UCSD Moores Cancer Center Neuro-Oncology Program

Recent Progress in Brain Tumors

6DQWRVK.HVDUL0'3K' 'LUHFWRU1HXUR2QFRORJ\ 3URIHVVRURI1HXURVFLHQFHV 0RRUHV&DQFHU&HQWHU 8QLYHUVLW\RI&DOLIRUQLD6DQ'LHJR “Brain Cancer for Life”

Juvenile Pilocytic Astrocytoma Metastatic Brain Cancer Glioblastoma Multiforme Glioblastoma Multiforme

Desmoplastic Infantile Ganglioglioma Desmoplastic Variant Astrocytoma Medulloblastoma Atypical Teratoid Rhabdoid Tumor Diffuse Intrinsic Pontine Glioma

-Mutational analysis, microarray expression, epigenetic phenomenology

-Age-specific biology of brain cancer

-Is there an overlap? ? Neuroimmunology ? Stem cell hypothesis

Courtesy of Dr. John Crawford

Late Effects

Long term effect of chemotherapy and radiation on neurocognition

Risks of secondary malignancy secondary to chemotherapy and/or radiation

Neurovascular long term effects: stroke, moya moya

Courtesy of Dr. John Crawford Importance

„ Increase in aging population with increased incidence of cancer „ Patients with cancer living longer and developing neurologic disorders due to nervous system relapse or toxicity from treatments

Overview

„ Introduction „ Clinical Presentation „ Primary Brain Tumors „ Metastatic Brain Tumors „ Leptomeningeal Metastases „ Primary CNS Lymphoma „ Paraneoplastic Syndromes Classification of Brain Tumors

„ Tumors of Neuroepithelial Tissue „ Glial tumors (astrocytic, oligodendroglial, mixed) „ Neuronal and mixed neuronal-glial tumors „ Neuroblastic tumors „ Pineal parenchymal tumors „ Embryonal tumors „ Tumors of Peripheral Nerves „ Shwannoma „ Neurofibroma „ Perineurioma „ Malignant peripheral nerve sheath tumor

Classification of Brain Tumors

ƒ Tumors of the meninges „ Tumors of meningothelial cells „ Mesenchymal, non-meningothelial tumors „ Primary melanocytic tumors „ Tumors of uncertain histogenesis „ Lymphomas and hematopoetic neoplasms „ Germ cell tumors „ Tumors of Sella region „ Metastatic tumors Brain Cancer Incidence

Site New Cases Deaths Prostate 234,460 27,350 Breast 214,640 41,430 Lung 174,470 162,460 Colon 106,680 55,170 Lymphoma 66,670 20,330 Skin-melanoma 62,190 7,910 Kidney 38,890 12,840 Nervous system 18,820 12,820 Cervix 9,710 3,700 Testis 8,250 370

American Cancer Society (2006). Cancer Facts and Figures 2006.

Incidence Increases with Age

CBTRUS (2005). Statistical Report: Primary Brain Tumors in the U.S., 1998-2002. Adult Primary Brain Tumors

Hemangioma Sarcoma Craniopharyngioma Others Medulloblastoma

Neurinoma

Pituitary Gliomas Adenoma •55% Malignant Gliomas •10% Low Grade Gliomas •20% Meningiomas Meningiomas •5% Vestibular Schwanommas •5% Pituitary Tumors •5% Miscellaneous

Impact on Morbidity and Mortality

„ Primary Brain Tumors (PBT) account for only 2% of all cancers but a disproportionate share of morbidity and mortality „ CBTRUS: Incidence of 14 per 100,000 person-years benign and malignant brain tumors „ SEER: Incidence 6.4 cases per 100,000 person-years malignant brain tumors „ CBTRUS: 39,550 new cases per year benign and malignant brain tumors „ ACS: 17,000 new cases year of malignant brain tumors „ Prevalence: PBT is 130 per 100,000 (359,000 persons living) Impact on Morbidity and Mortality-2

„ 13,100 deaths in 2002 attributed to primary malignant brain tumors „ 2nd leading cause of cancer-related death <34 yrs „ 4th leading cause of cancer-related death 35-54 yrs „ Loss of productive work years „ Loss of independence „ Progressive physical and cognitive impairment

Overview

„ Introduction „ Clinical Presentation „ Primary Brain Tumors „ Metastatic Brain Tumors „ Leptomeningeal Metastases „ Primary CNS Lymphoma „ Paraneoplastic Syndromes Clinical Presentation

„ For tumors within the brain parenchyma there are two classes of symptoms : „ Increased intracranial pressure „ Focal cerebral syndromes „ For leptomeningeal disease or spinal metastases, back or radicular pain is the usual presenting symptom.

Symptoms/Signs

„ Headache 60% (early morning 15%) „ Lifetime prevalence 90% „ Seizures 33% „ Visual disturbance/papilledema 10-20% „ Nausea/vomiting „ Focal neurologic signs Non-acute Headache and Imaging

„435 patients with migraine with aura (age 17-52) with normal neurologic exam: „CT +contrast normal in all but 1 (incidental choroid plexus papilloma) (Cuetter and Aita, Headache 1983, 23: 195) „Meta-analysis of 2,377 patients (17 studies) with normal neurologic exam with CT or MRI „897 patients with migraine: „3 brain tumors (1 associated with seizure), 1 AVM (associated with seizure) (Yield 0.4%) „1825 patients with unspecified headache: „21 brain tumors, 6 AVM, 3 aneurysms, 5 SDH, 8 hydrocephalus (Yield 2.4%) (AAN Practice parameter Neurology 1994, 44:1353 & Frishberg Neurology 1994, 44:1191)

Recommendations

„ Neuroimaging warranted in: „ New-onset headache „ Change in pattern of headache „ Headache with progressive course „ Abnormal neurologic exam „ History of seizures „ Known malignancy

(Frishberg, Semin Neurol. 1997;17(4):373-82) Increased Intracranial Pressure

„ Early: „ Headache, nausea, vomiting, change in mental status „ Late: „ Coma from uncal or cerebellar-foramen magnum herniation

Cerebral Syndromes

„ Hemispheric Specialization „ Dominant (left for 90%) „ Language „ Speech „ Calculation „ Non-Dominant (right) „ Spatial perception Frontal Lobe

„ Inappropriate social behavior „ Cognitive deficits „ Contralateral Weakness „ Abulia/aphasia (Broca’s) „ Frontal release signs „ Seizures „ “Depression”

Temporal Lobe

„ Fluent aphasia (Wernicke’s) „ Homonymous superior quadrantianopsia „ Short term memory loss „ Irritability/Limbic system – judgment, emotion „ Seizures (olfactory, gustatory hallucinations) „ Hemiparesis (mass effect) Parietal Lobe

„ Sensory deficit „ Contralateral neglect, R/L confusion (tumor in non- dominant hemisphere) „ Dyslexia „ Dysgraphia „ Homonymous inferior quadrantianopsia

Occipital Lobe

„ Loss of visual acuity „ Visual hallucinations „ Prosopagnosia – inability to recognize familiar/famous faces „ Seizures Cerebellum

„ Gait ataxia with or without truncal ataxia „ Dysarthria „ Dysmetria „ Nystagmus „ May have obstructive symptoms related to 4th ventricle compression

Corpus Callosum

„ “Butterfly glioma” „ Progressive severe dementia „ Incontinence „ Bilateral pyramidal symptoms Imaging: CT scan

„ Primary screen for: „ Mass effect „ Hemorrhage „ Edema „ Calcification „ Advantages: „ Rapid emergency access

Imaging: MRI

T1 no contrast T1 with contrast FLAIR

Advantages: Multiplanar imaging, superior sensitivity Offers physiological information MRI as primary diagnostic tool?

Glioblastoma Breast cancer

MR Spectroscopy Low grade glioma Cho Choline>Creatine Cre NAA • increase reflects tumor cellularity (turnover) N-acetyl aspartate (NAA) • neuronal marker depicts normal functional neurons

High grade glioma Cho Choline>>>Creatine • reflects high cellularity Cre NAA N-acetyl aspartate • loss of peak reflects tumor replacing normal brain PET Scan Indications:

1. Evaluate enhancement ? Tumor FDG ? Scar ? Radiation effect 2. Document disease progression

BCNU 2 cycles

Biopsy and CSF Analysis

„ Stereotactic Biopsy „ CT or MRI guided biopsy „ Low risk, high yield although sample variability is a problem in gliomas „ Open Biopsy: Craniotomy „ Mortality <5% in major centers „ If localized tumor and likely will need resection, often maximal tumor removal at time of initial craniotomy „ CSF Analysis „ Not part of the workup of primary malignant tumor or solid tumor metastases (except medulloblastoma) „ Used to diagnose leptomeningeal metastases „ Usually contraindicated when large cerebral masses present Overview

„ Introduction „ Clinical Presentation „ Primary Brain Tumors „ Metastatic Brain Tumors „ Leptomeningeal Metastases „ Primary CNS Lymphoma „ Paraneoplastic Syndromes

Primary Brain Tumors: Etiology „ Challenges to epidemiological study „ Uncommon form of cancer „ Diversity of histologic brain tumor types „ Lack of uniformly accepted classification system „ Variable reliability of exposure assessment (cognitive impairment of subjects and remote exposures) Primary Brain Tumors: Etiology „ Genetic Syndromes: 1-5% of brain tumors „ NFI and NFII „ Li-Fraumeni syndrome (P53 mutation) „ Radiation „ Ionizing radiation: meningiomas, nerve sheath „ Electromagnetic radiation? „ Radiofrequency radiation: ? Cellular telephones „ Head trauma, Environmental toxins, Infections

Malignant Gliomas Oligodendroglioma Ependymoma

Low grade astrocytoma 5-8 yrs Glioblastoma 10-14 months

Anaplastic Astrocytoma 2-3 yrs Two pathways to Glioblastoma

Low grade glioma (II) H&E

Non-enhancing mass •High cellularity •Cellular pleomorphism •Infiltrative Anaplastic Astrocytoma (III) H&E T1 + gad

•High cellularity Non-enhancing mass, •Pleomorphism heterogeneous •Mitosis

Glioblastoma (IV) T1 + gad H&E

Enhancing mass, cystic •High cellularity components, variable necrosis •Pleomorphism •Microvascular prolif •Necrosis Oligodendroglioma Low grade (II) Anaplastic (III)

High cellularity, classic “fried Increased cellularity, mitosis, egg” appearance of cells Microvascular prolif, necrosis

Treatment of Malignant Gliomas

„ Surgery and Radiation, although standard treatments, are not curative because of the infiltrative nature of gliomas. „ Chemotherapy extends survival but there are no curative regimens. „ No significant change in overall survival for any stage glioma in the past 20 years, until recently with the use Temodar Surgery

„ Goals: „ Accurate diagnosis „ Maximum tumor debulking „ Preserve neurologic function „ Increases survival by 2-3 months „ New techniques: „ Intraoperative MRI „ Functional mapping

Intraoperative MRI Radiation Therapy

„ Prolongs overall survival for anaplastic gliomas and glioblastomas. „ Unclear benefit for low-grade astrocytomas where median survival may be 10 years. „ Radiation to tumor and adjacent field (T2 areas + 2 cm margin) as effective as WBRT „ Dose 54-60 Gy in 180-200 cGy fractions „ no benefit from hyperfractionation „ No agent with documented radiosensitization „ Brachytherapy „ possibly prolong survival but increased risk of radiation necrosis „ Stereotactic radiosurgery „ used primarily for recurrent disease – good local control „ 80-90% patients recur within primary site

Adjuvant Chemotherapy

„ Low grade astrocytoma „ Likely role for chemotherapy but used in progressive cases „ Anaplastic glioma (astrocytoma, oligo- astro, oligodendroglioma) „ Procarbazine, CCNU and vincristine „ BCNU „ Temozolamide (Temodar) „ Glioblastoma „ Temozolamide recently shown to be beneficial. Oligodendrogliomas are chemosensitive subset of gliomas

„ Characteristic genetic profile includes loss of 1p and 19q „ Example: “GBM” reclassified as Anaplastic Oligo „ rapid and durable response to chemo//XRT Jan 1999 May 2002

PCV +XRT

Temozolomide (Temodar)

