery or radiotherapy Palliative Chemotherapy Chemotherapy is given without curative intent. ■ The goal is to decrease tumor burden, provide symptomatic relief, and increase life expectancy. ■

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Central Nervous System Chemotherapy-Related Cognitive Impairment (“Chemobrain”) ■ The nature and extent of chemotherapy-related cognitive impairment is unknown. ■ Studies of cancer-related cognitive dysfunction (prior to chemotherapy administration) demonstrate baseline dysfunction in several cancer types.1 Clinical Features ■ Symptoms may be subtle but adversely affect quality of life. ■ They may arise shortly after starting chemotherapy and persist after the completion of chemotherapy. ■ The neuropsychological profile suggests disruption of frontal–subcortical networks, including problems with • Short-term memory • Executive function • Working memory • Sustained attention Risk Factors1 ■ Higher doses of chemotherapy (either through high-dose regimens or exposure to higher doses caused by impaired systemic clearance) ■ Multiagent chemotherapy ■ Intrathecal chemotherapy Pathophysiology ■ Unknown but postulated hypotheses include2 • Chemotherapeutic agents crossing the blood–brain barrier • DNA damage and shortened telomere length • Cytokine dysregulation resulting in higher levels of proinflammatory cytokines • Problems with neural repair • Decreased neurotransmitter activity

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Treatment There are no standard treatments because of a lack of studies. ■ Empirical treatments include psychostimulants and cognitive therapy. ■

Reversible Posterior Leukoencephalopathy Syndrome (RPLE) ■ Also known as posterior reversible encephalopathy syndrome (PRES) ■ Etiologies • Uncontrolled hypertension • Eclampsia • Immunosuppressants such as cyclosporine and FK-506 • Described in association with several antineoplastic agents, including asparaginase, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, doxorubicin, etanercept, fluorouracil, gemcitabine, interferon alpha, irinotecan, melphalan, methotrexate, oxaliplatin, paclitaxel, prednisone, sorafenib, tacrolimus, thalidomide, and vincristine3 • No single antineoplastic agent consistently associated with RPLE • More frequently associated with multidrug chemotherapy than single-agent chemotherapy3 ■ Characterized by bilateral, reversible, symmetric abnormalities predominantly involving white matter in the cerebral hemisphere ■ Clinical features • Typically subacute at onset • Characterized by headache and altered mental status with or without seizures • Occipital involvement may present with visual symptoms such as cortical blindness ■ MRI demonstrates bilateral T2-hyperintensities caused by vasogenic edema typically involving the subcortical white matter, although additional areas of the brain can be involved.

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Management3 • Early diagnosis important • Discontinuation of offending agent • Correction of high blood pressure, renal dysfunction, and low magnesium

CNS Neurotoxicity of Specific Agents Cytarabine ■ Also known as cytosine arabinoside and ara-C ■ Used in acute leukemias, chronic myelogenous leukemia, non-Hodgkin lymphoma, and neoplastic meningitis ■ High-dose cytarabine associated with an acute cerebellar syndrome4 • Clinical features ■ The predominant clinical feature is cerebellar dysfunction, including dysarthria, dysdiadochokinesia, dysmetria, and ataxia. ■ Many patients also develop a concomitant cerebral dysfunction characterized by somnolence, altered mentation, headache, or seizures. ■ Symptoms are usually noted between 3 and 8 days after initiation of therapy. • The outcome is variable, but neurologic dysfunction resolves within 5 days of discontinuing agent in the majority of cases.4 ■ Intrathecal liposomal cytarabine is associated with aseptic meningitis. • Signs and symptoms include headache, nuchal rigidity, nausea, vomiting, and fever. • The incidence is higher without dexamethasone prophylaxis.5 • It may resolve spontaneously or respond to steroid therapy. 5-Fluorouracil (5-FU) Used in colorectal cancer, gastric cancer, breast cancer, basal cell cancer, head and neck cancer, and bladder cancer ■ Associated with acute and delayed neurotoxicities, although both are uncommon6 ■

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• Acute cerebellar toxicity ■ Characterized by incoordination, ataxia, dysarthria, and nystagmus ■ Often reversible with drug discontinuation • Acute encephalopathy ■ Characterized by confusion, cognitive disturbances, and altered mentation ■ Associated with hyperammonemia and lactic acidosis • Subacute multifocal leukoencephalopathy ■ Reported in cases of fluorouracil and levamisole as combination therapy in patients with stage C colon cancer ■ Develops 3 to 5 months after beginning chemotherapy ■ Characterized by cognitive abnormalities, altered consciousness, dysarthria, focal extremity weakness, and ataxia ■ MRI that demonstrates multifocal enhancing white-matter lesions ■ Clinical improvement with discontinuation of fluorouracil and levamisole as well as administration of corticosteroids Fludarabine ■ Used in chronic lymphocytic leukemia and low-grade lymphoma ■ Associated with a severe neurotoxicity syndrome7 • Described at doses greater than 40 mg/m2/day • Signs and symptoms that include blindness, encephalopathy, coma • Caused by a diffuse, necrotizing leukoencephalopathy, most severe in the occipital lobes Ifosfamide Used in lung cancer, breast cancer, gastric cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, and softtissue sarcoma ■ Neurotoxicity often the dose-limiting toxicity when appropriate preventative measures are used to reduce urotoxicity8 ■

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Associated with encephalopathy7 • Seen in 10% to 16% of patients treated with ifosfamide • Signs and symptoms that range from agitation to seizures to coma • May improve with discontinuation of ifosfamide and administration of methylene blue

Interferon-a Uses include hairy cell leukemia, Kaposi sarcoma, melanoma, chronic myelogenous leukemia, follicular nonHodgkin lymphoma, multiple myeloma, kidney cancer, and bladder cancer ■ Associated with neuropsychiatric symptoms • Predominantly depression, which is often reversible • Rarely associated with cognitive dysfunction ■

Methotrexate Uses include acute lymphoblastic leukemia, acute myelogenous leukemia, neoplastic meningitis, trophoblastic tumors, breast cancer, lung cancer, head and neck cancers, Burkitt lymphoma, osteosarcoma, and primary CNS lymphoma ■ CNS toxicity may be associated to homocysteine levels, folate levels, and genetic variants of methionine metabolism ■ Associated with delayed leukoencephalopathy • Ranging from asymptomatic white matter changes on imaging to severe CNS demyelination • Rarely associated with a disseminated necrotizing leukoencephalopathy9,10 ■ May occur with intrathecal or intravenous methotrexate alone but more commonly associated with the combination of methotrexate and radiation ■ Presenting signs and symptoms that include personality changes, confusion, altered consciousness, seizures, and coma ■ MRI that demonstrates multifocal T2-weighted hyperintensities in the deep white matter with patchy or diffuse contrast enhancement ■ Often fatal ■

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Intrathecal methotrexate is associated with aseptic meningitis. • Signs and symptoms include headache, nuchal rigidity, nausea, vomiting, and fever occurring 2 to 4 hours after IT methotrexate and lasting for 12 to 72 hours. • CSF studies show pleocytosis with negative cultures. • This may resolve spontaneously or respond to steroid therapy.

Peripheral Nervous System Chemotherapy-Induced Peripheral Neuropathy (CIPN) CIPN is a common dose-limiting toxicity for many older chemotherapeutic agents. ■ CIPN may lead to chemotherapeutic dose reduction, treatment delay, or treatment discontinuation even if the patient is responding to the agent. ■ There is no standard of care for the prevention or treatment of CIPN. ■

Common Chemotherapeutic Agents That Cause Peripheral Neuropathy (Table 6-2) ■ Vincristine, paclitaxel, cisplatin, and thalidomide are the most neurotoxic. Risk Factors11 ■ Patient age ■ Dose intensity, cumulative dose, therapy duration ■ Coadministration of other neurotoxic agents ■ Preexisting conditions associated with neuropathy (i.e., diabetes, alcohol abuse) Clinical Signs and Symptoms The pattern depends on drug class (Table 6-2). • Vinca alkaloids, taxanes, and bortezomib are associated with length-dependent neuropathy predominantly affecting the small fibers. • Cisplatin is associated with ataxic neuropathy involving all four limbs. • Vincristine and taxanes are also associated with autonomic neuropathy.

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Vinorelbine

Vinblastine

Axonal transport

Inhibition of microtubule assembly

Vinca alkaloids

Vincristine

Pathophysiology

Drugs

.30–50 mg

Cumulative Toxic Dose

Autonomic neuropathy (especially paralytic ileus)

Optic neuropathy

Cranial nerves (oculomotor, facial, trigeminal, recurrent)

After effect

Recovery or improvement

Acute

Sensory more than motor painful lengthdependent neuropathy Chronic

Evolution

Installation

Neuropathy

Table 6-2: Chemotherapy-Induced Peripheral Neuropathy

Axonal distal neuropathy

(Continues)

Electrophysiology

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Oxaliplatin

Antiangiogenesis

Nerve hyperexcitability

Axonal transport

Dorsal root ganglion apoptosis

Cisplatin

Carboplatin

Inhibition of protein synthesis

Platinum analogues

Docetaxel

Axonal transport

Promotion of microtubule assembly

Taxanes

Paclitaxel

Pathophysiology

Drugs

Sensory neuronopathy (with all) Acute transient sensory neuropathy and neuromyotonia (with oxaliplatin)

400 mg/m2 for carboplatin

Autonomic dysfunction

Facial nerve palsy

Sensory . motor, painful, lengthdependent neuropathy

Neuropathy

.300 mg/m2 for cisplatin and oxaliplatin

.175–200 mg/m2

Cumulative Toxic Dose

Improvement After effect

Subacute

Recovery or improvement

Evolution

Acute

Acute

Installation

Table 6-2: Chemotherapy-Induced Peripheral Neuropathy (Continued)

Axonal sensory neuronopathy (Sensory evoked potentials show a ganglionopathy)

Axonal distal neuropathy

(Continues)

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Thalidomide

Inhibition of growth factors

Suramin

antiangiogenesis

Immunomodulation

Inhibition of nerve growth factor transcription factors

Ganglion

Inclusion in dorsal root

Lysosomal

Glycolipid

Pathophysiology

Drugs

50 mg/day

. 350 µg/mL max plasma level

Cumulative Toxic Dose

Rare sensorimotor neuropathy

Sensory neuronopathy

Sensory painful length-dependent neuropathy

Sensorimotor lengthdependent neuropathy

Guillain-Barré syndrome-like neuropathy

Neuropathy

Chronic

Installation

Table 6-2: Chemotherapy-Induced Peripheral Neuropathy (Continued)

Recovery or improvement

(Continues)

Axonal sensory neuropathy (sensory evoked potentials show a ganglionopathy)

Axonal distal neuropathy

Demyelinating polyneuropathy with conduction blocks

Improvement After effect

Electrophysiology

Evolution

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Proteasome inhibition

Promotion of microtubule assembly

Bortezomib

Epothilones

Unknown

Unknown

Cumulative Toxic Dose

Sensory neuropathy

Demyelinating neuropathy

Mononeuropathy multiplex

Sensorimotor length-dependent neuropathy

Sensory lengthdependent neuropathy

Neuropathy

Evolution Recovery or improvement

Installation Subacute

From Antoine JC, Camdessanche JP. Peripheral nervous system involvement. Lancet Neurol. 2007;6(1):75–86.

Pathophysiology

Drugs

Table 6-2: Chemotherapy-Induced Peripheral Neuropathy (Continued)

Mainly axonal sensory/motor neuropathy

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120 Chapter 6 ■

■

Paresthesias and dysesthesias are commonly seen in toes and fingers. Symptoms often begin distally and spread proximally to affect lower and upper extremities in a stocking-glove distribution.

Prevention ■ Calcium (Ca21) and magnesium (Mg21) infusions may reduce the severity of oxaliplatin-induced chronic peripheral sensory neurotoxicity without reducing response rates. • This is based on preliminary results from three randomized, placebo-controlled, double-blinded studies of intravenous Ca21–Mg21 in oxaliplatin-based treatment regimens for colon or colorectal cancer: the combined oxaliplatin neurotoxicity prevention trial (CONcePT),12,13 the North Central Cancer Treatment Group (NCCTG) N04C7 trial,14 and the Neuroxa trial.15,16 • Based on patient reported outcome analysis in the NCCTG trial, Ca 21–Mg 21 significantly reduced muscle cramps and chronic cumulative sensory neurotoxicity, but no effect was noted on phenomena associated with acute sensory neurotoxicity. ■ Vitamin E may reduce the incidence and/or severity of chemotherapy-induced peripheral neurotoxicity, but its effect on chemotherapy responses is unknown. • The benefit of vitamin E was shown in several trials. ■ Pilot open-label study of patients randomized to vitamin E 300 mg per day versus no intervention in patients receiving cisplatin-based regimens17 ■ Pilot open-label study of patients randomized to vitamin E 300 mg twice per day versus no intervention in patients receiving cisplatin and/or paclitaxel regimens18,19 ■ Preliminary results from prospective, randomized, placebo-controlled, double-blinded study of vitamin E 400 mg per day in patients receiving cisplatin-based regimens20

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Neurologic Complications of Chemotherapy 121

Preliminary results from a prospective, randomized, placebo-controlled, double-blinded study of vitamin E 300 mg twice per day in patients receiving a variety of neurotoxic chemotherapies21 • None of these trials determined whether vitamin E had adverse effects on responses to treatment. Glutathione may prevent cisplatin- or oxaliplatin-induced peripheral neurotoxicity without reducing response rates. • A randomized, double-blinded study of glutathione in patients receiving a cisplatin-based regimen for ovarian cancer showed that glutathione reduced neurotoxicity and improved quality of life.22 • Randomized, placebo-controlled, double-blinded studies of glutathione in patients receiving a cisplatinbased regimen for advanced gastric cancer23 or an oxaliplatin-based regimen for advanced colorectal cancer24 showed that glutathione reduced neurotoxicity without affecting response rates. Xaliproden may reduce the severity of oxaliplatin-induced peripheral neurotoxicity without reducing response rates. • Xaliproden is an orally administered nonpeptide neurotrophic agent. • Preliminary results from a phase III randomized, placebo-controlled, double-blinded study suggest that xaliproden reduces the risk of higher grade oxaliplatininduced peripheral sensory neuropathy without impacting antitumor activity.25 Other agents may protect against CIPN but have not been tested in large trials. • Glutamate: earlier small studies performed in patients receiving paclitaxel suggested a benefit with glutamate prophylaxis, but in a recent small randomized, placebo-controlled, double-blinded study with glutamate 500 mg three times per day in ovarian cancer patients receiving a paclitaxel-based regimen, glutamate failed to protect against peripheral neurotoxicity.26 • Glutamine for high-dose paclitaxel or oxaliplatininduced peripheral neurotoxicity.27 ■

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• Oxcarbazepine: in a small randomized, open-label study of oxcarbazepine 600 mg twice daily in patients receiving an oxaliplatin-based regimen for colon cancer, the incidence of peripheral neuropathy was reduced in patients receiving oxcarbazepine.28 Agents that may not be effective as prophylaxis include • Amifostine for the prevention of platinum- or paclitaxelassociated neuropathy: several randomized controlled trials have demonstrated inconsistent results29 • Nimodipine for the prevention of cisplatin-associated neuropathy30 • Org 2766 (an adrenocorticotrophic hormone analogue) for the prevention of vincristine-31 or cisplatinassociated32 neuropathy • rhuLIF (a recombinant human leukemia inhibitory factor) for the prevention of carboplatin/paclitaxelassociated neuropathy33

Treatment ■ Treatments for diabetic neuropathies are not necessarily helpful in CIPN. ■ Topical baclofen, amitriptyline, and ketamine (BAK): preliminary results from a randomized, placebo-controlled, double-blinded study of BAK in patients receiving a variety of neurotoxic agents suggest that BAK may improve tingling and functioning in the hands.34 ■ Other agents that have been tested in small randomized, placebo-controlled trials but demonstrated no benefit in improving neuropathic symptoms over placebo are11 • Tricyclic antidepressants, including amitriptyline and nortriptyline • Gabapentin • Lamotrigine Prognosis ■ Variable depending on the agent (may or may not be reversible)

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Neurologic Complications of Chemotherapy 123

References 1.

2.

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4. 5.

6. 7.

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12.