„ 2nd generation alkylating agent, bioavailable, crosses BBB „ Side effects profile „ 10-20% severe nausea and vomiting „ 3% myelosuppression „ Profound thrombocytopenia „ Single agent therapy „ Recurrent anaplastic glioma – 35% objective response rate, 27% stable disease, 46% 6 month PFS. „ Recurrent glioblastoma – reported response rate initial studies 5% and therefore is not initially approved for this indication. Recent Progress: New Standard of Care for Glioblastoma

Maximal surgical resection • Median survival 14.6 vs. 12.1 months • 2-year survival 26.5% vs. 10.4%

Involved-field RT + Concurrent temozolomide 75 mg/m2

6-12 cycles of temozolomide 150-200 mg/m2

*2005: Temodar: 1st new drug for brain tumor in decades Chemotherapy for Low-grade Gliomas

Oligodendroglioma PR after cycle 10

Oligodendroglioma MR after cycle 12

Astrocytoma PR after cycle 12

Astrocytoma PR 7 months after cycle 12

New Targets

Thalidomide Anti-VEGF Targeting specific genetic pathways

Gleevec EGFR antagonists (Iressa, Tarceva)

Mode of Action of Tyrosine Kinase Inhibitors

EGF/PDGF/IGF Antibody Extracellular R R Membrane Zarnestra Intracellular TKI EGFR-Iressa,Tarceva SCH66336 FTI 8 PDGFR-Gleevec VEGFR-PTK787 Ras 8 PI3K PTEN Raf AKT Bay 43- RAF inhibitor 9006 8Mek mTOR8mTOR Inhibitor Erk CCI-779, RAD001, AP23573 Proliferation Cell survival (anti-apoptosis)

Chemotherapy/ Angiogenesis radiotherapy resistance DNA Adult Brain Tumor: Targeted Therapeutics Responders Erlotonib/rapamycin Bevacizumab/CPT-11

10% 30%

*2009: Avastin 2nd new drug for brain tumor

Pediatric Brain Tumors: Everolimus for Subependymal Giant Cell Astrocytomas

100%

*2012: Affinitor:3rd new drug for brain tumors Novocure device approval

NovocureTM Establishes Initial Clinical Centers of Excellence for Treatment of Recurrent Glioblastoma Multiforme with Tumor Treating Fields (TTFields)TM Therapy

*2011: Novocure: 1st new device for brain tumors

MRI-Guided injection allowed accurate delivery of Toca 511 to multiple locations within the tumor

MRI-compatible ceramic cannula • Injection is started in the superior region of tumor

• Injection is completed in the inferior region tumor of the tumor

Tocagen Patient 171 Tumor regression after Toca 511 & Toca FC

Before Toca 511 & Toca FC After Toca 511 and 1st cycle of Toca FC

July, 2013 September, 2013 Tocagen patient 177

Overview

„ Introduction „ Clinical Presentation „ Primary Brain Tumors „ Metastatic Brain Tumors „ Leptomeningeal Metastases „ Primary CNS Lymphoma „ Paraneoplastic Syndromes Brain Metastases: A Growing Problem

„ Incidence: 25-40% of all cancer patients „ Symptomatic in 14% (~170,000 per year) „ Increasing as patients live longer with systemic disease „ Most common: lung (40%), breast (20%), melanoma (10%), renal (4%), unknown primary (1%) „ Melanoma and renal cell have high predilection for the brain „ 80% of metastases are supratentorial „ Median survival 2 – 9 months with aggressive treatment

Brain Metastases of Unknown Primary

„ Lung Cancer most common (>70-80%), especially adenocarcinoma and SCLC

„ Less Common: GI, melanoma, lymphoma, breast

„ Physical examination, stool guaic, urinalysis, CBC, tumor markers eg CEA, CXR, chest, abdomen, pelvic CT, bone scan, PET Mavrakis et al: Neurology 2005 27;65:908-11

„ Chest CT and brain MRI alone identified a biopsy site in 97% of patients with a newly detected brain mass

Treatment of Brain Metastases

„ Factors central to decision making: „ Status of systemic disease – prognosis without brain metastases „ Overall neurologic function „ Number of metastases „ Size of each lesion „ Location of each lesion Whole Brain Radiation Breast cancer – 10 mets

Indications: „ Previously, standard Rx for all cases „ Multifocal disease (>3 lesions) „ Symptomatic „ Not amenable to surgery or radiosurgery

Surgery for Metastases

„ Solitary or <3 metastases „ Surgery + WBRT vs. WBRT alone „ 2 randomized trials demonstrated survival benefit for addition of surgery, 1 did not „ Accepted “standard” therapy „ Multiple metastases „ ?Remove largest/symptomatic lesions Stereotactic Radiosurgery

„ Delivery of single fraction, high dose (15 Gy) radiation to a mass of <3 cm. „ Options for use: „ WBRT + Radiosurgery to 1-3 metastases „ ~ Equivalent to Surgery + WBRT „ Radiosurgery to control recurrent disease „ ?Radiosurgery as primary management without WBRT „ Survival data: wide variation depends on specifics of case.

Chemotherapy

„ Surgery, radiosurgery, radiation therapy do not result in cure „ Systemic therapy is treatment of choice but no active agents currently available „ Disease resistance to potentially active agents „ Inability to cross blood brain barrier „ Lack tumor-specific therapies „ Pts heavily pretreated with cytotoxic agents limits choice of drugs „ Desperate need for new therapies „ Need cooperative group input/planning Case: Metastatic Breast Cancer

„ 48yo female with breast cancer pre-treatment (A, B) and after treatment with whole-brain radiation and capecitabine chemotherapy (C, D). The enhancing lesions are markedly decreased in size. Because the patient had multiple, surgically inaccessible lesions, resection was not an option in this case.

Overview

„ Introduction „ Clinical Presentation „ Primary Brain Tumors „ Metastatic Brain Tumors „ Leptomeningeal Metastases „ Primary CNS Lymphoma „ Paraneoplastic Syndromes Leptomeningeal Metastases

„ Increasing „ 5-8% of patients with solid tumors „ Lung, breast, melanoma, prostate, renal cell, lymphoma (NHL) and myeloma „ SCLC: 9-18% of patients with prior cranial radiation; 20- 25% without prior radiation „ NHL: 5-29% „ 1% -2% of primary brain tumors „ Most patients (70%) have progressive systemic disease at presentation „ 1/3 of patients have concurrent epidural spinal or brain metastases „ Median survival 2-4 months

Mechanism of Tumor Spread to Meninges

„ Hematogenous spread to meninges

„ Spread from brain metastases

„ Invasion of meninges from vertebral metastases

„ Spread via nerve sheath

„ Hematogenous spread to choroid plexus

„ Spread via Batson’s plexus

„ Iatrogenic Clinical Diagnosis

„ LM should always be considered in a cancer patient with neurologic symptoms and signs involving several different sites in the neuroaxis

„ Usually occurs in the setting of disseminated systemic disease

Radiologic Diagnosis

76% sensitivity 77% specificity Pathology

CSF Cytology Leptomeningeal Metastases

„ Median survival 2-4 months „ Intrathecal chemotherapy is standard treatment „ Methotrexate, Thiotepa, Cytarabine „ Craniospinal radiation too toxic „ Radiation to localized sites of symptomatic disease „ Need for new systemic therapy – same issues as chemotherapy for brain metastases

Achieving adequate CSF levels of drugs Overview

„ Introduction „ Clinical Presentation „ Primary Brain Tumors „ Metastatic Brain Tumors „ Leptomeningeal Metastases „ Primary CNS Lymphoma „ Paraneoplastic Syndromes

Primary CNS Lymphoma

„ 2% of all intracranial tumors „ Increasing incidence over past 10 years „ HIV-related „ EBV-related „ Median survival >40 months Primary CNS Lymphoma

„ 25-50% are multifocal „ Cells can infiltrate spinal cord, CSF (~30%) uvea or vitreous of the eye (~10%) „ Histology: most are diffuse B cell „ Staging: must exclude systemic disease „ CT chest, abdomen, pelvis „ CSF analysis (minimum 10 cc) „ Slit lamp eye examination

Primary CNS Lymphoma - Treatment

„ Surgery: Biopsy only „ Radiation therapy: Whole brain radiation is not standard for patients anymore „ Chemotherapy: High-dose methotrexate improves long-term survival „ 3.5 g/m2 is standard - ? Benefit from higher dose „ Unclear added benefit from other cytotoxic agents „ Intrathecal therapy if CSF is positive – treat twice weekly until CSF clear x 3 „ Methotrexate „ Ara-C „ Thiotepa PCNSL: Chemosensitive tumors

Overview

„ Introduction „ Clinical Presentation „ Primary Brain Tumors „ Metastatic Brain Tumors „ Leptomeningeal Metastases „ Primary CNS Lymphoma „ Paraneoplastic Syndromes Paraneoplastic Syndromes

„ Group of neurologic disorders in cancer patients

„ Not caused by directs effects of the cancer itself or its metastases

„ Not caused by non-metastatic effects of the cancer such as:

„ Opportunistic infections

„ Side effects of therapy

„ Nutritional deficiency

„ Metabolic abnormalities

„ Cerebrovascular disorders

Incidence

„ Many cancer patients have mild neurologic findings such as neuropathies and myopathies (5-10%)

„ Clearly defined paraneoplastic syndromes are rare (<1%)

„ Increasingly diagnosed as recognition of clinical syndromes improve and specific antibody tests become widely available Significance

„ Accounts for a high percentage of patients with particular syndromes (e.g. > 60% LEMS, >50% PCD, opsoclonus- myoclonus)

„ Produce significant disability

„ Frequently precede diagnosis of cancer

„ May be mistaken for metastatic disease

„ Provides information regarding autoimmunity and tumor immunology

Pathogenesis

„ Unresolved but probably autoimmune in most cases

„ Antibodies against tumor antigens cross-reacts against neuronal antigens producing paraneoplastic syndrome

„ Cellular immunity probably also plays an important role Clinical Features of Paraneoplastic Syndrome

„ Characteristic clinical syndrome

„ Predominantly affecting one area of the nervous system

„ Acute or subacute onset

„ Results in severe neurologic disability

„ Often precedes diagnosis of cancer

„ CSF pleocytosis, elevated protein, oligoclonal bands Therapy For Paraneoplastic Cerebellar Degeneration

„ Prognosis: Generally poor „ Especially with anti-Yo positive patients „ Yo negative patients have slightly better prognosis „ Therapy: „ Treatment of underlying cancer „ Immunosuppression „ IVIG „ Steroids „ Cellcept, cytoxan „ Plasmapheresis (usually ineffective) NPH-Hydrocephalus

60yo female with history of recurrent NHL treated 15 years ago s/p auto stem cell transplant 12 months ago, now with 6 months of progressive decline in gait and now wheelchair bound.