Wefel JS, Witgert ME, Meyers CA. Neuropsychological sequelae of non-central nervous system cancer and cancer therapy. Neuropsychol Rev. 2008;18(2):121–131. Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer. 2007; 7(3):192–201. Bhatt A, Farooq MU, Majid A, Kassab M. Chemotherapyrelated posterior reversible leukoencephalopathy syndrome. Nat Clin Pract Neurol. 2009;5(3):163–169. Baker WJ, Royer GL, Jr., Weiss RB. Cytarabine and neurologic toxicity. J Clin Oncol. 1991;9(4):679–693. Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res. 1999;5(11):3394–3402. Pirzada NA, Ali, II, Dafer RM. Fluorouracil-induced neurotoxicity. Ann Pharmacother. 2000;34(1):35–38. Sioka C, Kyritsis AP. Central and peripheral nervous system toxicity of common chemotherapeutic agents. Cancer Chemother Pharmacol. 2009;63(5):761–767. Fleming RA. An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy. 1997;17(5 Pt 2): 146S–154S. Pande AR, Ando K, Ishikura R, et al. Disseminated necrotizing leukoencephalopathy following chemoradiation therapy for acute lymphoblastic leukemia. Radiat Med. 2006; 24(7):515–519. Matsubayashi J, Tsuchiya K, Matsunaga T, Mukai K. Methotrexate-related leukoencephalopathy without radiation therapy: distribution of brain lesions and pathological heterogeneity on two autopsy cases. Neuropathology. 2009; 29(2):105–115. Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer. 2008;44(11):1507–1515. Hochster H, Grothey A, Shpilsky A, Childs B. Effect of intravenous (IV) calcium and magnesium (Ca/Mg) versus placebo on response to FOLFOX 1 bevacizumab (BEV) in the CONcePT trial (abstract 280). Paper presented

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at 2008 Gastrointestinal Cancers Symposium; January 25–27, 2008; Orlando, FL. Grothey A, Hart LL, Rowland KM, et al. Intermittent oxaliplatin (oxali) administration and time-to-treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial. J Clin Oncol (Meeting Abstracts). 2008;26(Suppl):abstr 4010. Grothey A, Nikcevich DA, Sloan JA, et al. Evaluation of the effect of intravenous calcium and magnesium (CaMg) on chronic and acute neurotoxicity associated with oxaliplatin: Results from a placebo-controlled phase III trial. J Clin Oncol (Meeting Abstracts). 2009;27(Suppl):abstr 4025. Gamelin L, Boisdron-Celle M, Morel A, et al. Oxaliplatinrelated neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol. 2008; 26(7):1188–1189; author reply 1189–1190. Gamelin L, Boisdron-Celle M, Poirier A, Berger V, Morel A, Gamelin E. Prevention of oxaliplatin-induced neurotoxicity with Ca21/Mg 21 infusions: preliminary results of the NEUROXA randomized trial in patients with colorectal cancer (CRC) receiving the FOLFOX4 regimen (abstract 602). Gastrointest Cancer Res. 2007;1(6):259. Pace A, Savarese A, Picardo M, et al. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol. 2003;21(5):927–931. Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology. 2005;64(1):26–31. Argyriou AA, Chroni E, Koutras A, et al. A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: final results. Support Care Cancer. 2006;14(11):1134–1140. Pace A, Carpano S, Galie E, et al. Vitamin E in the neuroprotection of cisplatin induced peripheral neurotoxicity and ototoxicity. J Clin Oncol (Meeting Abstracts). 2007; 25(Suppl):abstr 9114. Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vitamin E for prevention of chemotherapy-induced peripheral neuropathy: a phase III double-blind, placebo controlled study—N05C31. J Clin Oncol (Meeting Abstracts). 2009; 27(Suppl):abstr 9532. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with

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ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Ann Oncol. 1997;8(6):569–573. Cascinu S, Cordella L, Del Ferro E, Fronzoni M, Catalano G. Neuroprotective effect of reduced glutathione on cisplatinbased chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol. 1995;13(1):26–32. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002; 20(16):3478–3483. Cassidy J, Bjarnason GA, Hickish T, et al. Randomized double blind (DB) placebo (Plcb) controlled phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in first-line treatment of patients (pts) with metastatic colorectal cancer (MCRC). J Clin Oncol (Meeting Abstracts). 2006;24(Suppl):abstr 3507. Loven D, Levavi H, Sabach G, et al. Long-term glutamate supplementation failed to protect against peripheral neurotoxicity of paclitaxel. Eur J Cancer Care (Engl). 2009;18(1): 78–83. Amara S. Oral glutamine for the prevention of chemotherapy-induced peripheral neuropathy. Ann Pharmacother. 2008;42(10):1481–1485. Argyriou AA, Chroni E, Polychronopoulos P, et al. Efficacy of oxcarbazepine for prophylaxis against cumulative oxaliplatin-induced neuropathy. Neurology. 2006;67(12): 2253–2255. Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol. 2009;27(1):127–145. Cassidy J, Paul J, Soukop M, et al. Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin. Cancer Chemother Pharmacol. 1998;41(2):161–166. Koeppen S, Verstappen CC, Korte R, et al. Lack of neuroprotection by an ACTH (4–9) analogue: a randomized trial in patients treated with vincristine for Hodgkin’s or nonHodgkin’s lymphoma. J Cancer Res Clin Oncol. 2004; 130(3):153–160.

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33.

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Roberts JA, Jenison EL, Kim K, Clarke-Pearson D, Langleben A. A randomized, multicenter, double-blind, placebo-controlled, dose-finding study of ORG 2766 in the prevention or delay of cisplatin-induced neuropathies in women with ovarian cancer. Gynecol Oncol. 1997;67(2): 172–177. Davis ID, Kiers L, MacGregor L, et al. A randomized, double-blinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy. Clin Cancer Res. 2005;11(5):1890–1898. Barton DL, Wos E, Qin R, et al. A randomized controlled trial evaluating a topical treatment for chemotherapyinduced neuropathy: NCCTG trial N06CA. J Clin Oncol (Meeting Abstracts). 2009;27(Suppl):abstr 9531.

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C H A P T E R

7

Paraneoplastic Disorders Introduction ■

■ ■

■

Paraneoplastic disorders (PND) are an extensive group of syndromes that can affect any part of the nervous system by mechanisms that are immune mediated. Symptoms may develop prior to discovery of a tumor. The diagnosis is complex. • Symptoms can mimic other neurological complications of cancer or its treatments. • Not all patients with PND have detectable or recognized paraneoplastic antibodies. • Not all patients with paraneoplastic antibodies have PND, although titers are usually much higher in patients with PND than those without PND.1,2 • There are patients in whom no tumor is ever detected despite presenting with classic PND and high titers of well-characterized onconeural antibody.3 Tumor treatment and immunotherapy may stabilize or improve symptoms.

Epidemiology ■

■

The true prevalence is unknown. • Based on serological screening of patients with suspected PND (generally unselected population), 553 of 60,000 consecutive cases over 4 years (0.9%) were positive for antibodies associated with PND.4 • Based on serological screening of preselected population using clinical criteria, 163 of 649 consecutive cases over 23 months (25%) were positive for antibodies associated with PND.5 The incidence varies depending on type of cancer: SCLC (3% develop a paraneoplastic disorder), thymoma (30%), 127

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128 Chapter 7

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■

plasma cell dyscrasias associated with malignant monoclonal gammopathy (5% to 15%), and other solid tumors (including breast cancer or ovarian cancer) (,1%).6 Central nervous system disorders are more frequently found in the following tumors: • Tumors that express neuroendocrine proteins (e.g., SCLC, neuroblastoma) • Tumors that affect organs with immunoregulatory properties (e.g., thymoma) • Tumors that contain mature or immature neuronal tissue (e.g., teratomas) Peripheral nervous system disorders are more frequently found in tumors that derive from cells that produce immunoglobulins (e.g., plasma cell dyscrasias, B-cell lymphomas).7

Pathogenesis ■ ■

The pathogenesis is not entirely clear. Most PNDs are probably caused by immunological responses against intraneuronal antigens expressed by the underlying cancer. • Tumor cells express antigens found in only the nervous system.8,9 • Tumor antigens are identified as foreign, resulting in an immune response. • The antitumor immune response cross-reacts with the normal nervous system.

Antibody-Mediated PND ■ The direct pathogenic role of antibodies has been demonstrated in a few disorders (i.e., development of characteristic syndrome after passive transfer of antibodies in mice or rats). • Myasthenia gravis (MG): antibodies to the acetylcholine receptor of the neuromuscular junction • Lambert-Eaton myasthenic syndrome (LEMS): antibodies to voltage-gated calcium channels • Stiff-person syndrome (SPS): antibodies to amphyphysin10

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Paraneoplastic Disorders 129

■

■

■

• Single case report of two patients in remission from Hodgkin lymphoma who developed cerebellar ataxia found to have antibodies against mGluR111 Antibodies usually react with cell surface antigens, but antibodies to intracellular antigens are also described (e.g., antibodies against amphiphysin in paraneoplastic stiff-person syndrome). Associated disorders can occur with or without cancer.12 • The likelihood of an underlying tumor with LEMS is 50%, most commonly SCLC.13 • The likelihood of an underlying tumor with MG is 10%, most commonly thymoma.13 The presence of antibodies does not confer disease because some paraneoplastic antibodies are commonly present in cancer patients without a PND.12,14

T-Cell–Mediated PND ■ Some PNDs may be mediated by T-cell immune responses against target antigens of accompanying antibodies, although the evidence is mostly circumstantial.5 • Yo- or Hu-specific T-cells identified in blood or CSF of patients with anti-Yo or anti-Hu antibodies • Difficulty in treating these T-cell–mediated disorders with strategies directed at humoral immune response • Extensive T-cell infiltrates in CNS

Clinical Features ■

■

■

■

There is a rapid development of symptoms and signs of inflammation in the CSF,5 including moderate lymphocytic pleocytosis (30–40 cells/mL), an elevated protein concentration (50–100 mg/dL), a high IgG index, and CSF-specific oligoclonal bands15 Neurologic symptoms are the first manifestation of tumor in 70% of patients with PND; 70% to 80% of these patients are found to have cancer on initial screening.5 Symptoms are progressive over weeks to months followed by stabilization. In 80% of patients with no known cancer history who develop a PND, cancer is usually diagnosed within months to years.16

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130 Chapter 7

Diagnosis Diagnostic Criteria (Figure 7-1)17 Definite PND ■ Classic syndrome with cancer diagnosed within 5 years of neurologic symptom development ■ Nonclassic syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission ■ Nonclassic syndrome with cancer diagnosed within 5 years of neurologic symptom development and positive neuronal antibodies ■ Neurologic syndrome (classic or not) without cancer and with well-characterized antineuronal antibodies (Hu, Yo, CV2/CRMP5, Ri, Ma2, or amphiphysin) Possible PND ■ Classic syndrome with high risk of cancer, without antineuronal antibodies ■ Neurologic syndrome (classic or not) without cancer and with partly characterized antineuronal antibodies

Figure 7-1: Paraneoplastic diagnosis flowchart. Graus F, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135–1140.

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Paraneoplastic Disorders 131 ■

Nonclassic syndrome with cancer diagnosed within 2 years of neurologic symptom development, without neuronal antibodies

Diagnostic Workup18 ■ If PND is suspected, the initial workup should include MRI, neurophysiologic studies, CSF studies, including paraneoplastic antibody testing, and serum paraneoplastic antibody testing. ■ If paraneoplastic antibodies are present or clinical suspicion is high, the workup should also include cancer screening. • In general, a full-body CT scan and an FDG-PET scan are recommended. • For breast cancer-associated syndromes, a careful breast examination and mammography are also recommended. • For gynecologic-associated syndromes (i.e., anti-Yo– associated paraneoplastic cerebellar degeneration), a careful pelvic examination and pelvic ultrasound are also recommended. • For testicular-associated syndromes (i.e., anti-Ma2– associated limbic encephalitis in young men), a testicular ultrasound is also recommended. • If an ovarian or testicular malignancy is strongly suspected but not found on screening, some advocate elective oophorectomy or orchidectomy.19 • For neuroblastoma-associated opsoclonus-myoclonus, when conventional imaging is negative, metaiodobenzylguanidine whole-body scintigraphy may identify occult cases.20 ■ If a tumor is not initially detected, continued surveillance at regular intervals is necessary.18

Common Paraneoplastic Disorders (Table 7-1) Paraneoplastic Cerebellar Degeneration ■ Commonly associated tumors: SCLC, gynecologic cancers, breast cancers, Hodgkin lymphoma5 ■ Clinical features

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Syndrome

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Breast cancer Gynecologic cancers Small cell lung cancer

Paraneoplastic cerebellar degeneration

Brainstem encephalitis

Opsoclonus-myoclonus

Breast cancer

Anti-Ri (ANNA-2)

Gynecologic cancers

Others

Small cell lung cancer

Paraneoplastic cerebellar degeneration

Autonomic dysfunction

Paraneoplastic sensory neuronopathy

Myelitis

Paraneoplastic cerebellar degeneration

Paraneoplastic encephalomyelitis, including cortical, limbic, brainstem encephalitis

Associated Tumors

Anti-Yo (PCA-1)

Anti-Hu (ANNA-1)

Well-characterized paraneoplastic antibodies (identified by several investigators)

Antibody

Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors

(Continues)

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Others

Antiamphiphysin

Anti-Ma proteins (Ma2, Ma1)

Thymoma

Chorea

Nonsmall cell lung cancer

Infrequently paraneoplastic cerebellar degeneration

Breast cancer

Myelopathy

Limbic encephalitis

Small cell lung cancer

Stiff-person syndrome

Paraneoplastic encephalomyelitis

Other solid tumors

Germ cell tumors of testis

Limbic, hypothalamic, brainstem encephalitis

Peripheral neuropathy

Optic neuritis

Uveitis

Small cell lung cancer

Paraneoplastic encephalomyelitis

Paraneoplastic cerebellar degeneration

Anti-CV2/CRMP5

Associated Tumors

Syndrome

Antibody

Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors (Continued)

(Continues)

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Syndrome

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Paraneoplastic cerebellar degeneration

Paraneoplastic cerebellar degeneration

Various paraneoplastic disorders of the CNS

Various paraneoplastic disorders of the CNS

Anti-Zic 4

mGluR1

ANNA3

PCA2

Anti-NR1/NR2 of NMDA receptor

Characteristic encephalitis with prominent psychiatric symptoms, memory loss, decreased consciousness with frequent hypoventilation, autonomic instability, dyskinesias

Antibodies that occur with and without cancer association

Paraneoplastic cerebellar degeneration

Anti-Tr

Partly characterized paraneoplastic antibodies

Antibody

Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors (Continued)

(Continues)

Teratoma (usually in the ovary)

Small cell lung cancer

Small cell lung cancer

Hodgkin lymphoma

Small cell lung cancer

Hodgkin lymphoma

Associated Tumors

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Lambert-Eaton myasthenic syndrome

Others

Modified from Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327–340.

Others

Limbic encephalitis

Thymoma

Stiff-person syndrome

Cerebellar ataxia

Anti-GAD

Others

Small cell lung cancer

Subacute pandysautonomia

Anti-nAChR

Thymoma

Small cell lung cancer

Myasthenia gravis

Paraneoplastic cerebellar degeneration

Anti-AChR

Anti-VGCC

Others

Small cell lung cancer

Other

Thymoma

Limbic encephalitis

Peripheral nerve hyperexcitability (neuromyotonia)

Anti-VGKC

Associated Tumors

Syndrome

Antibody

Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors (Continued)

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• Gait unsteadiness rapidly progresses into truncal and appendicular ataxia, nystagmus, diplopia, dysarthria, dysphagia • Occasionally prodromal symptoms (viral-like illness, dizziness, nausea, or vomiting) before the onset of neurologic signs that might be attributed to a vestibular process21 • Neurologic symptoms that begin abruptly, progress over weeks to months, and then stabilize but usually leave the patient significantly impaired • Occasionally blurry vision, oscillopsia, and transient opsoclonus5 • Anti-Yo, anti-Hu, anti-CRMP5 associated with more severe neurologic deficits5 CSF studies: may show signs of inflammation with elevated protein, lymphocytic pleocytosis, and oligoclonal banding Imaging • Early stages ■ The MRI is initially normal in most patients, although some may have transient diffuse cerebellar hemispheric enlargement or cortical-meningeal enhancement.22 ■ A fluorodeoxyglucose PET may show cerebellar hypermetabolism.23 • Later stages ■ An MRI shows cerebellar atrophy. ■ A PET shows hypometabolism. Differential diagnosis includes • Alcohol-related cerebellar degeneration • Infectious or postinfectious cerebellitis • Cerebellar metastasis • Vitamin deficiency (thiamine, vitamin E) • Toxins (antiepileptic agents, chemotherapy-related agents such as fluorouracil or cytarabine) • Creutzfeldt-Jakob disease (12% to 15% of patients with CNS PND have 14-3-3 protein in CSF24) • Glutamic acid decarboxylase (GAD)-associated cerebellar degeneration: slower progression than paraneoplastic

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cerebellar degeneration, milder and asymmetric limb ataxia (mainly affecting gait), associated with endocrine dysfunction (insulin-dependent diabetes, thyroiditis, pernicious anemia),25 may be associated with transient or self-limited muscle spasms26 Pathology: extensive loss of Purkinje cells Serologic testing • Gynecologic cancer or breast cancer is often associated with anti-Yo (cdr2).5 ■ Anti-Yo has high syndrome specificity. ■ Patients with anti-Yo usually have a significant longterm disability because of irreversible Purkinje cell destruction.27,28 • Hodgkin lymphoma is often associated with anti-Tr.29 ■ Anti-Tr has high syndrome specificity. ■ It is more commonly present in young men. • SCLC is associated with one or multiple antibodies: 41% develop antibodies against voltage-gated calcium channels with or without associated LEMS, 23% develop anti-Hu, and the minority develop antibodies against other targets (CRMP or CV2, amphiphysin, PCA2, ANNA3).5 Treatment • There is no standard of care. • The treatment of the underlying tumor is necessary for stabilization or symptom improvement. • Immunotherapy (corticosteroids, plasma exchange, intravenous immunoglobulin, cyclophosphamide, tacrolimus) does not substantially modify the neurologic outcome in patients whose tumors are successfully treated.5 • There are case reports where immunotherapy benefitted.30,31 ■ Patients with anti-Yo who improved were treated within 1 month of symptom onset and usually received concurrent cancer therapy.31 Prognosis • Antibodies associated with more severe neurological deficits (Yo, Hu, CRMP5) are the most refractory to treatment.5