After VP-Shunt Acknowledgments

„ NIH „ McDonnell Foundation „ American Brain Tumor Association „ Sontag Foundation „ National Brain Tumor Foundation „ Accelerate Brain Cancer Cure (ABC2) „ Boston Fire Department/John Kenney Foundation „ Florence Family Fund „ Patients and families

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ONCOLOGY Board Review Manual

Volume 10, Part 4 October 2013

Metastatic Brain Tumors

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STATEMENT OF EDITORIAL PURPOSE Metastatic Brain Tumors

The Hospital Physician Oncology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in oncology. Each manual reviews a topic essential Series Editor: to the current practice of oncology. Arthur T. Skarin, MD, FACP, FCCP Distinguished Physician, Dana-Farber Cancer Institute, PUBLISHING STAFF Harvard Medical School, Boston, MA

PRESIDENT, GROUP PUBLISHER Contributors: Bruce M. White Jai Grewal, MD Co-Medical Director, Long Island Brain Tumor Center at

SENIOR EDITOR NSPC, Lake Success, NY Robert Litchkofski Harpreet Kaur Grewal, MD University of Texas Health Sciences Center at Houston, EXECUTIVE VICE PRESIDENT Houston, TX Barbara T. White Santosh Kesari, MD, PhD Director, Neuro-Oncology Program, Translational Neuro- EXECUTIVE DIRECTOR Oncology Laboratories, Neurotoxicity Treatment Center, OF OPERATIONS Jean M. Gaul Moores Cancer Center, University of California San Diego Health System, La Jolla, CA

Table of Contents

Introduction ...... 2 Case Presentation ...... 3 NOTE FROM THE PUBLISHER: This publication has been developed with- Conclusion ...... 12 out involvement of or review by the Amer- Board Review Questions ...... 12 ican Board of Internal Medicine. References ...... 13

www.turner-white.com Oncology Volume 10, Part 4 1 Metastatic Brain Tumors ONCOLOGY BOARD REVIEW MANUAL

Metastatic Brain Tumors

Jai Grewal, MD, Harpreet Kaur Grewal, MD, and Santosh Kesari, MD, PhD

INTRODUCTION Brain metastases can present with a variety of symptoms (Figure 2), including focal neurological Systemic cancer can affect the central nervous deficits, headache, and seizures. The sudden onset system in several different ways, including direct of symptoms may be related to intracranial hemor- tumor metastasis and indirect remote effects. Intra- rhage associated with brain metastases. Given its cranial metastasis can involve the skull, dura, and relatively high incidence, lung cancer is the most leptomeninges (arachnoid and pia mater), as well common type of brain metastases to result in in- as the brain parenchyma. Of these, parenchymal tracranial hemorrhage. However, other cancer pri- brain metastases are the most common and have maries have, relative to their incidence, a very high been found in as many as 24% of cancer patients propensity to spontaneously develop tumor-associ- in autopsy studies.1 It has been reported that ated intracranial hemorrhage; they are melanoma, metastatic brain tumors outnumber primary brain renal cell carcinoma, choriocarcinoma, thyroid, and tumors 10 to 1.2 germ cell. Ultimately, any brain metastasis has the Metastasis to the brain generally occurs by he- potential for spontaneous hemorrhage. matogenous dissemination, with tumor cells having Often, the presentation of brain metastasis oc- a propensity to lodge and grow at the gray-white curs in a patient with established malignancy, in junction. The distribution of brain metastases is which case a clinical and radiological diagnosis proportionate to the cerebral blood flow, with 80% is usually sufficient. Magnetic resonance imaging occurring in the supratentorial region, 15% in the (MRI) with gadolinium contrast is preferred over cerebellum, and 5% in the brainstem.1 Unlike pri- computed tomography (CT) alone due to greater mary brain tumors, such as glioblastoma, brain sensitivity in identifying additional lesions. For ex- metastases do not typically involve the corpus ample, in approximately one-third of cases present- callosum or infiltrate across the midline. The most ing with a single metastasis on CT, MRI will lead to common primary histologies include lung, breast, the discovery of additional metastases (Figure 3).4 melanoma, renal, and colon cancer, and tumors of Occasionally, brain metastasis can occur as the unknown primary (Figure 1).3 presenting feature in a patient not known to have

Copyright 2013, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are sup- ported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment.

2 Hospital Physician Board Review Manual www.turner-white.com Metastatic Brain Tumors

Unknown Other 2% 10%

GYN 5%

GU 7% Lung 40%

GI 7%

Melanoma 10%

Breast 19%

Figure 1. Malignancies most commonly associated with brain metastasis. GI = gastrointestinal; GU = genitourinary; Gyn = gyne- cologic. (Data from Posner.3)

cancer. A thorough assessment is essential in iden- 5-fluorouracil. There are no other sites of meta- tifying the associated systemic malignancy and in static disease at diagnosis. determining which site of disease is safest for tissue Eight months after her diagnosis, she develops diagnosis. In the differential diagnosis, conditions right-sided headaches. She has an excellent per- apart from metastatic disease need to be consid- formance status. CT of the brain without contrast ered (Table 1). reveals a right parietal hypodensity with significant mass effect. MRI with gadolinium contrast does CASE PRESENTATION not reveal any additional lesions (Figure 4). There is no evidence of any active extracranial disease. INITIAL PRESENTATION AND EVALUATION A 54-year-old woman presents with a left • What are important prognostic factors in breast mass and is treated with a lumpec- brain metastasis? tomy and axillary lymph node dissection. Her tumor is negative for hormonal receptors (estro- PROGNOSIS gen receptor, progesterone receptor) and is also Several factors have been validated as important negative for HER2/neu (human epidermal growth prognostic factors in patients with brain metastasis. factor receptor 2). She has positive lymph nodes These include age, performance status, and extent and receives local radiation therapy and 8 cycles of extracranial disease. These factors have been of adjuvant cyclophosphamide, methotrexate, and used to stratify patients into several prognostic www.turner-white.com Oncology Volume 10, Part 4 3 Metastatic Brain Tumors

Headache 49

Cognitive 32

Weakness 30

Gait 21 Seizures 18

Speech 12

Vision 6

Percentage

Figure 2. Common presenting symptoms of brain metastasis. (Data from Posner.3)

ed: number of brain metastases. Known as graded prognostic assessment (GPA), this system scores patients from 0 to 4, with 4 corresponding to the most favorable prognosis.6 The most recent update found that significant prognostic factors differed for each of the following tumor types: non–small cell lung cancer (NSCLC), breast cancer, melanoma, renal cell carcinoma, and gastrointestinal cancers.7 In this analysis, patients with a low GPA score (0 to 1) tended to have a poor survival (of approximately Figure 3. (A) Computed tomography of the brain reveals a sin- 3 months) in all histologies examined. In addition, gle brain metastasis (arrow). (B) Magnetic resonance imaging performance status was found to be an important with contrast reveals a second small site of metastasis in the contralateral hemisphere (arrow). prognostic factor in all groups. With regard to breast cancer, there is emerging data that patients with hormone receptor–negative breast cancer may have increased risk of brain me- categories, known as RPA (recursive partitioning tastasis.8 Elevated serum lactate dehydrogenase analysis) classes.5 Discrete differences in survival (LDH) also has been suggested as a predictor for have been demonstrated based upon this clas- developing brain metastasis.9 The role of HER2/ sification (Table 2). Poor performance status sug- neu receptor status is unclear,10 but the prognosis gests a poor outcome (RPA class 3) regardless of of patients with brain metastasis in the setting of the other factors. The patient in this case is in the HER2-positive disease may be more favorable most favorable group, RPA class 1. due to better control of extracranial disease with Recently these prognostic categories were updat- trastuzumab.11 Features of breast cancer which ed and a fourth prognostic element was incorporat- may increase risk for developing brain metastasis

4 Hospital Physician Board Review Manual www.turner-white.com Metastatic Brain Tumors

Table 1. Differential Diagnosis of Brain Metastasis

Disease Process Example Demyelinating disease Multiple sclerosis Infection Cerebral abscess Primary brain tumor Glioblastoma Inflammatory/autoimmune Neurosarcoidosis Vascular Hemorrhagic stroke Idiopathic Radiation necrosis

Figure 4. Right parietal brain metastasis from breast cancer. Mag- include age less than 50 years, high-grade histol- netic resonance imaging of the brain with contrast (A) at diagnosis ogy, expression of basal cytokeratin CK5/6, over- and (B) after surgical resection. expression of HER2 or epidermal growth factor receptor (EGFR), and the lack of estrogen recep- tors.12 Stratification of breast cancer with gene expression arrays has identified subsets of breast of recurrent brain metastasis after initial treatment cancer with varying prognoses.13 Ongoing research has also been shown to be feasible in retrospective is exploring the implications of these categories analyses.20,21 Large tumor size, significant mass ef- with regard to brain metastasis. fect, noneloquent tumor location, and the need for diagnostic tissue are also considerations in making • What treatment options are available for a decision to perform an operation. brain metastasis? Whole Brain Radiation Therapy TREATMENT WBRT for brain metastases was described over Surgery 50 years ago by Chao and colleagues.22 This mo- Surgical resection is an important consideration dality, in contrast to the other local therapies, may for a patient with favorable prognostic factors (RPA address microscopic metastatic disease in the class 1 or 2) and a single brain metastasis in a sur- brain that is not yet clinically or radiographically gically accessible area. Several studies suggest im- evident. There is only one randomized study com- proved functional independence and overall survival paring WBRT and supportive care (with corticoste- if surgical resection is performed in addition to whole roids).23 In this study, 46 patients were randomized brain radiation therapy (WBRT),14–16 although one to either WBRT or supportive care; median survival randomized study and a subsequent meta-analysis was slightly longer in the group receiving WBRT dispute this benefit.17,18 Resection for several metas- (14 weeks versus 10 weeks). However, neither tases is less well-established than resection for sin- brain imaging with CT or MRI nor statistical analy- gle lesions, although it appears that resection of all sis was performed. Rates of local recurrence are intracranial metastases confers an outcome similar significantly higher in patients who have WBRT to resection of a single brain metastasis.19 Resection withheld and only receive local therapy (either sur- www.turner-white.com Oncology Volume 10, Part 4 5 Metastatic Brain Tumors

Table 2. Radiation Therapy Oncology Group (RTOG) A trial of PCI for locally advanced NSCLC re- Recursive Partitioning Analysis (RPA) Prognostic Classification vealed a decreased risk of brain metastasis with RPA Class Criteria Median Survival (months) increased neurocognitive toxicity.36,37 This trial was 1 KPS 70 7.1 ≥ closed prematurely due to poor accrual. Age <65 yr Controlled primary tumor No extracranial disease Stereotactic Radiosurgery 2 All other situations 4.2 Stereotactic radiosurgery (SRS) involves tech- 3 KPS <70 2.3 niques to precisely deliver high-dose radiation to KPS = Karnosky performance status. a small area of brain in a single or small number Adapted from Gaspar L, Scott C, Rotman M, et al. Recursive partition- of fractions. Theoretically, the surrounding tissue ing analysis (RPA) of prognostic factors in three Radiation Therapy is spared most of the dose. Small spherical brain Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745–51. tumors are the ideal target for SRS. SRS has indications outside the cancer setting, such as trigeminal neuralgia and arteriovenous malforma- tion. Depending on the technology, the dose is gery or stereotactic radiosurgery; see below),24–27 given either as a single fraction (most commonly) although overall survival appears similar, likely or over a small number of fractions. Use of a head- because death often results from extracranial dis- frame may be a necessary part of the technique ease. The effects of WBRT upon neurocognitive (eg, Gamma knife). A late and serious complica- function and quality-of-life are conflicting; declines tion of SRS is radionecrosis. Multiple studies have in neurocognitive function and quality-of-life have confirmed the ability of SRS to achieve local tumor been attributed to poor tumor control28–30 as well as control,38–42 even in radioresistant malignancies. to WBRT itself.31 Acute radiation toxicity includes SRS offers less morbidity than surgical resection headaches, nausea, vomiting, fatigue, alopecia, in treating patients with multiple brain metastases, ear fullness, dry mouth, and scalp irritation. Late and it may be more cost effective.43 Whether there toxicity from WBRT includes progressive cognitive is an upper limit to the number of brain metastases impairment, ataxia, and urinary incontinence.32,33 that can be treated with SRS is unclear; it appears Using smaller fraction size (3 Gy or less) decreas- feasible to treat patients with more than 10 metas- es the likelihood of such complications in the sub- tases.44 Randomized clinical trials evaluating surgi- set of patients who survive for a prolonged period cal resection, WBRT and SRS for brain metastasis of time. are summarized in Table 3.14,15,17,24,26,27,38,42,45,46 Prophylactic cranial irradiation (PCI) of approxi- mately 25 Gy of WBRT is considered standard of Pharmacologic Therapy care in the treatment of chemotherapy-sensitive In randomized trials, traditional chemotherapy small-cell lung cancer (SCLC), as there is both has demonstrated limited benefit in controlling a survival benefit and improved local control.34 metastatic brain tumors.47–50 There may be several A randomized study found that higher doses of PCI reasons for this. Most important, the blood-brain (36 Gy) for SCLC led to increased neurocognitive barrier limits the penetration of chemotherapy into toxicity without benefit.35 brain and brain tumor tissue. Additionally, because

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Table 3. Summary of Randomized Clinical Trials Regarding Treatments for Parenchymal Brain Metastases