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138 Chapter 7 • The median survival from time of PND diagnosis (defined as first positive antineuronal antibody result)28 is as follows: ■ Anti-Yo 13 months ■ Anti-Hu 7 months ■ Anti-Tr .113 months ■ Anti-Ri .69 months • Patients who received tumor treatment lived longer than those who did not, regardless of whether they also received immunotherapy or not.28 Paraneoplastic Opsoclonus-Myoclonus ■ Commonly associated tumors: SCLC, breast cancer, ovarian cancer in adults; neuroblastoma in children ■ Clinical features • Opsoclonus: involuntary, arrhythmic, chaotic, multidirectional saccades with horizontal, vertical and torsional components—may be constant, even during sleep • Myoclonic jerks involving limbs and trunk • Cerebellar ataxia, most often in children • Tremor • Encephalopathy ■ CSF Studies: may show mild pleocytosis ■ Imaging: brain MRI may be normal ■ Differential diagnosis: opsoclonus-myoclonus associated with infectious, toxic-metabolic disorders ■ Pathology: disinhibition of fastigial nucleus of cerebellum may be involved32,33 ■ Laboratory abnormalities • Most patients are antibody negative. • Anti-Ri ■ Found in a small subset of adults (usually with breast or ovarian cancer) with paraneoplastic brainstem and cerebellar dysfunction34 ■ Opsoclonus often present but not always35,36 • In neuroblastoma-associated opsoclonus-myoclonus, no consistent specific autoantibodies have been isolated, although antibodies to surface proteins in cerebellar granular neurons have been reported.37,38

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Treatment • Pediatric cases ■ Opsoclonus often responds to immunotherapies (corticosteroids, adrenocorticotropic hormone, intravenous immunoglobulin, plasma exchange, cyclophosphamide, rituximab).39 ■ There is a high frequency of residual motor, speech, behavioral, and sleep disorders.40 ■ Symptoms can relapse during illnesses. • Adult cases ■ There is improvement with tumor control.41 ■ Improvement with immunotherapy is only mild or not sustained unless the tumor is controlled.42 Prognosis • In children, neurologic symptoms may resolve spontaneously or with treatment, but may relapse.43 • In adults, partial or complete neurologic recovery may be seen with treatment of the underlying tumor.41

Paraneoplastic Limbic Encephalitis ■ Commonly associated tumors: SCLC, testicular germ-cell neoplasms, thymoma, Hodgkin lymphoma, and ovarian teratoma44 ■ Clinical features • Similar to nonparaneoplastic limbic encephalitis • Mood disturbances • Sleep disturbances • Seizures • Hallucinations • Short-term memory loss that can progress to dementia44 ■ CSF studies: may show signs of inflammation with elevated protein, lymphocytic pleocytosis, oligoclonal banding ■ Imaging and other studies • An EEG typically demonstrates foci of epileptic activity in one or both temporal lobes or focal or generalized slow activity.45 • A brain MRI typically demonstrates FLAIR or T2 hyperintensity in one or both mesial temporal lobes,44,45

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although these areas rarely demonstrate gadolinium enhancement. • A PET may demonstrate hypermetabolism in one or both temporal lobes that can precede MRI changes or clinical symptoms.46 The differential diagnosis includes • Viral encephalitis, including herpes simplex virus: the course is more rapid and severe than paraneoplastic limbic encephalitis • Encephalitis associated with rheumatic disease such as systemic lupus erythematous and Sjogren syndrome. • Primary autoimmune limbic encephalitis: some may be associated with antibodies to voltage-gated potassium channels without an underlying tumor.47,48 Laboratory abnormalities • Anti-Hu ■ Patients develop extensive or multifocal encephalomyelitis, which may begin as limbic encephalitis or cerebellar degeneration.5 ■ SCLC is the most commonly associated tumor, but only 50% of patients with SCLC and limbic encephalitis have anti-Hu antibodies. • Anti-CRMP5 (anti-CV2) ■ The disease is rarely confined to the limbic system because the antibody is also associated with encephalomyelitis, sensorimotor neuropathy, cerebellar ataxia, chorea, uveitis, and optic neuritis.5 ■ SCLC and thymoma are the most commonly associated tumors. • Anti-Ma2 (Ta) ■ This typically affects the limbic system, hypothalamus, and brainstem, resulting in limbic dysfunction as well as excessive daytime sleepiness, narcolepsy, cataplexy, REM-sleep abnormalities, hyperphagia, hypothalamic–pituitary hormone deficits, and supranuclear gaze palsy.5 ■ This may resemble CNS Whipple disease.49 ■ The commonly associated tumors are as follows: • In men less than 50 years old, anti-Ma2 encephalitis is almost always associated with testicular

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germ-cell tumors, which can be microscopic and difficult to diagnose.50 • In older men and women, NCLC and breast cancer are more common.5 • Anti-VGKC (voltage-gated potassium channels) ■ The two main CNS syndromes are as follows: • Limbic encephalitis • More diffuse encephalitis with psychiatric symptoms, hallucinations, peripheral nerve hyperexcitability, autonomic dysfunction (e.g., hyperhydrosis)5 ■ REM sleep disturbances and hyponatremia are common.51 ■ Approximately 30% with anti-VGKC have tumors. ■ CSF shows less pleocytosis, lower protein concentration, less intrathecal synthesis of IgG compared with other paraneoplastic disorders, or immunemediated limbic encephalitis.5 ■ Anti-SOX antibodies may help differentiate paraneoplastic limbic encephalitis from the nonparaneoplastic form. • Anti-NMDA receptors ■ This typically affects young women. ■ Patients first develop prodromal syndromes (including headache, fever, or viral-like illness) and then progress to develop severe psychiatric symptoms or memory loss, seizures, decreased consciousness associated with dyskinesias, hypoventilation, or autonomic instability.5 ■ Approximately 65% have an underlying tumor, usually a cystic ovarian teratoma (mature or immature). Treatment • For anti-Hu associated limbic encephalitis, early treatment can result in substantial and prolonged recovery.52 • For anti-CRMP5, treatment response is generally poor.53 • For anti-Ma2–associated limbic encephalitis in men with a testicular germ-cell tumor, treatment includes

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orchiectomy and immunotherapy (corticosteroids and intravenous immunoglobulin). • For anti-VGKC–associated limbic encephalitis, treatment includes corticosteroids, plasma exchange, or intravenous immunoglobulin. About 80% respond to treatment.5 • For patients with limbic encephalitis caused by ovarian teratoma and antibodies against NMDA receptors, an unstable clinical condition may hinder teratoma removal. ■ Immunotherapy (corticosteroids, plasma exchange, intravenous immunoglobulin, rituximab or cyclophosphamide) often results in sufficient improvement to enable tumor removal.54 ■ Patients who do not respond to one form of immunotherapy may respond to another. ■ Improvement may be slow and take several months. ■ Tumor removal speeds up recovery and decreases the relapse rate. Prognosis • In patients with SCLC, the prognosis is worse in patients without anti-Hu antibodies than patients with anti-Hu antibodies.55 • For anti-Hu-associated limbic encephalitis, early treatment can result in substantial and prolonged recovery.52 • For anti-Ma2-associated limbic encephalitis, 35% have neurologic responses to treatment.5 • For anti-VGKC-associated limbic encephalitis, the prognosis is worse in patients with lung cancer than those without lung cancer.56 • For patients with limbic encephalitis caused by ovarian teratoma and antibodies against NMDA receptors, 65% have near or full recovery.57

Stiff-Person Syndrome ■ This syndrome may be idiopathic or paraneoplastic. ■ The commonly associated tumors are breast cancer, SCLC, and Hodgkin lymphoma.

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The nonparaneoplastic variant is also autoimmune, associated with glutamic acid decarboxylase antibodies, and usually affects patients with other autoimmune diseases, especially diabetes mellitus type I.58 Clinical features are as follows: • Gradual onset of stiffness and rigidity, initially in axial muscles and progressing to proximal limb muscles, primarily involving the legs • EMG that demonstrates continuous motor unit activity in affected muscles • Paraspinal muscle rigidity that may lead to lumbar hyperlordosis, difficulty ambulating, and frequent falls • Continuously contracting antagonist muscles that cause a rock-hard or board-like sensation to palpation • Sudden, painful muscle spasms usually precipitated by touch or involuntary movement, sudden loud noise, or emotional stress59 CSF studies are usually normal.60 MRI studies are usually normal.60 The differential diagnosis includes tetanus, hyperekplexia, and myelopathy. Laboratory abnormalities are as follows: • Amphiphysin antibodies are most commonly detected in the paraneoplastic form. • There are reports of anti-GAD in paraneoplastic stiffperson syndrome, but this antibody is most commonly found in the nonparaneoplastic form. Treatment • Intravenous immunoglobulin proven effective in two placebo-controlled studies in nonparaneoplastic SPS and reported effective in paraneoplastic SPS in a few case reports61 • Dramatic response to diazepam in relieving stiffness62

Paraneoplastic Visual Syndromes Cancer-Associated Retinopathy (CAR) ■ CAR presents with progressive, painless visual loss, photosensitivity, peripheral and ring scotomata, and flickering, light-induced glare.

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An electroretinogram demonstrates evidence of coneand rod-mediated abnormalities. A funduscopic examination may demonstrate arteriolar narrowing.63 Antirecoverin is the most commonly associated antibody, usually in patients with SCLC.64

Melanoma-Associated Retinopathy (MAR) ■ MAR presents as an abrupt onset night blindness and flickering light phenomena with normal visual acuity.63 ■ Symptoms generally develop long after a diagnosis of melanoma, usually in the setting of tumor progression. ■ The exact target antigen is unknown. Paraneoplastic Optic Neuropathy ■ This typically presents with unilateral painless vision loss progressing to involve both eyes.63 ■ It is usually associated with encephalomyelopathy. ■ Anti-CMRP5 is the most commonly associated antibody, usually in patients with SCLC.65 Paraneoplastic Motor Neuron Disease ■ It is usually idiopathic. ■ There are rare case reports of association with solid tumors and motor neuron disease.18 ■ There is a slightly higher incidence of lymphoproliferative disorders (including Hodgkin lymphoma, non-Hodgkin lymphoma, Waldenström macroglobulinemia, multiple myeloma, chronic lymphocytic leukemia) in patients with motor neuron disease.18 ■ For both solid tumors and lymphoproliferative disorders, patients rarely recover despite treatment of the underlying tumor/disorder. Peripheral Neuropathy ■ Causes in cancer patients • More commonly caused by toxic-metabolic disorders (i.e., chemotherapy, diabetes, malnutrition) • Paraneoplastic peripheral neuropathy (i.e., subacute sensory neuronopathy)

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Classic paraneoplastic peripheral neuropathy Commonly associated tumor: SCLC (70% to 80% of cases67), Hodgkin lymphoma Clinical features68 • Subacute onset and rapidly progressive, although an indolent course has been reported69 • Asymmetric, multifocal pain and paresthesias, initially involving arms but progressing to include all extremities • Sensory ataxia and pseudoathetoid movements of the hands • Neuropathy isolated in only 24% of patients with anti-Hu, others have various combinations of central nervous system (e.g., encephalomyelitis, limbic encephalitis) and peripheral nervous system involvement70 CSF studies: elevated protein, pleocytosis, oligoclonal bands67 EMG/NCS: small or absent sensory nerve action potentials18 Pathophysiology: destruction of dorsal root ganglia by cytotoxic T-lymphocytes71 Laboratory testing: anti-Hu 99% specific and 82% sensitive for cancer diagnosis in patients with subacute sensory neuropathy66 Treatment • Tumor therapy • No clear benefit to immunosuppressive treatment Prognosis • Poor despite immunosuppressive treatment18 • Possible stabilization if tumor therapy initiated early

Paraneoplastic Sensory or Sensorimotor Neuropathy ■ Commonly associated tumors: SCLC or thymoma ■ Clinical features • Often with CNS dysfunction (i.e., cerebellar ataxia, limbic encephalitis, or ocular involvement) • Predominates in lower limbs

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EMG/NCS: axonal or mixed axonal/demyelinating pattern Laboratory testing: anti-CV2 (peripheral neuropathy occurs in 57% of patients with anti-CV2 antibodies67)

Paraproteinemic Neuropathy ■ Not included in diagnostic criteria but often considered paraneoplastic17 ■ Commonly associated with plasma cell dyscrasias, including • Monoclonal gammopathy of undetermined significance (MGUS): associated with a polyneuropathy that may improve with treatment of MGUS72 • Multiple myeloma: neuropathy that may be associated with amyloidosis (painful sensory or sensorimotor neuropathy mainly affecting small fibers73) or type 1 cryoglobulinemia • POEMS syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes ■ Associated with osteosclerotic myeloma ■ Primarily demyelinating and sensorimotor neuropathy similar to chronic inflammatory demyelinating polyneuropathy (CIDP)74 • Waldenström macroglobulinemia (lymphoplasmacytic lymphoma) ■ Monoclonal IgM antibodies against myelin-associated glycoprotein (anti-MAG) associated with chronic, distal, symmetric, large and small fiber, predominantly demyelinating polyneuropathy ■ Monoclonal IgM antibodies against sulfatide associated with more profound symptoms, sensory or sensorimotor neuropathy67 ■ Monoclonal IgM antibodies against disialosyl gangliosides associated with predominantly sensory neuropathy and ophthalmoplegia75 ■ Monoclonal IgM antibodies against GM1 associated with multifocal motor neuropathy67

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Autonomic Neuropathy Rarely occurs in isolation, most commonly with limbic encephalitis and subacute sensory neuronopathy in patients with SCLC or with LEMS in patients with voltage-gated calcium channel antibodies74 ■ Clinical features • Chronic gastrointestinal pseudo-obstruction caused by destruction of autonomic neurons in myenteric plexuses • Orthostatic hypotension • Bladder dysfunction • Impotence • Sudomotor alterations • Absence of heart rate variability ■

Neuromyotonia ■ Idiopathic or paraneoplastic ■ Commonly associated tumors: thymoma, SCLC, rarely Hodgkin lymphoma18 ■ Clinical features • Muscle twitching and myokymia (continuous, undulating, ripple of muscles described as a bag of worms) • Stiffness • Painful cramps worse with muscle contraction • Hyperhidrosis • Muscle hypertrophy • Pseudomyotonia (slow relaxation of muscle after contraction without percussion myotonia) ■ EMG/NCS: spontaneous, continuous, high-frequency (150–300 Hz) doublet, triplet or multiple single motor unit discharges76 ■ Laboratory abnormalities • Antibodies to voltage-gated potassium channels (VGKC) often present in autoimmune and paraneoplastic neuromyotonia • Anti-Hu antibodies in SCLC reported77

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Treatment • Responds well to plasma exchange more than intravenous immunoglobulin78 • Symptomatic treatment with anticonvulsants such as phenytoin and carbamazepine Prognosis: may remit after tumor treatment

Lambert-Eaton Myasthenic Syndrome Idiopathic or paraneoplastic, underlying malignancy in 60% of cases79 ■ Commonly associated tumor: SCLC (LEMS affects 3% of patients with SCLC)80 ■ Clinical features • Proximal muscle weakness (usually legs worse than arms) • Generalized fatigue • Depressed tendon reflexes • Autonomic dysfunction ■ Dry mouth ■ Eye dryness, blurred vision ■ Impotence ■ Constipation ■ Impaired sweating ■ Orthostatic hypotension • Improved strength and tendon reflexes with exercise • Very rarely ocular and bulbar muscle involvement • Respiratory muscle weakness as a late complication but rare ■ EMG/NCS • Decreased CMAP amplitudes with repetitive nerve stimulation between 1 to 5 Hz • More than 100% increment in CMAP amplitudes after repetitive nerve stimulation at 20 Hz or greater or after brief maximal effort • Normal motor and sensory latencies and conduction velocities • Jitter on single-fiber EMG ■ Pathology: antibodies to presynaptic P/Q voltage-gated calcium channels preventing calcium influx into the cell and acetylcholine release ■

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Laboratory abnormalities • P/Q voltage-gated calcium channel (VGCC) antibodies present in almost 100% of patients with cancer and 90% without cancer81 • Anti-SOX antibodies found in 65% of patients with cancer-associated LEMS and may help differentiate paraneoplastic from nonparaneoplastic LEMS82 Treatment • Treatment of the underlying malignancy is important. • Immunotherapy without treatment of underlying tumor usually produces little or no improvement in strength.83 • 3,4-Diaminopyridine improves strength regardless of etiology.84 Prognosis: LEMS may remit with tumor therapy, good response to treatment.

Myasthenia Gravis Idiopathic or paraneoplastic (10% to 15%)18 ■ Commonly associated tumor: thymoma (up to 40% of patients with thymoma will develop MG85) ■ Clinical features • Weakness: ocular and bulbar symptoms predominate, may progress to generalized weakness • Normal deep tendon reflexes • No associated autonomic features • Muscle fatigability, noticeable to patients later in the day or with prolonged use, which may be elicited on examination through repetitive confrontational strength testing or sustained upgaze (extraocular muscles) ■ EMG/NCS • Greater than 10% CMAP amplitude decrement after exercise or with repetitive nerve stimulation at 2 to 5 Hz76 • Jitter on single-fiber EMG ■ Pathology: antibodies against postsynaptic acetylcholine receptor, resulting in activation of complement, accelerated receptor degradation, or blocking of acetylcholine receptor binding86 ■

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Laboratory abnormalities18 • Anti-acetylcholine receptor (AChR) antibodies are found in 80% to 90% of patients with MG and almost all patients with thymoma-associated MG. • Anti-titin antibodies and anti-ryanodine antibodies are also associated with thymoma-associated MG. Treatment • All patients with MG should have CT or MRI of the anterior mediastinum to look for thymoma. • A select population should have a thymectomy. • Short-term symptomatic treatment should include acetylcholinesterase inhibitors. • Long-term symptomatic control may be achieved with immunosuppression. • Exacerbations or myasthenic crisis may be managed with intravenous immunoglobulin and/or plasma exchange. Prognosis • The presence of thymoma is a poor prognostic factor in MG. • Long-term neurologic outcome is similar to patients with nonthymomatous MG with early thymectomy.87

Inflammatory Myopathies Polymyositis ■ Idiopathic or paraneoplastic, increased risk of malignancy ■ Commonly associated tumors: non-Hodgkin lymphoma, lung cancer, bladder cancer88 ■ Clinical features: symmetrical proximal muscle weakness ■ EMG/NCS: small polyphasic motor unit potentials and abnormal spontaneous activity ■ Pathophysiology: T-cell mediated ■ Laboratory abnormalities • Elevated creatine kinase • Autoantibodies found in idiopathic polymyositis (antiJo-1, anti-OJ, anti-Mi-2) less commonly found in paraneoplastic polymyositis18

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Treatment: same as idiopathic polymyositis. Immunosuppression with corticosteroids, intravenous immunoglobulin, plasma exchange, immunomodulatory drugs (methotrexate, azathioprine, cyclosporine, mycophenolate mofetil), TNF-a inhibitors (infliximab, etanercept) Prognosis: good response to treatment

Dermatomyositis ■ Idiopathic or paraneoplastic, increased risk of malignancy (higher than polymyositis) ■ Commonly associated tumors: ovarian, lung, gastric, colorectal, pancreatic cancers, non-Hodgkin lymphoma88 ■ Clinical features: symmetrical proximal muscle weakness with characteristic skin changes (purplish heliotrope rash of the eyelids, Grotton’s sign, photosensitive erythematous rash of chest and shoulders) ■ EMG/NCS: small polyphasic motor unit potentials and abnormal spontaneous activity ■ Pathophysiology: complement-mediated intramuscular microangiopathy leading to ischemia, muscular fiber necrosis, and perifascicular atrophy89 ■ Laboratory abnormalities • Creatine kinase may be elevated. • Patients with interstitial lung disease may have anti-Jo 1.68 ■ Treatment: same as idiopathic polymyositis. Immunosuppression with corticosteroids, intravenous immunoglobulin, plasma exchange, immunomodulatory drugs (methotrexate, azathioprine, cyclosporine, mycophenolate mofetil), TNF-a inhibitors (infliximab, etanercept) ■ Prognosis: good response to treatment Inclusion Body Myositis ■ Idiopathic or paraneoplastic ■ Clinical features: distal weakness ■ EMG/NCS: small polyphasic motor unit potentials and abnormal spontaneous activity ■ Pathology: rimmed vacuoles, congophilic inclusions

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Laboratory abnormalities: mildly elevated or normal creatine kinase Treatment: generally unresponsive to corticosteroids or immunosuppressive drugs. Intravenous immunoglobulin may be beneficial in a small number of cases. Prognosis: generally resistant to therapies.

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Sutton IJ, Barnett MH, Watson JD, Ell JJ, Dalmau J. Paraneoplastic brainstem encephalitis and anti-Ri antibodies. J Neurol. 2002;249(11):1597–1598. Blaes F, Fuhlhuber V, Korfei M, et al. Surface-binding autoantibodies to cerebellar neurons in opsoclonus syndrome. Ann Neurol. 2005;58(2):313–317. Korfei M, Fuhlhuber V, Schmidt-Woll T, Kaps M, Preissner KT, Blaes F. Functional characterisation of autoantibodies from patients with pediatric opsoclonus-myoclonussyndrome. J Neuroimmunol. 2005;170(1–2):150–157. Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol. 2006;28(9):585–593. Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al. Opsoclonus-ataxia caused by childhood neuroblastoma: developmental and neurologic sequelae. Pediatrics. 2002; 109(1):86–98. Bataller L, Graus F, Saiz A, Vilchez JJ. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonusmyoclonus. Brain. 2001;124(Pt 2):437–443. Erlich R, Morrison C, Kim B, Gilbert MR, Alrajab S. ANNA-2: an antibody associated with paraneoplastic opsoclonus in a patient with large-cell carcinoma of the lung with neuroendocrine features—correlation of clinical improvement with tumor response. Cancer Invest. 2004;22(2):257–261. Wong A. An update on opsoclonus. Curr Opin Neurol. 2007;20(1):25–31. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123(Pt 7):1481–1494. Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S. Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc. 2003;78(11):1363–1368. Scheid R, Lincke T, Voltz R, von Cramon DY, Sabri O. Serial 18F-fluoro-2-deoxy-D-glucose positron emission tomography and magnetic resonance imaging of paraneoplastic limbic encephalitis. Arch Neurol. 2004;61(11): 1785–1789. Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S. Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology. 2004;62(7):1177–1182.

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Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004;127(Pt 3):701–712. Castle J, Sakonju A, Dalmau J, Newman-Toker DE. AntiMa2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple’s disease. Nat Clin Pract Neurol. 2006;2(10):566–572; quiz 573. Mathew RM, Vandenberghe R, Garcia-Merino A, et al. Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis. Neurology. 2007; 68(12):900–905. Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eyemovement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol. 2006;5(7):572–577. Fadul CE, Stommel EW, Dragnev KH, Eskey CJ, Dalmau JO. Focal paraneoplastic limbic encephalitis presenting as orgasmic epilepsy. J Neurooncol. 2005;72(2):195–198. Tuzun E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist. 2007; 13(5):261–271. Shimazaki H, Ando Y, Nakano I, Dalmau J. Reversible limbic encephalitis with antibodies against the membranes of neurones of the hippocampus. J Neurol Neurosurg Psychiatry. 2007;78(3):324–325. Alamowitch S, Graus F, Uchuya M, Rene R, Bescansa E, Delattre JY. Limbic encephalitis and small cell lung cancer: clinical and immunological features. Brain. 1997; 120 (Pt 6):923–928. Pozo-Rosich P, Clover L, Saiz A, Vincent A, Graus F. Voltagegated potassium channel antibodies in limbic encephalitis. Ann Neurol. 2003;54(4):530–533. Novillo-Lopez ME, Rossi JE, Dalmau J, Masjuan J. Treatment-responsive subacute limbic encephalitis and NMDA receptor antibodies in a man. Neurology. 2008; 70(9):728–729. Solimena M, Folli F, Denis-Donini S, et al. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med. 1988;318(16):1012–1020.

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Lockman J, Burns TM. Stiff-person syndrome. Curr Treat Options Neurol. 2007;9(3):234–240. Murinson BB. Stiff-person syndrome. Neurologist. 2004; 10(3):131–137. Pittock SJ, Lucchinetti CF, Parisi JE, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol. 2005;58(1):96–107. Lorish TR, Thorsteinsson G, Howard FM, Jr. Stiff-man syndrome updated. Mayo Clin Proc. 1989;64(6):629–636. Damek DM. Paraneoplastic retinopathy/optic neuropathy. Curr Treat Options Neurol. 2005;7(1):57–67. Bataller L, Dalmau J. Neuro-ophthalmology and paraneoplastic syndromes. Curr Opin Neurol. 2004;17(1):3–8. Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5IgG. Ann Neurol. 2003;54(1):38–50. Molinuevo JL, Graus F, Serrano C, Rene R, Guerrero A, Illa I. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol. 1998;44(6): 976–980. Antoine JC, Camdessanche JP. Peripheral nervous system involvement in patients with cancer. Lancet Neurol. 2007;6(1):75–86. Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the peripheral nerves. Curr Opin Neurol. 2005;18(5):598–603. Graus F, Bonaventura I, Uchuya M, et al. Indolent anti-Huassociated paraneoplastic sensory neuropathy. Neurology. 1994;44(12):2258–2261. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124(Pt 6):1138–1148. Kuntzer T, Antoine JC, Steck AJ. Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies). Muscle Nerve. 2004;30(3):255–268. Eurelings M, Lokhorst HM, Kalmijn S, Wokke JH, Notermans NC. Malignant transformation in polyneuropathy associated with monoclonal gammopathy. Neurology. 2005;64(12):2079–2084. Kelly JJ, Jr., Kyle RA, O’Brien PC, Dyck PJ. The natural history of peripheral neuropathy in primary systemic amyloidosis. Ann Neurol. 1979;6(1):1–7.

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Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood. 2003;101(7): 2496–2506. Kobayashi M, Kato K, Funakoshi K, Watanabe S, Toyoshima I. Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody. Muscle Nerve. 2005;32(2):216–222. American Association of Electrodiagnostic Medicine Quality Assurance Committee. Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome: summary statement. Muscle Nerve. 2001;24(9):1236–1238. Toepfer M, Schroeder M, Unger JW, Lochmuller H, Pongratz D, Muller-Felber W. Neuromyotonia, myocloni, sensory neuropathy and cerebellar symptoms in a patient with antibodies to neuronal nucleoproteins (anti-Huantibodies). Clin Neurol Neurosurg. 1999;101(3):207–209. van den Berg JS, van Engelen BG, Boerman RH, de Baets MH. Acquired neuromyotonia: superiority of plasma exchange over high-dose intravenous human immunoglobulin. J Neurol. 1999;246(7):623–625. Wirtz PW, Smallegange TM, Wintzen AR, Verschuuren JJ. Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases. Clin Neurol Neurosurg. 2002; 104(4):359–363. Elrington GM, Murray NM, Spiro SG, Newsom-Davis J. Neurological paraneoplastic syndromes in patients with small cell lung cancer: a prospective survey of 150 patients. J Neurol Neurosurg Psychiatry. 1991;54(9):764–767. Lennon VA. Serologic profile of myasthenia gravis and distinction from the Lambert-Eaton myasthenic syndrome. Neurology. 1997;48(Suppl 5):S23–S27. Sabater L, Titulaer M, Saiz A, Verschuuren J, Gure AO, Graus F. SOX1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology. 2008; 70(12):924–928. Sanders DB. Lambert-Eaton myasthenic syndrome: diagnosis and treatment. Ann N Y Acad Sci. 2003;998:500–508.

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Sanders DB, Massey JM, Sanders LL, Edwards LJ. A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology. 2000;54(3):603–607. Vernino S, Lennon VA. Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res. 2004;10(21): 7270–7275. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest. 2006;116(11): 2843–2854. Kim HK, Park MS, Choi YS, et al. Neurologic outcomes of thymectomy in myasthenia gravis: comparative analysis of the effect of thymoma. J Thorac Cardiovasc Surg. 2007; 134(3):601–607. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet. 2001;357(9250):96–100. Dalakas MC. Advances in the immunobiology and treatment of inflammatory myopathies. Curr Rheumatol Rep. 2007;9(4):291–297.

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C H A P T E R

8

Cerebrovascular Complications Introduction ■

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Conflicting data exist between autopsy and clinical series on whether cerebrovascular disease is elevated in cancer patients. • Based on a large autopsy series, cerebrovascular complications, including hemorrhages and infarctions, were the second most common CNS lesion in patients with cancer.1 • Based on large modern clinical series, the frequency of ischemic stroke was not elevated in cancer patients.2,3 • The risk of cerebral hemorrhages appears to be elevated in hematological malignancies.4 Although some of the causes of cerebrovascular disease in cancer patients may be similar to noncancer patients, there are several cancer-specific and treatment-related causes to be considered.

Ischemic Strokes Risk Factors in Cancer Patients ■ Similar risk factors as the noncancer population, including hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, smoking, and carotid artery disease ■ Additional risk factors in cancer patients that are treatment and/or disease related discussed later in this chapter Management of Ischemic Strokes in Cancer Patients ■ Guidelines for stroke management in cancer patients should generally follow recommendations for noncancer patients with special consideration of cancer-specific causes of stroke. 161

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• The American Stroke Association and American Heart Association have published guidelines for early management of adults with ischemic stroke.5 • The American Stroke Association and American Heart Association have published guidelines for secondary prevention of ischemic stroke.6 Patients with acute stroke symptoms should be urgently referred to the hospital for early management, including diagnosis, imaging, treatment of acute complications, and consideration of thrombolysis. After emergency department management, additional management may include the following: • Risk factor management includes hypertension, hyperlipidemia, and diabetes mellitus. • Noninvasive vessel imaging should be performed to look for vascular stenoses, dissections, and so forth. ■ Carotid duplex ultrasound (although does not provide information about intracranial vasculature) ■ CT angiogram ■ MR angiogram • A cardiac ultrasound should be performed to look for valvular abnormalities, left ventricular thrombus, and so forth. ■ A transthoracic echocardiogram may be sufficient, but if the suspicion for endocarditis is high, then a transesophageal echocardiogram may be more sensitive in detecting valvular vegetations. ■ If strokes appear embolic in origin and there is no left-sided source, then consider performing a bubble study with the cardiac ultrasound to look for a cardiac shunt. • If strokes appear embolic in origin and the patient has a patent foramen ovale, then venous studies should be considered, including lower-extremity Doppler ultrasound and pelvic MR venography (as pelvic veins may be an important source of paradoxical emboli).

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Treatment Considerations in Cancer Patients The American Stroke Association and American Heart Association have published guidelines for secondary prevention of stroke.6 ■ Additional considerations regarding thrombolysis in cancer patients include the following: • Further investigations are needed to determine the role of thrombolysis in cancer patients, as large studies of recombinant tissue plasminogen activator (rTPA) excluded patients with malignancy. • Case series have reported the use of thrombolysis in cancer patients.3 • Neither brain tumor nor cancer is an established exclusion criteria for thrombolysis. • Established exclusion criteria that may apply to cancer patients include thrombocytopenia (platelet count ,100,000), major surgery within 14 days, and a prior history of intracranial hemorrhage.5 ■

Embolism ■

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Signs and symptoms may not be limited to the CNS, as emboli may spread to multiple organs or extremities. The most common source of emboli in the general population is the heart (usually caused by atrial fibrillation). Other cancer-related causes of embolism are discussed later in this chapter.

Tumor Embolism ■ Rare cause of stroke in cancer patients ■ Common sources of tumor emboli include • Atrial myxomas and other cardiac tumors • Lung cancer: most often occurs within 48 hours of surgical manipulation of lung tissue but may also result form tumor invasion of pulmonary veins or the left atrium of the heart7

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164 Chapter 8 Nonbacterial Thrombotic Endocarditis (NBTE) Formerly known as marantic endocarditis ■ Defined as sterile vegetations on cardiac valves in the absence of bacteremia ■

Clinical Features ■ Cases have been reported in several malignancies, including lung (especially adenocarcinoma), pancreatic, gastric, breast, prostate, colorectal, ovarian, and thyroid.8 ■ Although more common in cancer patients, NBTE may also occur in patients with nonneoplastic hypercoagulable disorders such as antiphospholipid antibody syndrome. ■ NBTE may occur in association with disseminated intravascular coagulopathy (DIC). ■ Systemic emboli occur in nearly 50% of patients with NBTE.8 ■ Presenting signs and symptoms may depend on the site(s) of embolization. • Central nervous system infarcts may present as focal or diffuse neurologic symptoms depending on the location and number of emboli. • Renal infarcts may present as hematuria. • Splenic infarcts may present as left upper quadrant pain. • Peripheral artery emboli may present as a cold, cyanotic, or pulseless limb. ■ Cardiac murmurs are infrequently noted. Characteristics of Vegetations8 ■ The most commonly affected valves are the aortic and mitral valves. ■ Vegetations generally do not alter or impede valve function. ■ Vegetations contain degenerating platelets interwoven with strands of fibrin. ■ Vegetations observed in NBTE tend to detach and cause extensive infarction more readily than vegetations observed in infective endocarditis.