Randomized Study Clinical Situation All Received Intervention N Conclusions Patchell Single brain WBRT Surgical resection 48 Undergoing surgical resection prior to WBRT improved local et al (1990)14 metastasis control at original site of metastasis, overall survival, and functional independence Vecht et al Single brain WBRT Surgical resection 63 Undergoing surgical resection prior to WBRT improved local (1993)15 metastasis control at original site of metastasis, overall survival, and functional independence,* particularly in patients with well- controlled extracranial disease Mintz et al Single brain WBRT Surgical resection 84 Undergoing surgical resection prior to WBRT failed to dem- (1996)17 metastasis onstrate an improvement in overall survival or functional independence Patchell Single brain Surgical WBRT 95 The addition of WBRT following surgical resection de- et al (1998)24 metastasis resection creased the risk of intracranial relapse and risk of neuro- logic death, but did not improve overall survival or func- tional independence Kondziolka 2–4 brain WBRT SRS 27† Adding SRS to WBRT was well tolerated and improved local et al (1999)42 metastases control, but did not improve overall survival Andrews Unresectable WBRT SRS 333 In patients with a single unresectable brain metastasis, add- et al (2004)38 1–3 brain ing SRS to WBRT led to improved overall survival. The metastases (RTOG SRS group experienced improved performance status. In 9508) subset analysis, patients with favorable histology (NSCLC), RPA class I, and age <50 also experienced a survival ad- vantage with the addition of SRS to WBRT. Aoyama 1–4 small SRS WBRT 132 Omitting WBRT after SRS increased the risk of local recur- et al (2006)26 (<3 cm) brain rence, but did not change overall survival. There were no metastasis significant differences in neurological function and toxicity between the 2 groups. Muacevic Single resectable – Resection + WBRT 33† The group treated with SRS alone experienced an increased et al (2008)45 brain metastasis versus SRS alone rate of distant intracranial relapse, although these distant sites could be salvaged with additional SRS. Other conclusions are difficult to make due to limited accrual to the study. Kocher 1–3 brain Either WBRT 359 Omitting WBRT after local therapy (with either surgery or et al (2011)27 metastases resection SRS) led to increased risk of intracranial relapse and (EORTC or SRS neurologic death; however, there were no significant differ- 22952) ences in overall survival or functional independence. Sepa- rately published analysis demonstrated improved QOL in the group that did not receive WBRT.‡ Sperduto 1–3 brain WBRT and 3-arm study of con- 126† The study was underpowered to derive conclusions; how- et al (2013)46 metastases SRS current/adjuvant: te- ever, there was a suggestion of improved survival and im- (RTOG 0320) mozolomide versus proved time to CNS progression in the control group,* that erlotinib versus none is, the group that received radiotherapy without drug. CNS = central nervous system; NSCLC = non–small cell lung cancer; QOL = quality of life; RPA = reverse partitioning analysis; SRS = stereotactic radiosurgery; WBRT = whole-brain radiation therapy. *Trend, but not statistically significant. †Study terminated early. ‡Soffietti R, Kocher M, Abacioglu UM, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality- of-life results. J Clin Oncol 2013;31:65–72. www.turner-white.com Oncology Volume 10, Part 4 7 Metastatic Brain Tumors brain metastasis can develop as a late feature in breast cancer, responses are observed (objective the course of cancer, the tumor may have already response rate of 38%) with the combination of been treated with several chemotherapy regimens, lapatinib plus capacitabine.55 Experimental thera- leading to some degree of chemoresistance in the pies for brain metastasis include the placement of metastatic tissue. BCNU (bis-chloroethylnitrosourea)–impregnated However, systemic chemotherapy does play an wafers into the resection cavity at the time of sur- important role in controlling extracranial disease. gery for single metastasis.60 For example, patients with brain metastasis from HER2-positive breast cancer may have improved Radiation Sensitizers survival compared to patients with brain metasta- Another approach in treating brain metastasis is sis associated with HER2-negative disease due to to utilize agents that may serve as a radiosensitizer. the efficacy of agents such as trastuzumab in con- Agents tested in a randomized controlled fashion in- trolling extracranial disease.51 Trastuzumab itself clude lonidamine,61 metronidazole,62 thalidomide,63 has no significant penetration across the blood- misonidazole,64 bromodeoxyuridine,65 gefitinib,54 brain barrier.52 and motexafin gadolinium.66 None of these agents Newer agents with better penetration into the cen- has been shown to prolong overall survival in brain tral nervous system, such as temozolomide,46,53,54 metastases, but motexafin gadolinium has been capecitabine, lapatinib,55 and erlotinib,46 have been shown to improve time to neurological progression investigated as treatment options for brain metas- as well as neurocognitive function in the subset of tasis, and as potential radiosensitizers. Many such patients with NSCLC.67,68 Based on the success agents are small-molecule compounds with rela- of the concurrent use of temozolomide with radia- tively favorable toxicity profiles. The optimal role of tion therapy in glioblastoma,69 temozolomide and chemotherapy in the treatment of brain metastasis erlotinib were separately tested as radiosensitiz- is still evolving. ers in a randomized controlled trial (RTOG-0320) The histology of the primary tumor is an impor- for patients with 3 or fewer brain metastases from tant consideration when selecting drug therapies. NSCLC. All arms of the study included SRS and In patients with metastatic melanoma and brain WBRT. Patients were randomized to either temo- metastasis, ipilumimab does not appear to con- zolomide, erlotinib, or no chemotherapy during the tribute to toxicity and may warrant further explora- period of radiotherapy and were allowed to con- tion.56,57 Sorafenib may decrease the incidence of tinue the drug as adjuvant therapy. Unfortunately, brain metastasis in patients with renal cell carci- the study was terminated early due to poor accrual, noma.58 and it appeared that overall survival was in fact EGFR mutations predict response to therapy worsened by adding 1 of the 2 agents compared with anti-EFGR agents such as erlotinib. Systemic with SRS/WBRT alone, although the study was resistance may occur while the metastatic disease underpowered to confirm this trend.46 in the central nervous system remains sensitive;59 Efaproxiral, an allosteric modifier of hemoglobin, higher concentration of drug might be achievable demonstrated improved survival and quality of life in the central nervous system via weekly “pulsa- when randomly assigned to 106 patients with breast tile” dosing of erlotinib. Finally, in HER2-positive cancer receiving WBRT and supplemental oxygen.70

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Supportive Care In addition to selecting definitive treatment of the central nervous system neoplasm, managing neu- rological symptoms is an important aspect of care of patients with metastatic brain tumors. There are several measures which can be taken to improve quality of life. Cerebral edema and mass effect from the tumor may result in many neurological symptoms. Surgi- cal resection of tumor, when feasible, is the most direct way of ameliorating this problem. Corti- costeroids improve vasogenic edema and are a mainstay in treating cerebral edema from primary or metastatic brain tumors. A typical dose of dexa- Figure 5. (A) Sulcal enhancement of the cerebellum (arrows) on methasone consists of an intravenous bolus of 10 brain magnetic resonance imaging (MRI), consistent with lepto- meningeal metastasis. (B) Leptomeningeal metastasis on lumbar to 20 mg followed by 4 to 24 mg/day in divided spine MRI with enhancement near the conus medullaris (arrows). doses. Vigilance is needed for side effects includ- ing hyperglycemia, peptic ulcer disease, weight gain, edema, psychosis, immunosuppression, and proximal weakness due to steroid myopathy. Cor- clinically and radiologically stable 6 months after ticosteroids are often continued until tumor control the completion of WBRT. After the eighth month, is achieved with definitive treatment (eg, surgery or she reports impaired balance and urinary incon- WBRT) and should then be tapered. tinence. Contrast MRI of the brain reveals sulcal Seizures can occur in patients with brain me- enhancement within the cerebellum. MRI of the tastasis. However, anticonvulsants should be re- spine shows leptomeningeal enhancement near served for patients who have actually experienced the conus medullaris (Figure 5). Lumbar puncture a seizure.71 Anticonvulsants that do not induce is performed; cerebrospinal fluid (CSF) analysis hepatic enzymes, such as levetiracetam, valpro- reveals elevated protein (121 mg/dL) and the pres- ate, gabapentin, and pregabalin, are less likely to ence of malignant cells on CSF cytology. These interact with chemotherapy and are preferred. cells are consistent with the primary cancer cells.

CASE 1 CONTINUED • What is the significance of these findings? The single metastasis is surgically resected without significant neurological sequelae LEPTOMENINGEAL METASTASIS (Figure 4). The pathological review is consistent The clinical, radiological, and laboratory find- with metastatic breast cancer. The patient then ings are suggestive of leptomeningeal metastasis receives WBRT to a total dose of 30 Gy in 15 (LM). LM refers to infiltration of the leptomeninges fractions. She receives surveillance brain MRI (arachnoid and pia mater) with neoplastic cells. with gadolinium every 3 months. She remains Synonyms for this condition include neoplastic www.turner-white.com Oncology Volume 10, Part 4 9 Metastatic Brain Tumors

Table 4. Signs and Symptoms of Leptomeningeal Metastasis at Initial Presentation

Symptoms Percentage Signs Percentage Cerebral Headache 38 Papilledema 12 Mental change 25 Abnormal mental state 50 Nausea and vomiting 12 Seizures 14 Gait difficulty 46 Extensor plantar response 50 Dysarthria/dysphagia 4 Diabetes insipidus 1 Loss of consciousness 6

Cranial nerve Visual loss 8 Optic neuropathy 2 Diplopia 8 Ocular motor paresis 30 Facial numbness 0 Trigeminal neuropathy 12 Hearing loss 6 Facial weakness 25 Dysphagia 2 Hearing loss 20 Hypoglossal neuropathy 8 Spinal Pain 25 Nuchal rigidity 16 Back 18 Straight leg raising 12 Radicular 12 Absent reflex 60 Paresthesias 10 Dermatomal sensory loss 50 Weakness 22 Lower motor neuron weakness 78 Bladder/bowel dysfunction 2 Adapted from DeAngelis LM, Boutros D. Leptomeningeal metastasis. Cancer Invest 2005;23:145–54.

meningitis, meningeal carcinomatosis, and lepto- each may be associated with a specific set of signs meningeal disease. The presence of malignant cells and symptoms (Table 4).73 Elevated intracranial pres- on CSF cytology is considered the diagnostic gold sure may result in headache, nausea, vomiting, and standard for this condition and is highly specific; confusion. Hematological malignancies are frequent- however, a single negative cytology does not nec- ly associated with LM, as are many types of solid essarily exclude the diagnosis. Three serial lumbar malignancies and primary brain tumors (Table 5).74 punctures for CSF analysis has a sensitivity of ap- The disease process may be diffuse or nodular. proximately 90%.72 CSF protein is commonly elevat- Diffuse LM may be difficult to detect on MRI. Nodu- ed. When unequivocal evidence of LM is noted on lar LM can cause symptoms due to mass effect MRI, a radiographic diagnosis of LM may be made and can result in spinal cord compression. Use of without CSF. intra-CSF chemotherapy may have limited benefit Simultaneous involvement of multiple levels of the for bulky leptomeningeal tumors greater than 2 mm neuroaxis is a clinical hallmark of LM. Cerebral, cra- in size due to limited penetration of drug.75–77 MRI nial nerve, and spine involvement are common and findings in LM are noted in Table 6.78,79

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Table 5. Malignancies Associated with Leptomeningeal Table 6. Magnetic Resonance Imaging Findings in Metastasis Leptomeningeal Metastasis