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Diagnosis An MRI is more sensitive and specific for diagnosing embolic strokes acutely than CT. ■ A two-dimensional echocardiogram is useful, but a transesophageal echocardiogram may be more sensitive in detecting valvular vegetations than a transthoracic echocardiogram. ■ Blood cultures are negative in NBTE. ■

Treatment Optimal treatment is not well established. ■ Anticoagulation has been reported to prevent recurrent embolism.8 • Several reports show successful management with unfractionated heparin. • Low molecular weight heparin may also be effective, although the experience is limited. • Recurrent thromboembolic events may occur on warfarin and therefore warfarin is not recommended. ■ Anticoagulation may need to be continued indefinitely. ■ Cardiac surgery may be indicated for severe valvular dysfunction and recurrent emboli despite anticoagulation.9 ■

Septic Embolism ■ Immunocompromised patients and leukemic patients are susceptible to septic infection, infectious endocarditis, and infectious vasculitis. ■ Causes include Aspergillus and Candida. ■ Infarctions may be multiple and/or hemorrhagic and may evolve into cerebral abscesses. Paradoxical Embolism Embolism of venous origin through cardiac shunt (e.g., patent foramen ovale [PFO], atrial septal defect [ASD], ventricular septal defect [VSD]) ■ Strokes in patients with PFOs cannot be assumed due to paradoxical embolism, as PFOs are common (detected in 20% to 35% of the general population at autopsy10). ■

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Diagnostic criteria for the diagnosis of paradoxical embolism11 • Cerebral or systemic embolism without a left-sided source • Presence of a venous thrombus or pulmonary embolism • Demonstration of a right-to-left shunt • Elevated right heart pressure, either constant elevation (e.g., pulmonary hypertension) or transient elevation (e.g., cough, Valsalva maneuver)

Thrombotic Disease (Including Small, Medium, and Large Vessel Disease) Postradiation Vasculopathy ■ Can affect intracranial and extracranial vessels ■ Typically involves medium and large vessels Internal Carotid Artery (ICA) Stenosis The frequency of ICA stenosis after external neck radiation ranges from 12% to 60%.12 ■ In a meta-analysis based on case series and retrospective studies, the odds of a cerebrovascular event after neck irradiation were 9.0 compared with nonirradiated patients.13 ■ Neck irradiation is associated with intimal damage with mural thrombosis formation in 5 years, fibrotic occlusion in 10 years, and atheroma formation with periarterial fibrosis in 20 years or more.14 ■ Other vascular pathologies after radiation have been described, including vascular malformations, aneurysm formation, and accelerated atherosclerosis.15 ■

Postoperative Complications ■ Neurosurgical patients with brain tumors have an increased risk of thromboembolic disease.16,17 ■ Adjacent ischemic lesions are found on MRI in about 70% of high-grade glioma patients after craniotomy.18

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Intravascular Lymphoma Also known as angiotropic large-cell lymphoma or malignant angioendotheliomatosis ■ Rare type of non-Hodgkin lymphoma, typically a large B-cell lymphoma, characterized by selective growth of neoplastic cells within the lumina of small- and mediumsized blood vessels ■

Clinical Features ■ Typically disseminated, although clinical presentations often different depending on geographical location of patient ■ In Western countries, propensity to manifest more frequently in the central nervous system and skin19 • The central nervous system is affected in almost two thirds of cases in Western patients with IVL.20 • Neurologic manifestations depend on location of involvement but may include multifocal cerebrovascular events, dementia, subacute encephalopathy, seizures, and myelopathy. • Neurologic signs are caused by obliteration of vessels and may transiently respond to corticosteroid treatment. ■ In Asian countries, often presents as a hemophagocytic syndrome (bone marrow involvement, fever, hepatosplenomegaly, thrombocytopenia)21 Diagnosis Suggested workup based on international consensus meeting22 • Physical examination with emphasis on nervous system and skin (suspicious skin lesions should be referred for biopsy) • Routine blood studies, including hepatic, pulmonary, renal, and thyroid function tests (with any abnormal results further investigated by imaging or biopsy) • Peripheral blood smear

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• Body CT with contrast • Brain MRI with contrast • Lumbar puncture for CSF examination and cytology • Bone marrow biopsy • Possibly PET study Laboratory findings are not specific and may include anemia, increased serum lactate dehydrogenase, and increased b2-microglobulin levels. CSF may demonstrate elevated protein and pleocytosis, with lymphona cells ancedotally reported in cases. Neuroimaging and body CT are associated with a relatively high proportion of false negatives.19 A brain MRI may demonstrate multiple infarct-like lesions in the white matter, focal parenchymal enhancement, dural and arachnoid enhancement, and vasculitislike lesions.23

Treatment Limited data on best treatment options, although international consensus guidelines have been published22 ■ Anthracycline-based chemotherapy recommended by consensus panel, although a more intensive regimen with greater CNS penetration is needed in patients with CNS involvement ■

Prognosis Commonly fatal disease characterized by an aggressive course and short outcome with few long-term survivors reported19 ■ Aggressive chemotherapy early in the disease process increases survival24 and therefore early diagnosis important ■

Hyperviscous Obstruction ■ Hyperviscosity may be caused by an increase in serum proteins or an increase in cells. ■ Symptoms from hyperviscosity usually occur at a serum viscosity greater than 5 centipoises (normal serum viscosity is between 1.4 and 1.8 centipoises).25 ■ Symptoms of hyperviscosity include

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• Spontaneous bleeding from mucous membranes • Visual disturbances caused by retinopathy • Neurologic symptoms, including headaches, vertigo, seizures, altered consciousnesses, and cerebral infarction Cerebral infarction caused by hyperviscous obstruction is rarely seen with polycythemia vera, acute myelogenous leukemia (cell count .100,000 mm3), chronic lymphatic leukemia (cell count .250,000 mm3), and multiple myeloma.4

Intracranial Hemorrhages Types of Intracranial Hemorrhages Intraparenchymal Hemorrhage ■ This occurs more frequently in hematological malignancies, especially acute myelogenous leukemia, and in patients with coagulation disorders.4 ■ This may occur as a result of venous infarction (see cerebral venous thrombosis section later in this chapter). ■ Other causes include hypertension and cerebral amyloid angiopathy. Intratumoral Hemorrhage ■ Hemorrhage can be the presenting sign of a brain mass. • Can obscure the tumor’s appearance on imaging studies • Neuroimaging clues to an underlying tumor include ■ More perifocal edema than expected for the hemorrhage ■ Hemorrhage in unusual locations (e.g., close to the subarachnoid space) ■ Pattern of contrast enhancement not expected for the age of the hemorrhage ■ CNS metastases • The risk of bleeding into CNS metastases varies according to histology. • Brain metastases from lung cancer, especially bronchogenic carcinoma, are the most common hemorrhagic

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lesions because they occur in greater numbers; however, fewer than 1% of brain metastases are from lung cancer bleed.26 • The risk of bleeding into CNS metastases is high in thyroid cancer, melanoma (40% to 50%), renal cell carcinoma (70%), and choriocarcinoma.26 Primary brain tumors • The reported rates in primary brain tumors range from 0.6% to 14.6% with the majority of cases involving high-grade astrocytomas and oligodendrogliomas.27 • Intracranial hemorrhage rates in patients with meningiomas range from 1.3% to 2.4%28,29 and may present as subarachnoid, intratumoral, or subdural hemorrhage.

Intraventricular Hemorrhage Rare in cancer patients ■ May be seen in primary brain tumors in or near the ventricular space ■

Subarachnoid Hemorrhage ■ Neoplastic aneurysms (discussed further later in this chapter) ■ Infectious aneurysms caused by fungal (e.g., Aspergillus, Candida) or bacterial infections ■ Other causes include trauma, coagulation disorders Subdural Hemorrhage Tumors with propensity to invade or metastasize to the subdural space may include leukemia, lymphoma, prostate cancer, and breast cancer. ■ MRI with contrast may demonstrate thickened dura and subdural hemorrhage. ■ Other causes include trauma, coagulation disorders, and thrombocytopenia. ■

Epidural Hemorrhage May occur in association with a primary brain tumor or skull metastasis

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Clinical Features Presentation depends on the size and location of hemorrhage and is similar to hemorrhages from noncancer causes. ■ Presenting signs and symptoms may include acute onset neurologic deficits, headache, and altered consciousness. ■

Diagnosis ■ A noncontrast head CT is the first-line diagnostic approach. ■ MRI with gradient echo can also detect hyperacute hemorrhages and may be more accurate for detecting microhemorrhages.30 ■ Angiography (CT or MR) may help identify aneurysms, arteriovenous malformations, and vasculitis. Management ■ This is based on management principles of intracranial hemorrhages in the noncancer population. ■ Urgent referral to the hospital is recommended for diagnosis by imaging, correction of any potentially reversible causes of hemorrhage (e.g., thrombocytopenia, anticoagulation), and management of any adverse events (e.g., neurologic deterioration, cardiovascular instability). Cancer-Related Causes of Intracranial Hemorrhage Coagulation Disorders ■ This may result in intraparenchymal or subdural hemorrhages. ■ Examples of coagulopathies seen in cancer patients include chemotherapy-induced thrombocytopenia, disseminated intravascular coagulopathy, vitamin K deficiency (due to poor diet), clotting factor deficiencies caused by liver damage, immune-mediated platelet destruction, and thrombotic thrombocytopenia purpura. Neoplastic Aneurysms These are aneurysms caused by neoplastic infiltration of arteries.

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Rupture may result in subarachnoid or intraparenchymal hemorrhages. Neoplastic aneurysms are usually small and located in distal artery branches. They are typically caused by metastasis of cardiac myxoma or choriocarcinoma, although cases of lung cancer metastasis have been reported.

Pituitary Tumor Apoplexy ■ Refers to hemorrhage or infarction of a preexisting pituitary adenoma ■ Uncommon syndrome ■ Often spontaneous ■ Signs/symptoms caused by a sudden increase in sellar contents compressing surrounding structures and portal vessels • Sudden, severe headache • Visual disturbances • Impairment in pituitary function ■ Management • Supportive therapy with intravenous fluids and corticosteroids • Clinically unstable patients may require urgent surgical decompression • Long-term follow-up for management of tumor and pituitary dysfunction Vascular Endothelial Growth Factor (VEGF) Pathway Inhibitors ■ Includes monoclonal antibodies against VEGF (e.g., bevacizumab) and tyrosine kinase inhibitors targeting the VEGF receptor (e.g., sorafenib, sunitinib) ■ Increased risk of bleeding noted in early clinical studies of bevacizumab ranging from minor mucocutaneous bleeding (e.g., epistaxis) to major life-threatening bleeding (e.g., hematemesis, hemoptysis)26 ■ CNS metastases • Until recently, patients with brain metastases were often excluded from clinical trials of VEGF and VEGFR inhibitors.26,31

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• Based on a review of clinical trials of VEGF and VEGFR therapies in systemic cancer, rates of intracranial hemorrhage are negligible.26 In patients with known brain metastases treated with anti-VEGFR therapy, there were no episodes of intracranial hemorrhage. • Preliminary results from retrospective review of all patients treated with bevacizumab in clinical trials (undiagnosed brain metastases at time of enrollment or developed brain metastases during trial) are as follows31: ■ Data set A (13 completed randomized controlled phase II and III trials in which 187 patients with CNS metastases identified): low incidence of hemorrhage, 3/91 (3.29%) in bevacizumab arm, and 1/96 (1.04%) in nonbevacizumab arm ■ Data set B (2 open-label, single-arm safety studies in which 321 patients with CNS metastases identified): low incidence of cerebral hemorrhage 3/321 (0.93%) ■ Data set C (2 ongoing trials in which 131 patients with NSCLC and pretreated CNS metastases were included): low incidence of cerebral hemorrhage, 1/131 (0.8%) High-grade gliomas • Based on phase II clinical trials of bevacizumab in recurrent high-grade gliomas, rates of major intracranial hemorrhage have ranged from 0 to 2.9%.32–37 Of note, many of these trials excluded patients with evidence of intracranial hemorrhage on imaging prior to the initiation of therapy. • In a small retrospective study of high-grade glioma patients, the addition of anticoagulation to bevacizumab treatment was not associated with major intracerebral hemorrhage causing neurologic deficits or death.38

Cerebral Venous Thrombosis (CVT) ■

Nonseptic thrombosis of the intracranial veins and/or sinuses

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174 Chapter 8 Risk Factors Similar risk factors as deep venous thrombosis, including coagulation disorders, cancer, and pregnancy ■ May also be caused by compression or invasion of cerebral sinuses from dural-based lesions such as meningiomas, brain metastases, or lymphoma ■

Clinical Features ■ Clinical presentation is often nonspecific. ■ Most common signs and symptoms are headache, seizures, focal neurologic deficits, altered consciousness, and papilledema. ■ The onset of symptoms may be acute ( ,48 hours), subacute (48 hours to 30 days), or chronic (.30 days). ■ Main patterns of presentation include39 • Isolated intracranial hypertension (headache and papilledema) • Focal syndrome (focal deficit, seizure) • Cavernous sinus syndrome including orbital pain, chemosis, proptosis, oculomotor palsies • Subacute encephalopathy Diagnosis ■ Imaging of the venous system demonstrating occlusion is most helpful. Options include MR venography or CT venography. ■ MRI and MR venography have been the noninvasive imaging techniques of choice, although CT venography is emerging as a competing technique.40 • Thrombus may manifest as absence of flow void, best seen on FLAIR images and T2-weighted spin-echo images. • Imaging may demonstrate indirect signs of CVT, including ■ Diffuse cerebral edema ■ Venous infarction • Suspicion for a venous infarction should be raised if the infarction does not conform to an arterial vascular territory.

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• The lesion may be hemorrhagic. • Deep venous thrombosis is typically associated with bilateral or unilateral infarction in the thalami, basal ganglia, and internal capsules. A head CT may show direct or indirect signs of CVT, although it may be negative in 10% to 30% of cases of CVT.40 • Noncontrast head CT may demonstrate a dense clot sign from thrombosis of the dural sinus or a cord sign from thrombosis of a cortical vein. • Contrast-enhanced head CT may demonstrate an empty delta sign from thrombosis of the dural sinus. • A head CT may also demonstrate indirect signs of CVT, as seen in MRI (discussed previously in this chapter).

Treatment ■ Therapeutic anticoagulation • Acute treatment of CVT with intravenous or subcutaneous heparin has been demonstrated on the basis of randomized trials, a meta-analysis, and case series.39 • The length of treatment is unclear, although anticoagulation with warfarin should be continued for at least 6 to 12 months, possibly longer depending on the risk of further thromboses. ■ The utility of thrombolysis for CVT in cancer and noncancer patients is unclear. ■ The management of elevated intracranial pressure is the same as the management of elevated intracranial pressure from other causes. Prognosis39 ■ The prognosis in all patients with acute CVT (not just cancer patients) is a 15% overall death and dependency rate. ■ Long-term predictors of poor prognosis include any type of cancer, CNS infection, deep venous system thrombosis, intracranial hemorrhage, and age greater than 37 years. ■ Predictors of death at 30-days include depressed consciousness, deep venous system thrombosis, right hemispheric hemorrhage, and posterior fossa lesions.

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The main causes of acute death include transtentorial herniation caused by large hemorrhage, multiple lesions, or diffuse brain edema.

References 1.

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4. 5.

6.

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8.

Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore). 1985; 64(1):16–35. Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM. Stroke in patients with cancer: incidence and etiology. Neurology. 2004;62(11):2025–2030. Oberndorfer S, Nussgruber V, Berger O, Lahrmann H, Grisold W. Stroke in cancer patients: a risk factor analysis. J Neurooncol. 2009;94(2):227. Grisold W, Oberndorfer S, Struhal W. Stroke and cancer: a review. Acta Neurol Scand. 2009;119(1):1–16. Adams HP, Jr., del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38(5):1655–1711. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(2):577–617. Lefkovitz NW, Roessmann U, Kori SH. Major cerebral infarction from tumor embolus. Stroke. 1986; 17(3): 555–557. el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in cancer patients: pathogenesis, diagnosis, and treatment. Oncologist. 2007;12(5):518–523.

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Rabinstein AA, Giovanelli C, Romano JG, Koch S, Forteza AM, Ricci M. Surgical treatment of nonbacterial thrombotic endocarditis presenting with stroke. J Neurol. 2005; 252(3):352–355. Thaler DE, Saver JL. Cryptogenic stroke and patent foramen ovale. Curr Opin Cardiol. 2008;23(6):537–544. Meister SG, Grossman W, Dexter L, Dalen JE. Paradoxical embolism: diagnosis during life. Am J Med. 1972;53(3): 292–298. Cheng SW, Wu LL, Ting AC, Lau H, Lam LK, Wei WI. Irradiation-induced extracranial carotid stenosis in patients with head and neck malignancies. Am J Surg. 1999; 178(4):323–328. Scott AS, Parr LA, Johnstone PA. Risk of cerebrovascular events after neck and supraclavicular radiotherapy: a systematic review. Radiother Oncol. 2009;90(2):163–165. Butler MJ, Lane RH, Webster JH. Irradiation injury to large arteries. Br J Surg. 1980;67(5):341–343. Perry A, Schmidt RE. Cancer therapy-associated CNS neuropathology: an update and review of the literature. Acta Neuropathol. 2006;111(3):197–212. Kayser-Gatchalian MC, Kayser K. Thrombosis and intracranial tumors. J Neurol. 1975;209(3):217–224. van der Sande JJ, Veltkamp JJ, Bouwhuis-Hoogerwerf ML. Hemostasis and intracranial surgery. J Neurosurg. 1983; 58(5):693–698. Ulmer S, Braga TA, Barker FG II, Lev MH, Gonzalez RG, Henson JW. Clinical and radiographic features of peritumoral infarction following resection of glioblastoma. Neurology. 2006;67(9):1668–1670. Ferreri AJ, Campo E, Seymour JF, et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the “cutaneous variant.” Br J Haematol. 2004; 127(2):173–183. Szots M, Szomor A, Kover F, et al. Intravascular lymphomatosis of the nervous system. J Neurol. 2008; 255(10): 1590–1592. Murase T, Nakamura S, Kawauchi K, et al. An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma

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associated with haemophagocytic syndrome. Br J Haematol. 2000;111(3):826–834. Ponzoni M, Ferreri AJ, Campo E, et al. Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting. J Clin Oncol. 2007;25(21):3168–3173. Iijima M, Fujita A, Uchigata M, Katoo H. Change of brain MRI findings in a patient with intravascular malignant lymphomatosis. Eur J Neurol. 2007;14(5):e4–e5. Baumann TP, Hurwitz N, Karamitopolou-Diamantis E, Probst A, Herrmann R, Steck AJ. Diagnosis and treatment of intravascular lymphomatosis. Arch Neurol. 2000; 57(3):374–377. Park MS, Kim BC, Kim IK, et al. Cerebral infarction in IgG multiple myeloma with hyperviscosity. J Korean Med Sci. 2005;20(4):699–701. Carden CP, Larkin JM, Rosenthal MA. What is the risk of intracranial bleeding during anti-VEGF therapy? Neuro Oncol. 2008;10(4):624–630. White JB, Piepgras DG, Scheithauer BW, Parisi JE. Rate of spontaneous hemorrhage in histologically proven cases of pilocytic astrocytoma. J Neurosurg. 2008;108(2):223–226. Martinez-Lage JF, Poza M, Martinez M, Esteban JA, Antunez MC, Sola J. Meningiomas with haemorrhagic onset. Acta Neurochir (Wien). 1991;110(3–4):129–132. Wakai S, Yamakawa K, Manaka S, Takakura K. Spontaneous intracranial hemorrhage caused by brain tumor: its incidence and clinical significance. Neurosurgery. 1982; 10(4):437–444. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373(9675):1632–1644. Rohr UP, Augustus S, Lasserre SF, Compton P, Huang J. Safety of bevacizumab in patients with metastases to the central nervous system. J Clin Oncol (Meeting Abstracts). 2009;27(Suppl):abstr 2007. Sathornsumetee S, Vredenburgh JJ, Rich JN, et al. Phase II study of bevacizumab and erlotinib in patients with recurrent glioblastoma multiforme. J Clin Oncol (Meeting Abstracts). 2008;26(Suppl):abstr 13008. Cloughesy TF, Prados MD, Wen PY, et al. A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT)

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on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol (Meeting Abstracts). 2008;26(Suppl):abstr 2010b. Rich JN, Desjardins A, Sathornsumetee S, et al. Phase II study of bevacizumab and etoposide in patients with recurrent malignant glioma. J Clin Oncol (Meeting Abstracts). 2008;26(Suppl):abstr 2022. Vredenburgh JJ, Desjardins A, Herndon JE II, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253–1259. Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25(30):4722–4729. Kreisl TN, Kim L, Moore K, et al. Phase II trial of singleagent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740–745. Nghiemphu PL, Green RM, Pope WB, Lai A, Cloughesy TF. Safety of anticoagulation use and bevacizumab in patients with glioma. Neuro Oncol. 2008;10(3):355–360. Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol. 2007;6(2):162–170. Poon CS, Chang JK, Swarnkar A, Johnson MH, Wasenko J. Radiologic diagnosis of cerebral venous thrombosis: pictorial review. AJR Am J Roentgenol. 2007;189(6 Suppl):S64–S75.

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C H A P T E R

9

Medical Complications of Brain Tumor Patients Seizures Epidemiology Up to 60% of patients with brain tumors may present with seizures or may have a seizure for the first time after diagnosis of the tumor.1 ■ The risk of seizure depends on the type of brain tumor, grade, location, changes in peritumoral environment, and genetic factors.1,2 • Slow-growing tumors (i.e., low-grade gliomas) are the most epileptogenic, although the high frequency of seizures may be related to longer survival. • Seizure frequency is based on tumor type: dysembryoplastic neuroepithelial tumors 100%, low-grade astrocytomas and oligodendrogliomas 60% to 85%, glioblastomas 30% to 50%, and brain metastases 20% to 35%. • Cortical tumors (frontal, temporal, parietal more than occipital) cause seizures more frequently than infratentorial or sellar tumors. ■ In patients with systemic cancer, the incidence of seizures unrelated to brain metastases is only 5%.3 ■ Incidence of seizures in patients with brain metastases is approximately 25% to 40%.4 ■

Clinical Features ■ May present as simple or complex seizures with or without secondary generalization ■ Causes of seizures in patients with cancer • Related to parenchymal tumor: epileptogenic activity likely arises from adjacent cortex since tumors are usually electrically inert5 181

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182 Chapter 9 • Related to infiltrative lesions such as leptomeningeal carcinomatosis or intravascular lymphomatosis • Related to radiation necrosis, including temporal lobe radionecrosis from head and neck radiation • Related to central nervous system infection or opportunistic infection • Related to epileptogenic medications including some antidepressants, neuroleptics, antibiotics, and chemotherapy (e.g., high-dose busulfan, cisplatin, chlorambucil, isophosphamide, paclitaxel, methotrexate) • Related to paraneoplastic syndromes such as limbic encephalitis • Related to metabolic disorders • Related to cerebrovascular complications such as intracranial hemorrhages, venous sinus thrombosis, or stroke Seizure Prophylaxis Perioperative Period ■ Conflicting data regarding the prophylactic use of antiepileptic drugs in patients undergoing surgery for a brain tumor2 Outside the Perioperative Period ■ American Academy of Neurology Practice Parameters6 • “Because of their lack of efficacy and their potential side effects, prophylactic anticonvulsants should not be routinely used in patients with newly diagnosed brain tumors.” • “In patients with brain tumors who have not had a seizure, tapering and discontinuing anticonvulsants after the first postoperative week is appropriate. . . .” ■ Cochrane Review: “Evidence for seizure prophylaxis with phenobarbital, phenytoin, and divalproex sodium in people with brain tumors is inconclusive. . . . Therefore, there are no data supporting the use of prophylactic antiepileptics and the risk of adverse events lessens their overall potential benefit.”1

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Sirven et al. meta-analysis: “In patients with no history of seizures, evidence does not support the use of seizure prophylaxis with phenobarbital, phenytoin, or valproic acid for gliomas, cerebral metastases or meningiomas.”7

Seizure Treatment ■ Limited data are available on the efficacy of specific antiepileptic medications in patients with brain tumors. • Several prospective and retrospective studies showed that add-on levetiracetam decreased seizure frequency in 27% to 90% of patients with brain tumors.2 • Small prospective study of add-on gabapentin showed seizure reduction in all patients with 57% becoming seizure free.8 ■ Some patients may develop medical refractory epilepsy due to several reasons, including multidrug resistance. Treatment options include • Surgical resection of epileptogenic zone: 70% to 90% of patients become seizure free or enjoy a substantial reduction in seizure frequency after total resection of the epileptogenic zone.2 • Radiation: small series demonstrated reductions in seizure frequency following radiation.9,10 • Chemotherapy: temozolomide reduced seizure frequency in 50–60% of glioma patients.11,12 ■ Side effects are more frequent in patients with brain tumors compared with the overall epilepsy population.2 Antiepileptic Drug–Drug Interactions Enzyme-inducing antiepileptic drugs (EIAED) (Table 9-1) • Includes phenobarbital, primidone, carbamazepine, and phenytoin • Induce cytochrome P450 coenzymes, resulting in decreased effectiveness of medications metabolized by the P450 system, including several chemotherapeutic agents and corticosteroids

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Trade Name

Special Considerations in Brain Tumor Patients

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Klonopin

Neurontin

Lamictal

Keppra

Ativan

Gabitril

Topamax

Clonazepam

Gabapentin

Lamotrigine

Levetiracetam

Lorazepam

Tiagabine

Topiramate

(Continues)

Weak enzyme inducer; side effects that include cognitive slowing; slow titration needed to minimize CNS adverse effects.

Side effects that include depression

Used for status epilepticus; side effects that include sedation

Therapeutic starting dose; side effects that include depression

Slow titration to minimize rash risk and therefore may take several weeks to get to therapeutic levels

Three to four times daily dosing, perceived as less efficacious than other antiepileptics, although data are conflicting

Used as adjuvant therapy; side effects that include sedation

Drugs that cause little or no induction of P450 enzymes

Generic Name

Table 9-1: Common Antiepileptic Medications

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Depakote, Depakene

Zonegran

Valproic Acid

Zonisamide

Trileptal

Luminal

Dilantin

Mysoline

Oxcarbazepine

Phenobarbital

Phenytoin

Primidone

Similar side effects as phenobarbital but possibly more sedating that phenobarbital

Strong P450 inducer

Behavioral and cognitive side effects

Dose-related effects that are similar to carbamazepine, although oxcarbazepine is a weaker P450 inducer

Side effects that include hyponatremia, small risk of bone marrow suppression

Side effects that include cognitive impairment; slow titration necessary

Side effects that include hepatotoxicity, thrombocytopenia and abnormal coagulation at higher doses, enzyme inhibiting effects (which may raise levels of certain chemotherapeutic agents)

Special Considerations in Brain Tumor Patients

Data are from Bromfield EB. Epilepsy. In: Samuels MA, ed. Manual of Neurologic Therapeutics, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2004:33–64. Porter RJ, Meldrum BS. Antiseizure drugs. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology, 11th ed. New York: McGraw-Hill Companies; 2009:399–422.

Tegretol

Carbamazepine

Drugs that induce P450 enzymes

Trade Name

Generic Name

Table 9-1: Common Antiepileptic Medications (Continued)

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• Chemotherapeutic agents affected by EIAEDs include nitrosureas (e.g., temozolomide), paclitaxel, cyclophosphamie, etoposide, topotecan, irinotecan, thiotepa, doxorubicin, and methotrexate • Phenytoin and phenobarbital shorten the half-life of dexamethasone and prednisone13 Valproic acid is an enzyme-inhibiting antiepileptic drug, which may result in raised plasma concentrations of other agents and possibly increased toxic effects. Many chemotherapeutic agents may affect the plasma concentrations of antiepileptic medications.2 Agents with minimal or no induction of P450 enzymes are found in Table 9-1.

Practice Considerations New-onset seizures in a patient with known systemic cancer should raise suspicion for brain metastases. A brain MRI with contrast is the imaging modality of choice for brain metastases. ■ Seizure prophylaxis is generally not recommended in patients with no history of seizures. ■ Antiepileptic treatment is recommended in patients with brain tumors after the first seizure. ■ The length of treatment after the first and only seizure is unclear, although patients may require lifetime antiepileptic treatment, especially if the tumor is still present. ■ Each state has specific laws regarding driving after a seizure. In general, physicians should warn their patients regarding the risks of driving and other behaviors that could result in injury or death should a seizure occur (i.e., swimming). ■ Consider drug–drug interactions and side-effect profiles (e.g., bone marrow suppression, cognitive impairment) when choosing an antiepileptic for a patient. ■

Venous Thromboembolism (VTE) ■

VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE).

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Epidemiology VTE is common in patients with cancer, including primary brain tumors. ■ The incidence of symptomatic VTE in patients with high-grade glioma outside the perioperative period is 20% to 30%.14 ■ The risk for VTE in high-grade glioma patients is higher in the postoperative period and in patients with hemiplegia. ■ The incidence of symptomatic VTE in primary CNS lymphoma is 18%.14 ■ The incidence of VTE is higher in patients with cancer than patients without cancer.15 ■ It is the second leading cause of death in cancer patients.16 ■

Risk Factors14 ■ Postoperative period ■ Hemiparesis ■ Age ⬎60 ■ Large tumor size ■ Chemotherapy ■ Hormonal therapy ■ Steroids and osmotic diuretic agents, which may also increase the rate of clot formation17 Clinical Features ■ DVT: erythema, warmth, pain, tenderness, and edema in one leg ■ PE: chest pain, cough, tachypnea, tachycardia, and shortness of breath Diagnosis ■ DVT: duplex ultrasonography ■ PE: chest CT angiogram Prophylaxis Prophylaxis is recommended in the perioperative setting and during hospitalization.

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An optimal prophylactic regimen has not been established. Options for prophylaxis include the following: • Compression stockings and sequential pneumatic compression devices • Unfractionated heparin • Low molecular weight heparin (LMWH) (e.g., enoxaparin, dalteparin, tinzaparin, and nadroparin) In patients with brain tumors, LMWH and unfractionated heparin reduce the risk of VTE from 12.5% to 6.2% and carry a 2% risk for major bleeding.18 The need for prophylaxis beyond the perioperative period is less clear. • A randomized phase III clinical trial of malignant glioma patients that tested the safety and efficacy of long-term dalteparin for prevention of VTE versus placebo closed early due to expiration of study medication.19 • In this study, there was a trend in favor of dalteparin in reducing VTE but the results were not statistically significant (although the study may have been underpowered). • There was also a trend for increased intracranial hemorrhage in the dalteparin group, although the difference was not statistically significant.

Treatment ■ The main objective of treatment of a DVT is to prevent PE, as pulmonary emboli are associated with increased morbidity and mortality. ■ Consider a noncontrast head CT before initiating therapy to evaluate for intracerebral hemorrhage. ■ Options for treatment include the following: • Low molecular weight heparin (LMWH) • Unfractionated heparin IV or LMWH with transition to warfarin • In patients with a contraindication to therapeutic anticoagulation (i.e., intracerebral hemorrhage, recent craniotomy, prolonged thrombocytopenia), an inferior vena cava (IVC) filter should be placed.

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An IVC filter is not necessary if the patient is able to receive therapeutic anticoagulation. ■ IVC filters are associated with a higher complication rate and are less effective in preventing PEs as compared to anticoagulation.20 ■ IVC filter complications include pneumothorax, infection, bleeding, IVC wall damage, recurrent VTE, postphlebitic syndrome, and IVC thrombosis. • In patients with heparin-induced thrombocytopenia, direct thrombin inhibitors (e.g., lepirudin, argatroban, bivalirudin) should be used instead. Clinical trials and systematic reviews comparing different anticoagulants in cancer patients with VTE suggest that LMWHs are more effective than unfractionated heparin and at least as effective or possibly more effective than warfarin. • In a multicenter, randomized, open-label trial comparing enoxaparin versus warfarin for 3 months, warfarin was associated with a high bleeding rate, although the differences were not statistically significant.21 When combining recurrent VTE and major hemorrhage as the primary endpoint, the enoxaparin group had statistically significant lower rates of this combined endpoint. • In a multicenter, randomized, open-label trial comparing dalteparin followed by warfarin versus dalteparin alone for 6 months, rates of recurrent VTE were lower in the dalteparin alone group. There was no significant difference in the rate of major bleeding or any bleeding. • Meta-analyses show that LMWHs are more effective than unfractionated heparin for the initial treatment of VTE and are associated with less major bleeding.22,23 Initial treatment with unfractionated heparin (as opposed to LMWH) should be considered in patients with serious PEs and in patients at high risk for hemorrhage (as protamine is able to reverse unfractionated heparin more completely than LMWH). ■

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Properly monitored anticoagulation can be relatively safe in patients with primary and metastatic brain tumors.20 • The incidence of cerebral hemorrhage is generally not significantly elevated in studies. • Hemorrhagic complications most commonly occur in the setting of supratherapeutic anticoagulation. The optimal length of treatment after an initial VTE is unknown. • No clinical trials have been performed to answer this question. • Some advocate using therapeutic anticoagulation indefinitely in patients with cancer or at least as long as the cancer is active.24

Cerebral Edema ■

■

There are two main types of cerebral edema. • Vasogenic edema is most commonly associated with brain tumors. • Cytotoxic edema is due to hypoxia and is often caused by ischemic strokes or traumatic brain injury. Vasogenic edema results from the extravasation of intravascular fluid and proteins into cerebral parenchyma extracellular space due to breakdown of tight endothelial junctions in the blood–brain barrier.

Clinical Features ■ Depend on location of cerebral edema ■ May include focal neurologic deficits, headaches, nausea, vomiting, and lethargy Diagnosis ■ The diagnosis is based on clinical history, symptoms, and imaging. ■ MRI is the best imaging modality for assessment of cerebral edema. • Cerebral edema is hypointense on T1-weighted images and hyperintense on T2-weighted images. • It may be difficult to differentiate cerebral edema from an infiltrating tumor.