Malignancy Frequency (%) Finding Frequency (%) Non-CNS solid tumors Brain Lung Parenchymal volume loss 93 SCLC 15 Sulcal (pial) enhancement 57 NSCLC 1 Enhancing nodules 36 Breast 5 Ependymal enhancement 21 Melanoma 5 Communicating hydrocephalus 7 Gastrointestinal 1 Spine Head and neck 1 Cauda equina nerve root thickening 20 Hematologic malignancies Lineal pial enhancement 32 Leukemia 5–15 Enhancing subarachnoid nodules Not reported Lymphoma 6 Adapted from Chamberlain MC, Sandy AD, Press GA. Leptomeningeal Primary CNS tumors metastasis: a comparison of gadolinium-enhanced MR and contrast- PCNSL 42 enhanced CT of the brain. Neurology 1990;40(3 Pt 1):435–8; and Col- Glioma 14 lie DA, Brush JP, Lammie GA, et al. Imaging features of leptomeningeal metastases. Clin Radiol 1999;54:765–71. CNS = central nervous system; SCLC = small cell lung cancer; NSCLC = non-small-cell lung cancer; PCNSL = primary CNS lymphoma. Adapted from Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin 2003;21:27 sible from an Ommaya reservoir, it offers a means of delivering intra-CSF chemotherapy as well as obtaining CSF sampling with greater convenience than serial lumbar puncture. A radionucleotide CSF The prognosis of LM is poor and survival is typically flow study (cisternogram) may be performed prior less than 6 months. However, a small subset of pa- to delivering intrathecal chemotherapy to identify tients with LM (including those with breast cancer) may any sites of obstruction to CSF flow; these areas experience prolonged survival of 1 year or greater. may be treated with focal radiotherapy to restore normal flow patterns.80 Agents which may be ad- • What treatment options are available for pa- ministered into CSF for LM are listed in Table 7. tients with LM? Arachnoiditis, a common acute complication of intra- CSF chemotherapy, may present within 72 hours of Treatment options for patients with LM are pallia- drug administration as headache, nausea, and vomit- tive and include intrathecal chemotherapy, sys- ing, and is treated with systemic cortico-steroids. temic chemotherapy, and radiotherapy. Systemic chemotherapy may play a role in treat- ing LM as well as managing the extracranial ma- Chemotherapy lignancy (Table 8).81 Supportive care for patients Intra-CSF chemotherapy can be delivered via lum- with LM includes CSF shunting,82 corticosteroids, bar puncture (intrathecal) or via a ventricular catheter and anticonvulsants. connected to a reservoir placed under the scalp Radiation therapy can also be used to palliate (Ommaya reservoir). While complications are pos- LM. The extent of the central nervous system www.turner-white.com Oncology Volume 10, Part 4 11 Metastatic Brain Tumors

Table 7. Agents That Have Been Administered into Cerebrospinal Table 8. Chemotherapy Options in Leptomeningeal Metastasis. Fluid for Leptomeningeal Metastasis Drug CSF–Plasma Ratio (%) Methotrexate Antimetabolites Cytarabine (ara-C) Methotrexate 3 Liposomal cytarabine (DepoCyt) 6-Mercaptopurine 25 Thiotepa Cytarabine 20 Topotecan Capecitabine* Unknown Trastuzumab* Alkylating agents Rituximab* Thiotepa >90 Interleukin-2 Temozolomide† 20

*Perissinotti AJ, Reeves DJ. Role of intrathecal rituximab and trastu- *Rogers LR, Remer SE, Tejwani S. Durable response of breast cancer zumab in the management of leptomeningeal carcinomatosis. Ann leptomeningeal metastasis to capecitabine monotherapy. Neuro Oncol Pharmacother 2010;44:1633–40. 2004;6:63–4. †Ostermann S, Csajka C, Buclin T, et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma pa- tients. Clin Cancer Res 2004;10:3728–36. Adapted from Berg SL, Chamberlain MC. Systemic chemotherapy, treated may vary and can range from very limited intrathecal chemotherapy, and symptom management in the treatment radiation therapy to irradiation of the entire neu- of leptomeningeal metastasis. Curr Oncol Rep 2003;5:29–40. roaxis (craniospinal radiation therapy). This deci- sion may depend on many factors including the sites involved, neurological symptoms, functional status, extent of extracranial disease, and likeli- as patients survive longer with cancer. Brain me- hood of response to other therapies. tastases and leptomeningeal metastases are 2 types of central nervous system metastases which CASE CONTINUED require careful selection of treatment modalities for Treatment consisted of radiation therapy to each individual patient. The prognosis is generally the caudal equina area with improvement in poor for both conditions, but prognostic factors urinary incontinence. Following radiation therapy, in- have been identified which help to stratify patients trathecal liposomal cytarabine was administered via and determine the appropriateness of available an Ommaya reservoir with clearing of CSF cytology therapies. In addition to treatment of malignancy, after 3 doses. The patient remained neurologically management of neurological complications is im- stable, but developed new lung metastases which portant in managing these patients. More effec- were unresponsive to salvage treatment and result- tive therapies for these conditions are essential, ed in significant functional impairment. She decided as they represent a critical obstacle to the overall to pursue comfort care and died shortly thereafter. progress of cancer treatment.

CONCLUSION BOARD REVIEW QUESTIONS Test your knowledge of this topic. Go to www.turner-white.com and select Oncology Metastatic disease to the central nervous sys- from the drop-down menu of specialties. tem is an issue that has become more significant

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A phase 3 trial a phase II randomized trial Radiation Therapy Oncology of whole brain radiation therapy and stereotactic radio- Group (RTOG) 0212: impact of different total doses and surgery alone versus WBRT and SRS with temozolomide schedules of prophylactic cranial irradiation on chronic or erlotinib for non-small cell lung cancer and 1 to 3 brain neurotoxicity and quality of life for patients with limited- metastases: Radiation Therapy Oncology Group 0320. Int disease small-cell lung cancer. Int J Radiat Oncol Biol J Radiat Oncol Biol Phys 2013;85:1312–8. Phys 2011;81:77–84. 47. Mornex F, Thomas L, Mohr P, et al. [Randomised phase 36. Gore EM, Bae K, Wong SJ, et al. Phase III comparison III trial of fotemustine versus fotemustine plus whole brain of prophylactic cranial irradiation versus observation in irradiation in cerebral metastases of melanoma]. Cancer patients with locally advanced non-small-cell lung cancer: Radiother 2003;7:1–8. primary analysis of radiation therapy oncology group study 48. Postmus PE, Haaxma-Reiche H, Smit EF, et al. Treatment RTOG 0214. J Clin Oncol 2011;29:272–8. of brain metastases of small-cell lung cancer: comparing 37. Sun A, Bae K, Gore EM, et al. Phase III trial of prophy- teniposide and teniposide with whole-brain radiotherapy--a lactic cranial irradiation compared with observation in phase III study of the European Organization for the Re- patients with locally advanced non-small-cell lung cancer: search and Treatment of Cancer Lung Cancer Cooperative neurocognitive and quality-of-life analysis. J Clin Oncol Group. J Clin Oncol 2000;18:3400–8. 2011;29:279–86. 49. Robinet G, Thomas P, Breton JL, et al. Results of a phase 38. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain III study of early versus delayed whole brain radiotherapy radiation therapy with or without stereotactic radiosurgery with concurrent cisplatin and vinorelbine combination in boost for patients with one to three brain metastases: inoperable brain metastasis of non-small-cell lung cancer: phase III results of the RTOG 9508 randomised trial. Lan- Groupe Francais de Pneumo-Cancerologie (GFPC) Proto- cet 2004;363(9422):1665–72. col 95-1. Ann Oncol 2001;12:59–67. 39. Auchter RM, Lamond JP, Alexander E, et al. A multiinsti- 50. Ushio Y, Arita N, Hayakawa T, et al. Chemotherapy of brain tutional outcome and prognostic factor analysis of radio- metastases from lung carcinoma: a controlled randomized surgery for resectable single brain metastasis. Int J Radiat study. Neurosurgery 1991;28:201–5. Oncol Biol Phys 1996;35:27–35. 51. Kirsch DG, Loeffler JS. Brain metastases in patients 40. Flickinger JC, Kondziolka D, Lunsford LD, et al. A multi- with breast cancer: new horizons. Clin Breast Cancer

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2005;6:115–24. bined with radiation in the treatment of patients with brain 52. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin metastases (RTOG-7916). Int J Radiat Oncol Biol Phys Oncol 2000;18:2349–51. 1991;20:53–8. 53. Gamboa-Vignolle C, Ferrari-Carballo T, Arrieta O, et al. 65. Phillips TL, Scott CB, Leibel SA, et al. Results of a ran- Whole-brain irradiation with concomitant daily fixed-dose domized comparison of radiotherapy and bromodeoxy- temozolomide for brain metastases treatment: a ran- uridine with radiotherapy alone for brain metastases: domised phase II trial. Radiother Oncol 2012;102:187–91. report of RTOG trial 89-05. Int J Radiat Oncol Biol Phys 54. Pesce GA, Klingbiel D, Ribi K, et al. Outcome, quality of 1995;33:339–48. life and cognitive function of patients with brain metasta- 66. Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and ses from non-small cell lung cancer treated with whole neurologic outcomes in a randomized trial of motexafin brain radiotherapy combined with gefitinib or temozolo- gadolinium and whole-brain radiation therapy in brain me- mide. A randomised phase II trial of the Swiss Group for tastases. J Clin Oncol 2003;21:2529–36. Clinical Cancer Research (SAKK 70/03). Eur J Cancer 67. Mehta MP, Shapiro WR, Phan SC, et al. Motexafin gado- 2012;48:377–84. linium combined with prompt whole brain radiotherapy pro- 55. Lin NU, Eierman W, Greil R, et al. Randomized phase II longs time to neurologic progression in non-small-cell lung study of lapatinib plus capecitabine or lapatinib plus topo- cancer patients with brain metastases: results of a phase tecan for patients with HER2-positive breast cancer brain III trial. Int J Radiat Oncol Biol Phys 2009;73:1069–76. metastases. J Neurooncol. 2011;105:613–20. 68. Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive 56. Weber JS, Amin A, Minor D, et al. Safety and clinical activ- function and progression in patients with brain metastases ity of ipilimumab in melanoma patients with brain metas- treated with whole-brain radiation and motexafin gado- tases: retrospective analysis of data from a phase 2 trial. linium: results of a randomized phase III trial. J Clin Oncol Melanoma Res 2011;21:530–4. 2004;22:157–65. 57. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in 69. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy patients with melanoma and brain metastases: an open- plus concomitant and adjuvant temozolomide for glioblas- label, phase 2 trial. Lancet Oncol 2012;13:459–65. toma. N Engl J Med 2005;352:987–96. 58. Massard C, Zonierek J, Gross-Goupil M, et al. Incidence 70. Scott C, Suh J, Stea B, et al. Improved survival, quality of brain metastases in renal cell carcinoma treated with of life, and quality-adjusted survival in breast cancer pa- sorafenib. Ann Oncol 2010;21:1027–31. tients treated with efaproxiral (Efaproxyn) plus whole-brain 59. Grommes C, Oxnard GR, Kris MG et al. "Pulsatile" radiation therapy for brain metastases. Am J Clin Oncol high-dose weekly erlotinib for CNS metastases from 2007;30:580–7. EGFR mutant non-small cell lung cancer. Neuro Oncol 71. Glantz MJ, Cole BF, Forsyth PA, et al. Practice param- 2011;13:1364–9. eter: anticonvulsant prophylaxis in patients with newly 60. Ewend MG, Brem S, Gilbert M, et al. Treatment of single diagnosed brain tumors. Report of the Quality Standards brain metastasis with resection, intracavity carmustine Subcommittee of the American Academy of Neurology. polymer wafers, and radiation therapy is safe and pro- Neurology 2000;54:1886–93. vides excellent local control. Clin Cancer Res 2007;13: 72. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and 3637–41. treatment of leptomeningeal metastases from solid tumors: 61. DeAngelis LM, Currie VE, Kim JH, et al. The combined experience with 90 patients. Cancer 1982;49:759–72. use of radiation therapy and lonidamine in the treatment of 73. DeAngelis LM, Boutros D. Leptomeningeal metastasis. brain metastases. J Neurooncol 1989;7:241–7. Cancer Invest 2005;23:145–54. 62. Eyre HJ, Ohlsen JD, Frank J, et al. Randomized trial of ra- 74. Kesari S, Batchelor TT. Leptomeningeal metastases. Neu- diotherapy versus radiotherapy plus metronidazole for the rol Clin 2003;21:25–66. treatment metastatic cancer to brain. A Southwest Oncol- 75. Benjamin JC, Moss T, Moseley RP, et al. Cerebral distri- ogy Group study. J Neurooncol 1984;2:325–30. bution of immunoconjugate after treatment for neoplastic 63. Knisely JP, Berkey B, Chakravarti A, et al. A phase III meningitis using an intrathecal radiolabeled monoclonal study of conventional radiation therapy plus thalidomide antibody. Neurosurgery 1989;25:253–8. versus conventional radiation therapy for multiple brain 76. Burch PA, Grossman SA, Reinhard CS. Spinal cord metastases (RTOG 0118). Int J Radiat Oncol Biol Phys penetration of intrathecally administered cytarabine and 2008;71:79–86. methotrexate: a quantitative autoradiographic study. J Natl 64. Komarnicky LT, Phillips TL, Martz K, et al. A randomized Cancer Inst 1988;80:1211–6. phase III protocol for the evaluation of misonidazole com- 77. Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous www.turner-white.com Oncology Volume 10, Part 4 15 Metastatic Brain Tumors

meningitis: Leptomeningeal metastases in solid tumors. of 111indium-DTPA CSF flow studies in leptomeningeal Surg Neurol Int 2013 May 2;4(Suppl 4):S265–88. metastases. Neurology 1996;46:1674–7. 78. Chamberlain MC, Sandy AD, Press GA. Leptomenin- 81. Berg SL, Chamberlain MC. Systemic chemotherapy, intra- geal metastasis: a comparison of gadolinium-enhanced thecal chemotherapy, and symptom management in the MR and contrast-enhanced CT of the brain. Neurology treatment of leptomeningeal metastasis. Curr Oncol Rep 1990;40(3 Pt 1):435–8. 2003;5:29–40. 79. Collie DA, Brush JP, Lammie GA, et al. Imaging features of 82. Omuro AM, Lallana EC, Bilsky MH, DeAngelis LM. Ven- leptomeningeal metastases. Clin Radiol 1999;54:765–71. triculoperitoneal shunt in patients with leptomeningeal 80. Chamberlain MC, Kormanik PA. Prognostic significance metastasis. Neurology 2005;64:1625–7.