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Management14 Corticosteroids ■ Indicated for symptomatic peritumoral edema (usually not necessary in asymptomatic patients with peritumoral edema on neuroimaging) ■ Usually adequate for managing most peritumoral edema ■ Mechanism of action not well understood ■ Side effects (also discussed later in “Treatment Complications and Their Management” section) • The side effects include osteoporosis, compression fractures, avascular necrosis, steroid myopathy, gastrointestinal bleeding, pneumocystis jiroveci pneumonitis (PJP), Cushingnoid features, adrenal insufficiency, and cataracts. • The severity of complications corresponds to the dose and duration of symptoms. • Most resolve after stopping steroids (except for osteoporosis and posterior subcapsular cataracts). • The severity may be reduced with using the lowest dose possible.14 ■ Dexamethasone • This is the preferred corticosteroid because of less mineralocorticoid activity, and possibly lower risk of infection and cognitive impairment compared with other corticosteroids.25 • Dosing depends on the severity of symptoms. ■ The typical starting dose is 10 mg. ■ The typical initial maintenance dose is 16 mg per day (divided into two to four times a day dosing), but lower doses may be used if less symptomatic. ■ PO and IV dosing are equivalent. ■ In general, use the lowest dose that still provides symptomatic benefit. ■ If lowering the dose, the dose should be tapered. The longer the patient has been on steroids, the slower the taper, although the length of the taper will vary from patient to patient according to symptoms. • This induces improvement of neurologic symptoms caused by peritumoral edema within 48 hours.

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192 Chapter 9 • Improvement on imaging studies often lags behind clinical improvement. • Prophylactic treatment for potential side effects from dexamethasone should be considered for the following complications: ■ Gastrointestinal complications: histamine H 2 receptor blocker (e.g., famotidine, ranitidine) or proton pump inhibitor (e.g., omeprazole, lansoprazole, pantoprazole) ■ Pneumocystis jiroveci pneumonitis (PJP) ■ Osteoporosis Vascular Endothelial Growth Factor (VEGF) Pathway Inhibitors • VEGF is a major proangiogenic peptide that is partly responsible for the loss of integrity of the blood–brain barrier in brain tumors.26 • Anti-VEGF agents could be used to reduce vasogenic cerebral edema. ■ In a phase II study of cediranib in patients with glioblastoma patients, this agent significantly reduced tumor-associated edema.27 ■ For significantly elevated intracranial pressure and mass effect not responsive to corticosteroids or for impending herniation, hospitalization is warranted. • Immediate measures to decrease intracranial pressure such as elevation of the head of the bed, hyperventilation, and fluid restriction should be started before providing more definitive therapy. • Hypertonic fluids • Mannitol • Surgical debulking

Pain Headaches Causes ■ These are typically caused by increased intracranial pressure from the brain tumor and/or peritumoral edema.

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Other causes should be considered in the correct clinical context, including intratumoral hemorrhages, meningeal processes, venous sinus thrombosis, analgesic medication overuse, depression, and migraines.

Clinical Features Headaches that cause early morning awakening or are more prominent on waking should raise suspicion for increased intracranial pressure. ■ Headaches are typically associated with nausea and vomiting. ■ Headaches are worse with coughing or Valsalva maneuver. ■ Papilledema may be present on funduscopic examination. ■

Treatment ■ Steroids are an option. ■ All classes of pain medications, including opioids, may be considered; however, nonsteroidal anti-inflammatory medications may increase the risk of gastric toxicity from corticosteroids. Neuropathic Pain Potential Causes ■ Leptomeningeal disease ■ Lymphomatous invasion of nerves ■ Skull base involvement ■ Herpes zoster ■ Radiation ■ Chemotherapy (see Chapter 6 for chemotherapy-induced peripheral neuropathy) Clinical Features ■ Painful dysesthesias typically localized to specific dermatomes, nerve root distributions, or peripheral extremities in a stocking-glove distribution ■ May be spontaneous and/or evoked by a stimulus Treatment May require a combination of agents ■ Spontaneous resolution ■

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• Pain associated with acute chemotherapy-induced neuropathy may resolve after discontinuation of the culprit chemotherapy. • Neuropathic symptoms may progress for up to 2 months after stopping oxaliplatin or cisplatin. • Recovery may be incomplete in some patients, resulting in chronic neuropathic pain. Antiepileptic medications for neuropathic pain, including gabapentin, carbamazepine, and pregabalin • High doses of gabapentin may be required for pain control (maximum up to 3,200 mg per day divided in TID or QID dosing). Antidepressants for neuropathic pain, including tricyclics (desipramine, amitriptyline, nortriptyline) and serotonin/norepinephrine reuptake inhibitors (venlafaxine, duloxetine) Topical or transdermal agents, including lidocaine patches All classes of pain medications, including opioids; however, nonsteroidal anti-inflammatory medications may increase the risk of gastric toxicity. Corticosteroids for patients with neuropathic pain from leptomeningeal disease

Cognitive Impairment Potential causes Brain tumor ■ Radiation (see Chapter 5) ■ Chemotherapy (see Chapter 6) ■ Epilepsy and antiepileptic drugs • In a study of low-grade gliomas, the presence of epilepsy and the use of antiepileptic drugs were independently associated with changes in memory, attention, and communication.28 • The use of antiepileptics is associated with a sixfold increase in cognitive deficits (such as attention, psychomotor speed, executive function) as compared with radiation.29 ■ Other medical factors and complications contributing to cognitive and neurobehavioral changes include endocrine ■

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dysfunction, metabolic disturbances, infection, pain, fatigue, anxiety, and depression. Treatment Only a few treatment trials in patients with brain tumors have been conducted. ■ Psychostimulants • Methylphenidate ■ Case study of methylphenidate in three high-grade glioma patients with cognitive deficits from primary brain tumors or radiation described improvements in arousal, attention, initiation speed of tasks, and mood.30 ■ Open-labeled study of methylphenidate in highgrade glioma patients showed significant improvements in psychomotor speed, memory, visual–motor function, executive function, motor speed, and dexterity, as well as subjective improvements in their ability to function despite progressive disease and increasing radiation damage.31 • Modafinil ■ In a pilot study of primary brain tumor patients with fatigue or cognitive dysfunction, modafinil improved cognition, mood, and fatigue.32 ■ Donepezil • In a study of brain tumor patients who received radiation, donepezil improved cognitive functioning, including memory, mood, and quality of life in patients with brain tumors who received radiation therapy.33 ■ Ventriculoperitoneal shunting • Could be considered in patients with cognitive dysfunction due to communicating hydrocephalus34 ■ Cognitive rehabilitation ■

Fatigue ■

Negatively affects quality of life

Potential Causes Radiation (fatigue tends to increase with the number of fractions)

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Antiepileptics Chemotherapy Anemia Metabolic disturbances Depression Endocrine dysfunction

Treatment Psychostimulants (e.g., methylphenidate, pemoline, dextroamphetamine, modafinil) are generally well tolerated in brain tumor patients but may lower the seizure threshold (except for modafinil)

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Treatment Complications and Their Management Musculoskeletal Osteoporosis and Compression Fractures ■ Chronic corticosteroids (prednisone dose greater than 2.5 to 5 mg/day) increase the risk of osteoporosis, which, in turn, predisposes a patient to fractures such as vertebral compression fractures.35,36 ■ Clinical features associated with compression fractures include back pain, nerve impingement (numbness, tingling, weakness), urinary/stool incontinence, or retention due to spinal cord compression. ■ Diagnosis • Osteoporosis is diagnosed with a bone mineral density (BMD) test. • Vertebral compression fractures can be seen on X-rays or spine CT scans, but a spine MRI may be necessary to evaluate for spinal cord compression (if neurologic symptoms are present). ■ Prophylactic therapy should be provided to patients on chronic steroids. • Calcium supplementation 1,500 mg/day • Vitamin D 800 IU daily or activated vitamin D such as calcitriol 0.5 µm/day

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Treatment • Calcium and vitamin D should be given to all patients with osteoporosis. • Bisphosphonates (e.g., etidronate, alendronate, risedronate, zoledronate) improve BMD and may reduce the risk of fractures although the data are not definitive.20 • Compression fractures may require hospitalization if neurologic symptoms are present or if the pain is too severe to manage as an outpatient. • Spine surgeon consultation is warranted if the patient has spinal cord compression or spine instability. • Vertebroplasty is often used to relieve pain from compression fractures, but two recent multicenter randomized, placebo-controlled trials demonstrated no benefit for painful osteoporotic vertebral fractures. ■ In a randomized trial of 131 patients with painful osteoporotic vertebral compression fractures comparing vertebroplasty versus a simulated procedure without cement, improvements in pain and painrelated disability at 1 month were similar in both groups.37 ■ In a randomized trial of 78 patients with painful osteoporotic vertebral fractures comparing vertebroplasty with a sham procedure, the authors found no beneficial effect at 1 week or at 1, 3, or 6 months after treatment.38

Steroid Myopathy Occurs in up to 60% of cancer patients39 ■ More common in older persons and after prolonged use of high-dose corticosteroids ■ Clinical features • Subacute onset proximal muscle weakness and wasting (especially in the lower extremities) resulting in difficulty climbing stairs or rising from a seated position • Normal muscle enzymes ■

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198 Chapter 9 ■

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Diagnosis • Diagnosis is primarily based on clinical history. • Electromyography is nonspecific and may demonstrate myopathic changes. • Muscle biopsy is only necessary if the diagnosis is in question and may contain type IIb muscle fiber atrophy. Prophylactic therapy • Nonfluorinated steroids (e.g., prednisone, hydrocortisone) may carry a lower risk of steroid myopathy than fluorinated steroids (e.g., dexamethasone).20 • Regular exercise may attenuate symptoms of steroid myopathy. Treatment • Stopping steroids or decreasing to the lowest possible dose • Physical therapy Prognosis: recovery may take several months

Syndromes Associated With Steroid Withdrawal Adrenal Insufficiency ■ Caused by impaired adrenal steroid synthesis ■ Seen with mitotane, ketoconazole, aminoglutethimide, megestrol, prior cranial irradiation for childhood brain tumors, or rapid reduction in corticosteroid therapy ■ Rarely seen with replacement of both adrenal glands by metastases ■ Clinical features • Patients may develop nausea, vomiting, anorexia, and lethargy. • Acute adrenal crisis (hypotension, mental status changes, hypoglycemia) may occur with abrupt cessation. ■ Diagnosis: rapid ACTH stimulation test ■ Treatment • Mild symptoms can be managed as an outpatient by increasing the steroid dose and then tapering more gradually or using alternate day administration. • Acute adrenal insufficiency may require hospitalization for intravenous hydration, glucose, and steroids.

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Medical Complications of Brain Tumor Patients 199

Steroid-Withdrawal Syndrome Clinical features include nausea, headache, myalgias, malaise, and weight loss.40 ■ Treatment includes slower steroid taper or alternate day administration. ■

Steroid Pseudorheumatism41 ■ Clinical features include diffuse arthralgias. ■ Treatment includes slower steroid taper and NSAIDs. Gastrointestinal Complications Peptic Ulceration ■ Peptic ulceration may theoretically occur with continued use of corticosteroids. ■ From studies of patients on steroids, the overall incidence of peptic ulceration is low, but the incidence is increased in patients on both steroids and nonsteroidal anti-inflammatory medications.14 ■ Clinical features include nonspecific epigastric pain with variable relationship to meals, nausea, and anorexia. ■ Diagnosis • Upper endoscopy • Abdominal CT only when complications such as perforation, penetration, or obstruction suspected ■ Prophylaxis includes histamine H 2 receptor blocker (e.g., famotidine, ranitidine) or a proton pump inhibitor (e.g., omeprazole, lansoprazole, pantoprazole) ■ Treatment regimens differ based on presence or absence of H. pylori infection Upper Gastrointestinal Hemorrhage ■ This may occur as a complication from peptic ulcer disease. ■ Clinical features include melena, hematemesis, melenemesis, and hemodynamic instability. ■ Prophylaxis includes histamine H receptor blocker 2 (e.g., famotidine, ranitidine) or a proton pump inhibitor (e.g., omeprazole, lansoprazole, pantoprazole). ■ Hospitalization is indicated, as this could be a lifethreatening emergency.

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200 Chapter 9 Bowel Perforation This is a rare complication of VEGF inhibitors such as bevacizumab or peptic ulcer disease. ■ Clinical features include typically sudden-onset severe abdominal pain. Shock, fever, nausea, and vomiting may be present, although patients may be asymptomatic as steroids can mask symptoms. ■ Hospitalization is indicated, as this could be a lifethreatening emergency. ■

Opportunistic Infections Oropharyngeal Candidiasis (Thrush) ■ Most common opportunistic infection from steroid immunosuppression ■ Caused by the fungus Candida albicans ■ Clinical features • Oral pain, dysphagia, odynophagia, dysgeusia, and aversion to food • Thrush: characterized by white patches on the surface of the buccal and labial mucosa, tongue, and soft palate ■ Treatment • Nystatin oral suspension 100,000 units four times a day (swish and swallow) should be continued for several days after clinical healing. • If thrush does not improve with nystatin oral suspension, an azole antifungal agent should be provided. ■ Fluconazole 100 mg daily for 1 to 2 weeks ■ Clotrimazole troche 5 mL three to four times per day for a 2-week minimum ■ Itraconazole capsule or oral solution 100 mg daily for 2 weeks • “Miracle mouthwash” (containing diphenhydramine, lidocaine, and a Maalox-type aluminum/magnesium antacid) may help with symptomatic relief of pain but does not treat thrush. Pneumocystis Jiroveci Pneumonitis (PJP) ■ PJP was previously known as pneumocystis carinii pneumonitis (PCP).

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Medical Complications of Brain Tumor Patients 201 ■ ■

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It is caused by the fungus Pneumocystis Jiroveci. The frequency of PJP is low in cancer (187 cases per 100,000 patients with hematological cancer, 16 cases per 100,000 patients with solid tumors)42 but can be life threatening. Predisposing factors include corticosteroids, intensity of chemotherapy treatment (e.g., daily temozolomide treatment in glioma patients), and low CD4 cell count (⬍200 cells/mm3).43 Clinical features are similar to acute pneumonia. Diagnosis is as follows: • Radiological imaging demonstrates bilateral interstitial infiltrates. • Definitive diagnosis requires cytologic examination of bronchoalveolar lavage. There are no published guidelines for prophylaxis in patients without HIV, but the following regimens are commonly used: • Trimethoprim-sulfamethoxazole (TMP-SMZ) double strength three times a week or single strength daily • Aerosolized pentamidine 300 mg monthly • Dapsone 50 mg twice per day or 100 mg daily • Atovaquone 1,500 mg daily For treatment, consider consultation with an infectious disease specialist.