16 Hospital Physician Board Review Manual www.turner-white.com The new england journal of medicine

review article

Medical Progress Malignant Gliomas in Adults

Patrick Y. Wen, M.D., and Santosh Kesari, M.D., Ph.D.

From the Division of Neuro-Oncology, alignant gliomas account for approximately 70% of the 22,500 Department of Neurology, Brigham and new cases of malignant primary brain tumors that are diagnosed in adults Women’s Hospital; and the Center for 1-3 Neuro-Oncology, Dana−Farber Cancer In- Min the United States each year. Although relatively uncommon, malig- stitute — both in Boston. Address reprint nant gliomas are associated with disproportionately high morbidity and mortality. requests to Dr. Wen at the Center for Despite optimal treatment, the median survival is only 12 to 15 months for patients Neuro- Oncology, Dana−Farber/Brigham and Women’s Cancer Center, SW430D, with glioblastomas and 2 to 5 years for patients with anaplastic gliomas. Recently, 44 Binney St., Boston, MA 02115, or at there have been important advances in our understanding of the molecular patho- [email protected]. genesis of malignant gliomas and progress in treating them. This review summa- N Engl J Med 2008;359:492-507. rizes the diagnosis and management of these tumors in adults and highlights some Copyright © 2008 Massachusetts Medical Society. areas under investigation.

EPIDEMIOLOGIC FEATURES

The annual incidence of malignant gliomas is approximately 5 cases per 100,000 people.1,2 Each year, more than 14,000 new cases are diagnosed in the United States.1,2 Glioblastomas account for approximately 60 to 70% of malignant gliomas, anaplastic astrocytomas for 10 to 15%, and anaplastic oligodendrogliomas and anaplastic oligoastrocytomas for 10%; less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas account for the rest.1,2 The incidence of these tumors has increased slightly over the past two decades, especially in the elderly,4 primarily as a result of improved diagnostic imaging. Malignant gliomas are 40% more common in men than in women and twice as common in whites as in blacks.2 The median age of patients at the time of diagnosis is 64 years in the case of glioblastomas and 45 years in the case of anaplastic gliomas.2,4 No underlying cause has been identified for the majority of malignant gliomas. The only established risk factor is exposure to ionizing radiation.4 Evidence for an association with head injury, foods containing N-nitroso compounds, occupational risk factors, and exposure to electromagnetic fields is inconclusive.4 Although there has been some concern about an increased risk of gliomas in association with the use of cellular telephones,5 the largest studies have not demonstrated this.4,6,7 There is suggestive evidence of an association between immunologic factors and gliomas. Patients with atopy have a reduced risk of gliomas,8 and patients with glioblasto- ma who have elevated IgE levels appear to live longer than those with normal levels.9 The importance of these associations is unclear. Gene polymorphisms that affect detoxification, DNA repair, and cell-cycle regulation have also been implicated in the development of gliomas.4 Approximately 5% of patients with malignant gliomas have a family history of gliomas. Some of these familial cases are associated with rare genetic syndromes, such as neurofibromatosis types 1 and 2, the Li−Fraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcot’s syn- drome (intestinal polyposis and brain tumors).10 However, most familial cases have

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Downloaded from www.nejm.org by SANTOSH KESARI MD on July 30, 2008 . Copyright © 2008 Massachusetts Medical Society. All rights reserved. Medical Progress no identified genetic cause. Recently, an interna- and 3).18,22 Glioblastomas can be separated into tional consortium, GLIOGENE, was established two main subtypes on the basis of biologic and to study the genetic basis of familial gliomas.11 genetic differences.18,22 Primary glioblastomas t yp- ically occur in patients older than 50 years of age PATHOLOGICAL FEATURES and are characterized by EGFR amplif ication and mutations, loss of heterozygosity of chromosome Malignant gliomas are histologically heteroge- 10q, deletion of the phosphatase and tensin ho- neous and invasive tumors that are derived from mologue on chromosome 10 (PTEN), and p16 de- glia. The World Health Organization (WHO) clas- letion. Secondary glioblastomas are manifested in sif ies astrocytomas on the basis of histologic fea- younger patients as low-grade or anaplastic astro- tures into four prognostic grades: grade I (pilo- cytomas and transform over a period of several cytic astrocytoma), grade II (diffuse astrocytoma), years into glioblastomas. These tumors, which are grade III (anaplastic astrocytoma), and grade IV much less common than primary glioblastomas, (glioblastoma).1 Grade III and IV tumors are con- are characterized by mutations in the p53 tumor- sidered malignant gliomas. Anaplastic astrocy- suppressor gene,23 overexpression of the platelet- tomas are characterized by increased cellularity, derived growth factor receptor (PDGFR), abnor- nuclear atypia, and mitotic activity. Glioblastomas malities in the p16 and retinoblastoma (Rb) also contain areas of microvascular proliferation, pathways, and loss of heterozygosity of chromo- necrosis, or both (Fig. 1 and 2). Uncommon glio- some 10q.18,24 Secondary glioblastomas have tran- blastoma variants include gliosarcomas, which scriptional patterns and aberrations in the DNA contain a prominent sarcomatous element; giant- copy number that differ markedly from those of cell glioblastomas, which have multinucleated primary glioblastomas.18,22 Despite their genetic giant cells; small-cell glioblastomas, which are differences, primary and secondary glioblastomas associated with amplification of the epidermal are morphologically indistinguishable and respond growth factor receptor (EGFR); and glioblasto- similarly to conventional therapy, but they may re- mas with oligodendroglial features, which may be spond differently to targeted molecular therapies. associated with a better prognosis than standard High-grade oligodendrogliomas are character- glioblastomas.1,12 Oligodendrogliomas are divided ized by the loss of chromosomes 1p and 19q (in by the WHO into two grades: well-differentiated 50 to 90% of patients).1 Progression from low- oligodendrogli omas and oligoastrocytomas (WHO grade to anaplastic oligodendroglioma is associ- grade II), and anaplastic oligodendrogliomas and ated with defects in PTEN, Rb, p53, and cell- anaplastic oligoastrocytomas (WHO grade III) cycle pathways.1 (Fig. 1). All of these tumors may contain perinu- clear halos (Fig. 2C) and a delicate network of Deregulated Growth Factor Signaling branching blood vessels (chicken-wire pattern).1 The most common defects in growth-factor sig- Malignant gliomas typically contain both neo- naling involve EGFR and PDGFR (Fig. 3).18 Am- plastic and stromal tissues, which contribute to plification of EGFR occurs almost exclusively in their histologic heterogeneity and variable out- primary glioblastomas and is seen in approximate- come. Molecular studies such as gene-expression ly 40 to 50% of patients with that type of tumor. profiling potentially allow for better classification About half of the tumors with EGFR amplifica- of these tumors and separation of the tumors tion express a constitutively autophosphorylated into different prognostic groups.13-17 variant of EGFR, known as EGFRvIII, that lacks the extracellular ligand-binding domain (exons 2 MOLECULAR PATHOGENESIS through 7).14,18 This characteristic variant has become an important therapeutic target for ki- Recently, there has been important progress in our nase inhibitors, immunotoxins, and peptide vac- understanding of the molecular pathogenesis of cines.3,18 Recently, activating mutations in the ex- malignant gliomas, and especially the importance t r a c e l l u l a r d o m a i n o f E G F R h a v e b e e n i d e n t i f i e25 d . of cancer stem cells.18,19 Malignant transforma- PDGF signaling is a key regulator of glial devel- tion in gliomas results from the sequential accu- opment,26 and both ligand and receptors are fre- mulation of genetic aberrations and the deregu- quently expressed in gliomas, creating an auto- lation of growth-factor signaling pathways (Fig. 1 crine loop that stimulates proliferation of the

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Cell-of-Origin: Differentiated Glial or Stem or Progenitor Cells

Olig2 expression (100%) Olig2 expression (100%) Olig2 expression (100%) P53 mutated (>65%) EGFR amplified (~40%) LOH 1p, 4q, 19q PDGFA/PDGFR-α overexpressed (~60%) EGFR overexpressed (~60%) EGFR overexpressed EGFR mutated (~20–30%) PDGF/PDGFR overexpressed MDM2 amplified (~10%) Low-Grade Astrocytoma (5–10 yr)* MDM2 overexpressed (>50%) (WHO Grade II) LOH 10q (~70%) Low-Grade Oligodendroglioma (5–10 yr)* LOH 19q (~50%) P16Ink4a/P14ARF loss (~30%) (WHO Grade II) RB mutated (~25%) PTEN mutated (~40%) P16Ink4a/P14ARF loss CDK4 amplified (15%) PI3K mutated/amplified (~20%) RB mutated (~65%) MDM2 overexpressed (10%) RB mutated p53 mutated P16Ink4a/P14ARF loss (4%) VEGF overexpressed PTEN loss LOH 11p (~30%) LOH 9p, 10q Anaplastic Astrocytoma (2–3 yr)* CDK4/EGFR/MYC amplified (WHO Grade III) VEGF overexpressed LOH 10q (~70%) DCC loss (~50%) Anaplastic Oligodendroglioma (3–5 yr)* PDGFR-α amplified (~10%) (WHO Grade III) PTEN mutated (~10%) PI3K mutated/amplified (~10%) VEGF overexpressed Secondary Glioblastoma (12–15 mo)* Primary Glioblastoma (12–15 mo)* (WHO Grade IV) (WHO Grade IV)

Figure 1. Pathways in the Development of Malignant Gliomas. AUTHOR: Wen RETAKE 1st Genetic and chromosomal alterations involvedICM in the development of the three main types of malignant gliomas (primary and secondary 2nd REG F FIGURE: 1 of 5 glioblastomas and anaplastic oligodendroglioma) are shown. Oligodendrocyte transcription factor3rd 2 (Olig2) (blue) and vascular endo- thelial growth factor (VEGF) (red) are expressedCASE in all high-grade gliomas. Median lengthsRevised of survival (asterisks) are shown. A slash indicates one or the other or both. DCC denotesEMail deleted in colorectalLine carcinoma,4-C EGFR epidermalSIZE growth factor receptor, LOH loss of ARTIST: ts H/T H/T heterozygosity, MDM2 murine double minuteEnon 2, PDGF platelet-derived growth factor, PDGFR platelet-derived growth factor receptor, Combo 39p6 PI3K phosphatidylinositol 3-kinase, PTEN phosphatase and tensin homologue, and RB retinoblastoma. AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully.

tumor.18 Gr o w t h f a cJOB: t o r –35905 r e c e p t o r s i g n a l i n g , t h r o u g h importantISSUE: 7-31-08 role in the normal development of the intermediate signal-transduction generators, re- nervous system by promoting the proliferation of sults in the activation of transcriptional programs multipotent stem cells. Other developmental path- for survival, proliferation, invasion, and angio- ways that contribute to the biologic features of genesis. Common signal-transduction pathways gliomas are those involving sonic hedgehog, wing- activated by these growth factors are the Ras– less, Notch, CXC chemokine receptor 4 (CXCR4), mitogen-activated protein (MAP) kinase path- and bone morphogenetic proteins.19 In addition, way, which is involved in proliferation and cell- oligodendrocyte transcription factor 2 (Olig2), cycle progression, and the phosphatidylinositol a developmentally regulated, lineage-restricted 3-kinase (PI3K)–Akt–mammalian target of rapa- neural transcription factor, is a universal marker mycin (mTOR) pathways, which are involved in the of diffuse gliomas and stem cells that may be inhibition of apoptosis and cellular proliferation a prerequisite for early transformation.30 Drugs (Fig. 3).18 PTEN, a tumor-suppressor gene that neg- that target these pathways are under active in- atively regulates the PI3K pathway, is inactivated vestigation as treatment for gliomas. in 40 to 50% of patients with glio blastomas.18,27 Many of the above pathways lead to the up- Role of Stem Cells in Pathogenesis regulation of vascular endothelial growth factor and Resistance to Therapy (VEGF) and angiogenesis.28,29 EGFR, PDGFR, and Although the genetic and signaling pathways in- VEGF-receptor (VEGFR) pathways also play an volved in the development of malignant gliomas

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A B

* *

C D

E F

Figure 2. Pathological Features of Malignant Gliomas. Panels A and B show the histologic appearance of a glioblastoma, characterized by nuclear pleomorphism, dense cellu- larity, and pseudopalisading necrosis (asterisk) (Panel A, hematoxylin and eosin) as well as vascular endothelial prolifera- tion (asterisk) and mitotic figures (arrows)ICM (PanelAUTHOR B, hematoxylinwen and eosin).RETAKE Panels C 1stand D show the histologic features of an anaplastic oligodendroglioma, includingREG F FIGURE the typical 2a-f perinuclear halo (“fried egg”)2nd appearance (Panel C, hematoxy- CASE 3rd lin and eosin) and diffuse Olig2 staining (PanelTITLE D, brown color). The proliferationRevised index can be quantified by immunohis- tochemical analysis with the use of Ki67EMail staining (Panel E, blackLine color), 4-Cand heterogeneous EGFR amplification by colori- SIZE metric in situ hybridization showing moreEnon thanARTIST: two signalsmst (brownH/T spotsH/T in nuclei) in almost all tumor cells (Panel F). (Courtesy of Ali G. Saad, M.D., DepartmentFILL of Pathology, BrighamCombo and Women’s33p9 Hospital.) AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. have been relatively well characterized, the cellu- differentiation into distinctive mature cell types.31 JOB: 35905 ISSUE: 7-31-08 lar origins of these tumors are unknown. The There is increasing evidence that neural stem cells, adult nervous system harbors neural stem cells or related progenitor cells, can be transformed into that are capable of self-renewal, proliferation, and c a ncer st em cel ls a nd g ive r ise t o ma l ig na nt g l iom a s

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by escaping the mechanisms that control prolif- Figure 3 (facing page). Major Signaling Pathways eration and programmed differentiation (Fig. in Malignant Gliomas and the Corresponding Targeted 4).32-36 These stem cells are identified by several Agents in Development for Glioblastoma. immunocytochemical markers, such as CD133, RTK inhibitors that target epidermal growth factor a g l yc oprot ei n a l so k no w n a s prom i n i n 26,32,35,371. (EGF) receptor include gefitinib, erlotinib, lapatinib, Although stem cells account for only a minority BIBW2992, and vandetanib; those that target platelet- of the cells within malignant gliomas, they ap- derived growth factor (PDGF) receptor include ima- tinib, dasatinib, and tandutinib; those that target vas- 36,38 p e a r t o b e c r i t i c a l f o r g e n e r a t i n g t h e s e t u m o r s . cular endothelial growth factor (VEGF) receptor Recent studies suggest that glioma stem cells pro- include cediranib, pazopanib, sorafenib, sunitinib, vata- duce VEGF and promote angiogenesis in the tu- lanib, vandetanib, and XL184. EGF receptor antibodies mor microenvironment.39 In addition, tumor stem include cetuximab and panitumumab. Farnesyl trans- cells appear to require a vascular niche for opti- ferase inhibitors include lonafarnib and tipifarnib; HDAC inhibitors include depsipeptide, vorinostat, and 40 mal function. These observations raise the pos- LBH589; PI3K inhibitors include BEZ235 and XL765; sibility that antiangiogenic therapy may inhibit mTOR inhibitors include sirolimus, temsirolimus, the functioning of glioma stem cells. everolimus, and deforolimus; and VEGF receptor inhib- There is growing evidence that glioma stem itors include bevacizumab, aflibercept (VEGF-trap), cells may contribute to the resistance of malig- and CT-322. Growth factor ligands include EGF, PDGF, IGF, TGF, HGF/SF, VEGF, and FGF. Stem-cell pathways nant gliomas to standard treatments (Fig. 4). include SHH, wingless family, and Notch. Akt denotes Radioresistance in stem cells generally results murine thymoma viral oncogene homologue (also from the preferential activation of DNA-damage- known as protein kinase B), CDK cyclin-dependent ki- response pathways,41 whereas chemoresistance re- nase, ERK extracellular signal-regulated kinase, FGF fi- sults partly from the overexpression of O6-meth- broblast growth factor, FTI farnesyl transferase inhibi- tors, GDP guanine diphosphate, Grb 2 growth factor ylguanine−DNA methyltransferase (MGMT), the receptor-bound protein 2, GTP guanine triphosphate, up-regulation of multidrug resistance genes, and HDAC histone deacetylase, HGF/SF hepatocyte growth the inhibition of apoptosis.42-44 Therapeutic strat- factor/scatter factor, IGF insulin-like growth factor, egies that effectively target stem cells and over- MEK mitogen-activated protein kinase kinase, mTOR come their resistance to treatment will be neces- mammalian target of rapamycin, NF1 neurofibromin 1, PIP2 phosphatidylinositol (4,5) biphosphate, PIP3 sary if malignant gliomas are to be completely phosphatidylinositol 3,4,5-triphosphate, PI3K phos- eradicated (Fig. 4). A better understanding of the phatidylinositol 3-kinase, PKC protein kinase C, PLC biologic differences between normal and cancer phospholipase C, PTEN phosphatase and tensin ho- stem cells will be required to develop selective mologue, RAF v-raf 1 murine leukemia viral oncogene therapies that spare normal brain cells. homologue 1, RAS rat sarcoma viral oncogene homo- logue, RTK receptor tyrosine kinase inhibitor, SHH sonic hedgehog, SOS son of sevenless, Src sarcoma DIAGNOSIS (Schmidt-Ruppin A-2) viral oncogene homologue, TGF transforming growth factor family, and TSC1 and 2 tu- Clinical Presentation berous sclerosis gene 1 and 2. Red text denotes inhibi- 3 Patients with malignant gliomas may present with tors. Data are from Sathornsumetee et al., Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21 a variety of symptoms, including headaches, sei- zures, focal neurologic def icits, confusion, mem- ory loss, and personality changes. Although the typically show a heterogeneously enhancing mass classic headaches that are suggestive of increased with surrounding edema. Glioblastomas frequent- intracranial pressure are most severe in the morn- ly have central areas of necrosis and more exten- ing and may wake the patient from sleep, many sive peritumoral edema than that associated with patients experience headaches that are indistin- anaplastic gliomas.45 Functional MRI may help guishable from tension headaches. When severe, define the relationship of speech and motor ar- the headaches may be associated with nausea and eas to the tumor and aid in the planning of sur- vomiting. gery. Diffusion-weighted imaging, diffusion ten- sor imaging, dynamic contrast-enhanced MRI to Imaging measure vessel permeability, and perfusion im- The diagnosis of malignant gliomas is usually aging to measure relative cerebral blood volume suggested by magnetic resonance imaging (MRI) are increasingly used as diagnostic aids and as a or computed tomography. These imaging studies means of monitoring the response to therapy.46

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Proton magnetic resonance spectroscopy detects line peak (reflecting increased membrane turn- the levels of metabolites and may help differenti- over) and a decrease in the N-acetyl aspartate peak ate a tumor from necrosis or benign lesions. In (reflecting decreased neuronal cellularity), as com- patients with malignant gliomas, this imaging pared with the findings in unaffected areas of the technique typically shows an increase in the cho- brain.45,46 Positron-emission tomography that uses

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Figure 4. Resistance Mechanisms in Glioma Cells. Normal neural stem cells self-renew and give rise to multipotential progenitor cells that form neurons, oligodendro- glia, and astrocytes. Glioma stem cells arise from the transformation of either neural stem cells or progenitor cells (red) or, less likely, from differentiation of a oligodendrocytes or astrocytes (thin red arrows) and lead to malignant gliomas. Glioma stem cells are relatively resistant to standard treatments such as radiation and chemotherapy and lead to regrowth of the tumor after treatment. Therapies directed at stem cells can deplete these cells and poten- tially lead to more durable tumor regression (blue).

isotopes such as 18F-fluorodeoxyglucose, 18F-flu- are performed in the first month after radiothera- oro-l-thymidine, 11C-methionine, and 3,4-dihy- py show increased enhancement.48 In 50% of these droxy-6-18F-fluoro-l-phenylalanine is being eval- cases, the increased enhancement reflects a tran- uated for its usefulness in diagnosis and in mon- sient increase in vessel permeability as a result of itoring the response to therapy.47 radiotherapy, a phenomenon termed “pseudopro- In up to 40% of cases, the MRI studies that gression,” which improves with time.48 Differen-

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Downloaded from www.nejm.org by SANTOSH KESARI MD on July 30, 2008 . Copyright © 2008 Massachusetts Medical Society. All rights reserved. Medical Progress tiating this transient effect from true progres- of 20 to 30%.49,53 The risk of intratumoral hem- sion of the cancer can be challenging initially, orrhage associated with anticoagulation therapy even with advanced imaging techniques. in patients with gliomas who have venous throm- boembolism is low,49,54 whereas inferior vena cava TREATMENT filters are associated with high complication rates.55 Unless a patient with malignant glioma General Medical Management and venous thromboembolism has an intracere- Much of the care of patients with malignant bral hemorrhage or other contraindications, it is gliomas involves general medical management. generally safe to provide anticoagulation therapy The most common problems include seizures, per- for the venous thromboembolism. Low-molecular- itumoral edema, venous thromboembolism, fa- weight heparin may be more effective and safer tigue, and cognitive dysfunction.49 Patients who than warfarin.56 present with seizures should be treated with an- Patients with malignant gliomas frequently ex- tiepileptic drugs. Since antiepileptic drugs that perience fatigue and may benefit from treatment induce hepatic cytochrome P-450 enzymes, such with modafinil or methylphenidate.57 Methyl- as phenytoin and carbamazepine, increase the me- phenidate may also help abulia, and donepezil58 tabolism of many chemotherapeutic agents, anti- and memantine may reduce memory loss, although epileptic drugs that do not induce these enzymes, evidence supporting these approaches remains such as levetiracetam, are generally preferred. The limited. Depression is underdiagnosed in patients use of prophylactic antiepileptic drugs in patients with malignant gliomas, and antidepressants and with malignant gliomas who have never had a psychiatric support are often invaluable.59 seizure is controversial. The American Academy of Neurology issued a practice guideline indicating Specific Therapy for Newly Diagnosed that there is no evidence that prophylactic anti- Malignant Gliomas epileptic drugs are beneficial and advises against The standard therapy for newly diagnosed malig- the routine use of antiepileptic drugs in patients nant gliomas involves surgical resection when fea- with brain tumors who have not had seizures.50 sible, radiotherapy, and chemotherapy (Table 1). Corticosteroids such as dexamethasone are fre- Malignant gliomas cannot be completely eliminat- quently used to treat peritumoral edema. Cush- ed surgically because of their infiltrative nature, ing’s syndrome and corticosteroid myopathy may but patients should undergo maximal surgical develop in patients who require prolonged treat- resection whenever possible. Surgical debulking ment with high doses of corticosteroids. Patients reduces the symptoms from mass effect and pro- with brain tumors who receive corticosteroids are vides tissue for histologic diagnosis and molecu- at increased risk for Pneumocystis jiroveci pneumoni- lar studies. Advances such as MRI-guided neuro- tis, and prophylactic antibiotic therapy should be navigation, intraoperative MRI, functional MRI, considered,49 although a recent meta-analysis did intraoperative mapping,60 and fluorescence-guid- not show a benefit from this approach.51 As the ed surgery61 have improved the safety of surgery rate of survival among patients with malignant and increased the extent of resection that can be glioma improves, long-term complications from achieved. The value of surgery in prolonging sur- treatment with corticosteroids, including osteo- vival is controversial, but patients who undergo porosis and compression fractures, are becoming extensive resection probably have a modest sur- increasingly evident, and preventive measures, vival advantage.60-62 Stereotactic biopsies should such as treatment with vitamin D, calcium sup- be performed only in patients who have inoper- plements, and bisphosphonates, should be con- able tumors that are located in critical areas. sidered. Novel therapies such as corticotropin- Radiotherapy is the mainstay of treatment for releasing factor, bevacizumab (a humanized VEGF malignant gliomas. The addition of radiotherapy monoclonal antibody), and VEGFR inhibitors de- to surgery increases survival among patients with crease peritumoral edema and may reduce the glioblastomas from a range of 3 to 4 months to need for corticosteroids.49,52 a range of 7 to 12 months.63,64 Conventional ra- Patients with malignant gliomas are at in- diotherapy consists of 60 Gy of partial-field exter- creased risk for venous thromboembolism from nal-beam irradiation delivered 5 days per week leg and pelvic veins, with a cumulative incidence in fractions of 1.8 to 2.0 Gy. After standard radio-