Behavioral and Psychiatric Changes ■ Clinical features • Steroids may induce behavioral or psychiatric changes, including anxiety, insomnia, emotional lability, euphoria, and psychosis.44 • Steroids may also induce cognitive deficits such as distractibility and memory impairment.45 ■ Treatment • Stopping or tapering steroids to the lowest possible dose • Consider neuroleptics (e.g., haldol, olanzapine, risperidone, quetiapine) for more severe behavioral changes such as psychosis, aggression, or agitation • Consider antidepressants for depression

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202 Chapter 9 • Consider mood stabilizers for mania • Consider consultation with a psychiatrist Endocrine Abnormalities ■ Hyperglycemia should be monitored in patients on steroids because diabetes predisposes patients to infections. ■ Hyperglycemia is associated with shorter survival in patients with glioblastoma, even after controlling for mean daily dexamethasone dose.46

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Index A Acute cerebellar toxicity, 113 Acute encephalopathy, 113 American Academy of Neurology Practice Parameters on seizure prophylaxis, 182 Amifostine, 122 Anaplastic astrocytoma (WHO Grade III/IV) biology, 11 clinical features, 12 MRI appearance, 12 prognosis, 14–15 treatment chemotherapy, 12 radiation therapy, 12 recurrent disease, 14 surgery, 12 Anaplastic/malignant meningiomas, 23 Anaplastic oligodendroglioma biology, 19 clinical features, 19 MRI appearance, 19 prognosis, 21–22 treatment chemotherapy, 20–21 radiation therapy, 20 recurrent, 21 surgery, 19–20 Angiotropic large-cell lymphoma. See Intravascular lymphoma Antibody-mediated PND, 128–129 Anticoagulation, 100 Anti-CRMP5 (anti-CV2), 140 Antiepileptic drug-drug interactions, 183–186 Anti-Hu, 140

Anti-Ma2 (Ta), 140–141 Anti-NMDA receptors, 141 Anti-voltage-gated potassium channels, 141 Astrocytoma anaplastic astrocytoma, 11–15 diagnosis, 78–79 diffuse astrocytoma, 8–11 glioblastoma, 15–18 pathology of, 78 pilocytic astrocytoma, 8 treatment, 79 Atypical meningiomas, 23 Autonomic neuropathy, 147 Autosomal dominant disorders, 4–5

B Benign meningiomas, 23 Bevacizumab, 100 Bowel perforation, 200 Brachytherapy, 93 Brain biopsy, 44 Brain metastases breast cancer, 53–55 diagnosis, 44 epidemiology, 43 melanoma, 55–57 non-small cell lung cancer, 57–58 parenchymal metastases, 43 prognostic factors RPA classes, 45–46 renal cell carcinoma, 58 surgery approach for multi brain metastasis, 52 for single brain metastasis, 51

207

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208 Index Brain metastases (continued) vs. SRS, 52 with/without WBRT, 52 treatment approach chemotherapy, 52–53 SRS, 48–50 whole-brain radiation therapy, 46–48 Breast cancer, brain metastases epidemiology, 53–54 risk factors, 54 treatment recommendations stereotactic radiosurgery, 54–55 surgery, 54 systemic treatments, 55 whole-brain radiation therapy, 55

C Cancer-associated retinopathy (CAR), 143–144 Capecitabine, 55 Carcinomatous meningitis, 83 Central nervous system (CNS) chemotherapy-related cognitive impairment (Chemobrain), 110–111 focal radiation necrosis, 99–101 imaging abnormalities following radiation therapy, 96 metastases in breast cancer, 54 in melanoma, 57 in NSCLC, 56 neurocognitive dysfunction clinical features, 97 clinical studies, 97–98 pathophysiology, 97 radiation, 96–97 treatment, 98 neurotoxicity of specific agents, 112–115 radiation-induced brain tumors, 101 radiation toxicity, 94–96 RPLE, 111–112 Cerebral edema clinical features, 190 diagnosis, 190

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management corticosteroids, 191 dexamethasone, 191–192 VEGF pathway inhibitors, 192 types of, 190 Cerebral venous thrombosis (CVT) clinical features, 174 diagnosis, 174–175 prognosis, 175–176 risk factors, 174 treatment, 175 Chemical aseptic meningitis, 89 Chemotherapy agents, 55 anaplastic astrocytoma, 12 anaplastic oligodendroglioma, 20–21 astrocytomas, 79 brain metastases treatment, 52–53 common chemotherapy agents, 107–109 diffuse astrocytoma, 10–11 leptomeningeal metastases intrathecal chemotherapy, 88–89 systemic chemotherapy, 89 in melanoma, 58 metastatic epidural spinal cord compression, 72 nerve sheath tumors, 75 seizure treatment, 183 treatment schemes, 109 and WBRT, 48 Chemotherapy-induced peripheral neuropathy (CIPN) clinical signs and symptoms, 115, 120 common chemotherapeutic agents, 116–119 prevention, 120–122 risk factors, 115 treatments and prognosis, 122 Chemotherapy-related cognitive impairment (Chemobrain), 110–111 CIPN. See Chemotherapy-induced peripheral neuropathy CNS. See Central nervous system Coagulation disorders, 171 Corticosteroids, 70–71, 191

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Index 209 Cranial irradiation, 5, 94 CVT. See Cerebral venous thrombosis Cytarabine, 112

D Deep vein thrombosis (DVT). See Venous thromboembolism Dermatomyositis, 151 Dexamethasone, 191–192 Diffuse astrocytoma (WHO Grade II/IV) biology of, 8 clinical features, 8 MRI appearance, 8 prognosis, 11 treatment chemotherapy, 10–11 radiation therapy, 9–10 resection benefits, 9 surgery, 8–9 Diffuse large B-cell lymphoma (DLBCL), 29. See also Primary CNS lymphoma (PCNSL) Donepezil, 195

E Embolism NBTE characteristics of vegetations, 164 clinical features, 164 diagnosis and treatment, 165 paradoxical, 165–166 septic, 165 tumor, 163 Endocrine abnormalities, 202 Enzyme-inducing antiepileptic drugs (EIAED), 183–186 Epidural hemorrhage, 170 Epidural spinal cord space, 68 External beam therapy (EBRT), 93

F Fatigue, 195–196 Fludarabine, 113

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5-Fluorouracil (5-FU), 112–113 Focal external beam radiation therapy, 27 Focal radiation necrosis, 98–101 Fractionation, 93 Frontal skull base meningiomas, 23

G Gastrointestinal complications bowel perforation, 200 peptic ulceration, 199 upper gastrointestinal hemorrhage, 199 Glioblastoma (WHO Grade IV/IV) biology, 15 clinical features, 15 MRI appearance, 15 prognosis, 17–18 treatment newly diagnosed glioblastoma, 17 recurrent glioblastoma, 17 surgery, 16 Gliomas astrocytic vs. oligodendroglial tumors, 6–7 astrocytoma anaplastic, 11–15 diffuse, 8–11 glioblastoma, 15–18 pilocytic, 8 oligodendroglioma anaplastic, 19–22 oligodendroglioma, 18–19 Glutamate, 121 Glutathione, 121

H Headaches, 192–193 High-dose chemotherapy with autologous stem-cell transplantation, 32 High-dose cytarabine, 112 High-dose methotrexate monotherapy, 31 High-grade astrocytoma tumors, 79 High-grade gliomas, 173

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210 Index HIV-related PCNSL, 34–35 Hodgkin lymphoma, 137 Hyperbaric oxygen therapy, 100–101 Hyperglycemia, 202 Hyperviscous obstruction, 168–169

I Ifosfamide, 113–114 Inclusion body myositis, 151–152 Inflammatory myopathies dermatomyositis, 151 inclusion body myositis, 151–152 polymyositis, 150–151 Intensity-modulated radiation therapy (IMRT), 93 Interferon-␣, 114 Internal carotid artery (ICA) stenosis, 166 Intracranial hemorrhages cancer-related causes coagulation disorders, 171 neoplastic aneurysms, 171–172 pituitary tumor apoplexy, 172 VEGF pathway inhibitors, 172–173 clinical features, 171 diagnosis, 171 management principles, 171 types of, 169–170 Intramedullary astrocytoma. See Intramedullary spinal cord tumors Intramedullary metastasis, 79 Intramedullary spinal cord tumors astrocytoma diagnosis, 78–79 pathology of, 78 treatment, 79 clinical features, 77 ependymoma diagnosis, 77 treatment, 78 intramedullary metastasis, 79 Intraparenchymal hemorrhage, 169 Intrathecal (IT) chemotherapy, 31–32, 88–89 Intrathecal liposomal cytarabine, 112

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Intratumoral hemorrhage CNS metastases, 169–170 imaging studies, 169 primary brain tumors, 170 Intravascular lymphoma clinical features, 167 diagnosis, 167–168 prognosis and treatment, 168 Intraventricular hemorrhage, 170 Ionizing radiation exposure, 5 Ischemic strokes, cancer patients management guidelines, 161–162 risk factors, 161 treatment considerations, 163

K Karnofsky performance status (KPS) scale, 44–45

L Lambert-Eaton myasthenic syndrome (LEMS), 128, 148–149 Lapatinib, 55 Leptomeningeal carcinomatosis, 83 Leptomeningeal metastases clinical features, 84 diagnosis, 85–86 epidemiology, 83–84 pathogenesis, 84 prognosis, 86–87 treatment chemotherapy, 88–89 radiation therapy, 88 supportive care, 89–90 surgery, 87–88 Leukemic meningitis, 83 Li-Faumeni (TP53), 4 Low-grade astrocytoma tumors, 79 Low molecular weight heparin (LMWH), 188–189 Lymphomatous meningitis, 83 Lymphoplasmacytic lymphoma, 146

M Malignant angioendotheliomatosis. See Intravascular lymphoma

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Index 211 Malignant peripheral nerve-sheath tumors (MPNSTs), 74 Melanoma-associated retinopathy (MAR), 144 Melanoma, brain metastases epidemiology, 55 imaging, 56 treatment recommendations, 56–57 Meningeal layers, 68 Meningioma, 76 clinical features, 22–23 imaging characteristics, 26 pathology, 23, 26 prognosis, 28 risk factors, 22 treatment, 26–27 Metastatic epidural spinal cord compression (MESCC) clinical features, 69–70 diagnosis, 70 epidemiology, 68–69 pathophysiology, 69 prognosis, 73 treatment chemotherapy, 72 corticosteroids, 70–71 radiation therapy, 71 recurrence, 72 surgery, 71–72 Methotrexate, 31, 114–115 Methylphenidate, 195 Modafinil, 195 Monoclonal IgM antibodies, 146 Musculoskeletal complications, 196–198 Myasthenia gravis (MG), 128, 149–150 Myxopapillary ependymoma, 76–77

N NBTE. See Nonbacterial thrombotic endocarditis Neoplastic aneurysms, 171–172 Neoplastic meningitis, 83 Nerve sheath tumors diagnosis, 74

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histology MPNSTs, 74 neurofibromas, 74 schwannomas, 73–74 treatment, 74–75 Neurocognitive dysfunction clinical features, 97 clinical studies, 97–98 pathophysiology, 97 radiation, 96–97 treatment, 98 Neurofibromas, 74 Neurofibromatosis, 4 Neuromyotonia, 147–148 Neuropathic pain, 193–194 Newly diagnosed glioblastoma, 17 Nimodipine, 122 Nonbacterial thrombotic endocarditis (NBTE) characteristics of vegetations, 164 clinical features, 164 diagnosis and treatment, 165 Nonionizing radiation exposure, 5 Non-small cell lung cancer (NSCLC), brain metastases epidemiology, 55 risk factors, 56 treatment recommendations, 56–57

O Ocular lymphoma, 33 Oligodendroglial tumors, 18–22 Oligodendroglioma (WHO Grade II/IV), 18–19 Ommaya reservoir, 87–88 Opportunistic infections, 200–201 Org 2766, 122 Oropharyngeal candidiasis (Thrush), 200 Osteoporosis and compression fractures, 196–197 Oxcarbazepine, 122

P Pain headaches, 192–193 neuropathic, 193–194

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212 Index Palliative chemotherapy, 109 Paradoxical embolism, 165–166 Paraneoplastic cerebellar degeneration clinical features, 131, 136 differential diagnosis, 136–137 imaging stages, 136 prognosis, 137–138 serologic testing, 137 treatment, 137 Paraneoplastic disorders (PND) antibodies, paraneoplastic syndromes, and associated tumors, 132–135 clinical features, 129 diagnosis, 127 criteria, 130 workup, 131 epidemiology, 127–128 pathogenesis antibody-mediated PND, 128–129 T-cell mediated PND, 129 Paraneoplastic limbic encephalitis clinical features, 139 differential diagnosis, 140 imaging studies, 139–140 laboratory abnormalities, 140–141 prognosis, 142 treatment, 141–142 Paraneoplastic motor neuron disease, 144 Paraneoplastic opsoclonusmyoclonus, 138–139 Paraneoplastic optic neuropathy, 144 Paraneoplastic sensory neuropathy, 145–146 Paraneoplastic visual syndromes cancer-associated retinopathy, 143–144 melanoma-associated retinopathy, 144 paraneoplastic optic neuropathy, 144 Paraproteinemic neuropathy, 146 Parasagittal meningiomas, 23 Parenchymal metastases, 43 PCI. See Prophylactic cranial irradiation

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PCNSL. See Primary CNS lymphoma Peptic ulceration, 199 Peripheral nervous system CIPN clinical signs and symptoms, 115, 120 common chemotherapeutic agents, 116–119 prevention, 120–122 risk factors, 115 treatments and prognosis, 122 disorders, 128 postradiation optic neuropathy, 101–102 radiation-induced peripheral nerve tumors, 102–103 radiation plexopathy, 102 Peripheral neuropathy autonomic, 147 causes in cancer patients, 144–145 chemotherapy-induced neuropathy, 115–122 paraneoplastic sensory, 145–146 paraproteinemic, 146 sensorimotor neuropathy, 145–146 subacute sensory, 145 Pilocytic astrocytoma (WHO Grade I/IV), 8 Pituitary tumor apoplexy, 172 PND. See Paraneoplastic disorders Pneumocystis jiroveci pneumonitis (PJP), 200–201 Polymyositis, 150–151 Posterior reversible encephalopathy syndrome (PRES), 111–112 Postradiation optic neuropathy, 101–102 Postradiation vasculopathy, 166 Primary brain tumors astrocytic tumors anaplastic astrocytoma, 11–15 diffuse astrocytoma, 8–11 glioblastoma, 15–18 pilocytic astrocytoma, 8 diagnosis, 5 epidemiology, 1 histological classification of, 1–4

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Index 213 Primary brain tumors (continued) oligodendroglial tumors anaplastic oligodendroglioma, 19–22 oligodendroglioma, 18–19 risk factors, 4–5 Primary CNS lymphoma (PCNSL) clinical features, 29 diagnosis, 29–30 HIV-related PCNSL, 34–35 pathology, 29 prognosis, 33–34 risk factors, 28 treatment adjuvant corticosteroids, 32 adjuvant rituximab, 32–33 high-dose chemotherapy with autologous stem-cell transplantation, 32 high-dose methotrexate monotherapy, 31 intrathecal chemotherapy, 31–32 methotrexate-based multidrug regimens, 31 ocular lymphoma, 33 recurrent/refractory PCNSL, 33 surgery, 30 WBRT, 32 Prophylactic cranial irradiation (PCI), 94, 98 Prophylactic therapy, 196, 198 Psammomatous meningioma, 76 Psychiatric and behavioral complications, 201–202 Psychostimulants, 195 Pulmonary embolism (PE). See Venous thromboembolism

R Radiation effects central nervous system focal radiation necrosis, 99–101 imaging abnormalities following radiation therapy, 96 neurocognitive dysfunction, 96–98 pathology, 96

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radiation-induced brain tumors, 101 radiation toxicity, 94–96 peripheral nervous system postradiation optic neuropathy, 101–102 radiation-induced peripheral nerve tumors, 102–103 radiation plexopathy, 102 Radiation-induced brain tumors, 101 Radiation-induced peripheral nerve tumors, 102–103 Radiation necrosis, 100 Radiation plexopathy, 102 Radiation sensitizers, 47–48 Radiation therapy anaplastic astrocytoma, 12 anaplastic oligodendroglioma, 20 Radiation therapy diffuse astrocytoma, 9–10 leptomeningeal metastases, 88 meningioma, 27 MESCC, 71 Radiation toxicity acute effects, 94 early-delayed effects, 94–95 late-delayed effects, 95 risk factors, 95–96 Recombinant human leukemia inhibitory factor (rhuLIF), 122 Recurrent anaplastic oligodendroglioma, 23 Recurrent glioblastoma, 17 Recurrent MESCC, 72 Recurrent/refractory PCNSL, 33 Recursive partitioning analysis (RPA) classes, 45–46, 55 Renal cell carcinoma (RCC), brain metastases, 58 Reversible posterior leukoencephalopathy syndrome (RPLE), 111–112

S Schwannomas, 73–74 Seizures antiepileptic drug-drug interactions, 183–186

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214 Index Seizures (continued) clinical features, 181–182 epidemiology, 181 practice considerations, 186 prophylaxis, 182–183 treatment, 183 Sensorimotor neuropathy, 145–146 Septic embolism, 165 Spinal cord tumors anatomy of, 67–68 extradural tumors extradural space, 68 MESCC, 68–72 intradural tumors extramedullary tumors, 73–76 intramedullary tumors, 77–79 Spinal ependymoma, 77–78 Spinal meningioma, 75–76 Stereotactic radiosurgery (SRS), 27 in breast cancer, 54–55 in brain metastases, 48–49 description of, 93 with SRS/without WBRT, 50 surgery approach, 52 with WBRT/without SRS, 49 Stereotactic radiotherapy (SRT), 93 Steroid myopathy, 197–198 Steroid pseudorheumatism, 199 Steroid-withdrawal syndrome, 199 Stiff-person syndrome (SPS), 128, 142–143 Subacute multifocal leukoencephalopathy, 113 Subacute sensory neuronopathy, 145 Subarachnoid hemorrhage, 170 Subarachnoid spinal cord space, 68 Subdural hemorrhage, 170 Subdural spinal cord space, 68 Systemic chemotherapy, 89

postoperative complications, 166 postradiation vasculopathy, 166 Trastuzumab, 53–54 Tuberous sclerosis, 4 Tumor embolism, 163 Turcot syndrome, 5

V Valproic acid, 186 Vascular endothelial growth factor (VEGF) pathway inhibitors, 172–173, 192 Vasogenic edema, 190 Venous thromboembolism (VTE) clinical features, 187 diagnosis, 187 epidemiology, 187 prophylaxis, 187–188 risk factors, 187 treatment, 188–190 Vertebroplasty, 197 VTE. See Venous thromboembolism

W Whole-brain radiation therapy (WBRT), 32, 55 and chemotherapy, in brain metastases, 48 description of, 94 indications in brain metastases, 46 melanoma in brain metastases, 57 and radiation sensitizers, 47–48 and surgery in brain metastases, 52 treatment regimens, 47

T T-cell mediated PND, 129 Thrombotic disease hyperviscous obstruction, 168–169 intravascular lymphoma, 167–168

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X Xaliproden, 121

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