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Table 1. Summary of Current Treatments for Malignant Gliomas.*

Type of Tumor Therapy Newly diagnosed tumors Glioblastomas (WHO grade IV) Maximal surgical resection, plus radiotherapy, plus concomitant and adjuvant TMZ or carmustine wafers (Gliadel)† Anaplastic astrocytomas (WHO Maximal surgical resection, with the following options after surgery (no ac- grade III) cepted standard treatment): radiotherapy, plus concomitant and adjuvant TMZ or adjuvant TMZ alone† Anaplastic oligodendrogliomas Maximal surgical resection, with the following options after surgery (no ac- and anaplastic oligoastrocy- cepted standard treatment): radiotherapy alone, TMZ or PCV with or with- tomas (WHO grade III) out radiotherapy afterward, radiotherapy plus concomitant and adjuvant TMZ, or radiotherapy plus adjuvant TMZ†‡ Recurrent tumors Reoperation in selected patients, carmustine wafers (Gliadel), conventional chemotherapy (e.g., lomustine, carmustine, PCV, carboplatin, irinotecan, etoposide), bevacizumab plus irinotecan, experimental therapies‡

* Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21 PCV denotes procar- bazine, lomustine (CCNU), and vincristine, and TMZ temozolomide. † Radiotherapy is administered at a dose of 60 Gy given in 30 fractions over a period of 6 weeks. Concomitant TMZ is ad- ministered at a dose of 75 mg per square meter of body-surface area per day for 42 days with radiotherapy. Beginning 4 weeks after radiotherapy, adjuvant TMZ is administered at a dose of 150 mg per square meter per day on days 1 to 5 of the first 28-day cycle, followed by 200 mg per square meter per day on days 1 to 5 of each subsequent 28-day cycle, if the first cycle was well tolerated. ‡ PCV therapy consists of lomustine (CCNU), 110 mg per square meter, on day 1; procarbazine, 60 mg per square meter, on days 8 to 21; and vincristine, 1.5 mg per square meter (maximum dose, 2 mg), on days 8 and 29.

therapy, 90% of the tumors recur at the original apy results in a modest increase in survival (a 6 to site.65 Strategies to increase the radiation dose to 10% increase in the 1-year survival rate).75,76 the tumor with the use of brachytherapy 66 and The European Organisation for Research and stereotactic radiosurgery 67,68 have failed to im- Treatment of Cancer (EORTC) and the National prove survival. Newer chemotherapeutic agents,69 Cancer Institute of Canada (NCIC) conducted a targeted molecular agents,20 and antiangiogenic phase III trial comparing radiotherapy alone (60 Gy agents70 may enhance the effectiveness of radio- over a period of 6 weeks) with radiotherapy and therapy. concomitant treatment with temozolomide (75 mg Patients who are older than 70 years of age have per square meter of body-surface area per day a worse prognosis than younger patients and rep- for 6 weeks), followed by adjuvant temozolomide resent a particular challenge. Among these pa- therapy (150 to 200 mg per square meter per day tients, radiotherapy produces a modest benefit in for 5 days every 28 days for 6 cycles), in patients median survival (29.1 weeks) as compared with with newly diagnosed glioblastomas.64 As reported supportive care (16.9 weeks).71 Since older pa - by Stupp et al., the combination of radiotherapy tients often tolerate radiotherapy less well than and temozolomide had an acceptable side-effect younger patients, an abbreviated course of radio- profile and, as compared with radiotherapy alone, therapy (40 Gy in 15 fractions over a period of increased the median survival (14.6 months vs. 3 weeks)72 or chemotherapy with temozolomide 12.1 months, P<0.001).64 In addition, the survival (an oral alkylating agent with good penetration rate at 2 years among the patients who received of the blood–brain barrier) alone73 may be con- radiotherapy and temozolomide was significantly sidered, since the outcomes with these approach- greater than the rate among the patients who es are similar to the outcomes with conventional received radiotherapy alone (26.5% vs. 10.4%),64 radiotherapy regimens. establishing radiotherapy with concomitant and Chemotherapy is assuming an increasingly im- adjuvant temozolomide as a useful combination portant role in the treatment of malignant gliomas. for newly diagnosed glioblastomas. Although early studies of adjuvant chemotherapy MGMT is an important repair enzyme that con- for malignant gliomas with the use of nitroso- tributes to resistance to temozolomide. In a com- ureas failed to show a benefit,63,74 two meta- panion study to the EORTC–NCIC study reported analyses have suggested that adjuvant chemother- by Stupp et al., tumor specimens from the pa-

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Downloaded from www.nejm.org by SANTOSH KESARI MD on July 30, 2008 . Copyright © 2008 Massachusetts Medical Society. All rights reserved. Medical Progress tients were examined for epigenetic silencing of 19q,79 mediated by an unbalanced translocation the MGMT gene.15 MGMT promoter methylation of 19p to 1q,80 occurs in 61 to 89% of patients with silences the gene, thus decreasing DNA repair ac- anaplastic oligodendrogliomas and 14 to 20% of tivity and increasing the susceptibility of the tu- patients with anaplastic oligoastrocytomas. Tu- mor cells to temozolomide. Patients with glioblas- mors in patients with the 1p and 19q codeletion toma and MGMT promoter methylation (45% of the are particularly sensitive to chemotherapy with total) who were treated with temozolomide had PCV — procarbazine, lomustine (CCNU), and vin- a median survival of 21.7 months and a 2-year cristine — with response rates of up to 100%, as survival rate of 46%. In contrast, patients without compared with response rates of 23 to 31% among MGMT promoter methylation who were treated patients without the deletion of chromosomes 1p with temozolomide had a significantly shorter and 19q.81,82 The reason for the increased chemo- median survival of only 12.7 months and a 2-year sensitivity of tumors in patients with the 1p and survival rate of 13.8%.15 Currently, temozolomide 19q codeletion is unclear. One study suggested is used in the treatment of glioblastomas regard- that 1p loss is associated with decreased levels of less of MGMT promoter methylation status. How- stathmin and an increased sensitivity to nitroso­ ever, if the importance of MGMT promoter methy- ureas.83 The status of chromosomes 1p and 19q, lation is confirmed by the results of an ongoing rather than standard histologic assessment, is now study by the Radiation Therapy Oncology Group used as an eligibility criterion in studies involv- (RTOG 0525), patients with unfavorable MGMT ing patients with anaplastic oligodendrogliomas methylation status may be selected for other and anaplastic oligoastrocytomas, reflecting a par- treatments in future investigations. Studies of adigm shift in the design of clinical trials for pa- dose-intensive temozolomide regimens to deplete tients with these tumors. MGMT and of combinations of temozolomide Two large phase III studies of PCV chemother- with inhibitors of MGMT, such as O6-benzylgua- apy with radiotherapy, as compared with radio- nine, and inhibitors of other repair enzymes, such therapy alone, in patients with newly diagnosed as poly-(ADP-ribose)-polymerase, are in progress. anaplastic oligodendrogliomas or anaplastic oli- Another chemotherapeutic approach involves goastrocytomas, have been reported.84,85 In both the implantation of biodegradable polymers con- studies, the addition of chemotherapy to radio- taining carmustine (Gliadel Wafers, MGI Pharma) therapy increased the time to tumor progression into the tumor bed after resection of the tumor. by 10 to 12 months but did not improve overall The aim of treatment with these polymers, which survival (median, 3.4 and 4.9 years).84,85 The fail- release carmustine gradually over the course of ure of chemotherapy to increase survival may be several weeks, is to kill residual tumor cells. In partly explained by the fact that patients who ini- a randomized, placebo-controlled trial that inves- tially received radiotherapy alone subsequently re- tigated the use of these polymers in patients with ceived chemotherapy when they had a relapse, so newly diagnosed malignant gliomas, median sur- that most patients in both groups eventually re- vival increased from 11.6 months to 13.9 months ceived chemotherapy. In both studies, patients (P = 0 . 0 3 ) . 77 This survival advantage was main- with the codeletion of 1p and 19q had improved tained at 2 and 3 years.78 survival as compared with those without the code- letion of 1p and 19q. Although most studies Therapy for Anaplastic Gliomas involving patients with anaplastic oligodendro- Anaplastic astrocytomas are treated with radio- gliomas or anaplastic oligoastrocytomas were con- therapy and either concurrent and adjuvant temo- ducted with PCV chemotherapy, temozolomide is zolomide (as for glioblastomas) or adjuvant temo- likely to have similar activity and less toxicity79; zolomide alone. Currently, there are no findings however, studies directly comparing the two regi- from controlled trials that support the use of con- mens have not been performed. current temozolomide in patients with anaplastic astrocytomas. Therapy for Recurrent Malignant Gliomas Anaplastic oligodendrogliomas and anaplas- Despite optimal treatment, nearly all malignant tic oligoastrocytomas are an important subgroup gliomas eventually recur. For glioblastomas, the of malignant gliomas that are generally more re- median time to progression after treatment with sponsive to therapy than are pure astrocytic tu- radiotherapy and temozolomide is 6.9 months.64 mors.79 A codeletion of chromosomes 1p and If the tumor is symptomatic from mass effect, re-

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operation may be indicated Table( 1). However, sur- have poor penetration across the blood−tumor bar- gery performed in selected patients results in only rier. There has been considerable interest in iden- limited prolongation of survival.86 tifying molecular features of the tumor that pre- The usefulness of radiotherapy for recurrent dict a response, so that patients who are most malignant gliomas is controversial.87 Although likely to benefit can be selected for a particular some reports have suggested that fractionated ste- treatment. EGFR inhibitors appear to be more ef- reotactic reirradiation88 and stereotactic radiosur- fect i ve i n pat ient s who h ave t u mor s w it h EGFRvI I I gery68 may be beneficial, selection bias may have mutations and intact PTEN than in patients who influenced these results. do not have these molecular changes99; patients The value of conventional chemotherapy for re- who have tumors with increased activity of the current malignant gliomas is modest. In general, PI3K–Akt pathway, as indicated by an increase in chemotherapy is more effective for anaplastic phosphorylated Akt, generally do not have a re- gliomas than for glioblastomas.79,87 Temozolo- sponse.100 Current experimental strategies to in- mide was evaluated in a phase II study involving crease the effectiveness of targeted molecular ther- patients with recurrent anaplastic gliomas who apies include the use of a single agent targeted had previously been treated with nitrosoureas; the against several kinases, combinations of agents study showed a 35% response rate. The 6-month that inhibit complementary targets such as EGFR rate of progression-free survival was 46%,89 com- and mTOR (Table 2 and Fig. 5A through 5D), and paring favorably with the 31% rate of progression- targeted agents combined with radiotherapy and free survival at 6 months for therapies that were chemotherapy.3,18,20,21 reported to be ineffective.90 In contrast, temozolo- mide has only limited activity in patients with Antiangiogenic Agents recurrent glioblastomas (response rate, 5.4%; Malignant gliomas are among the most vascular 6-mont h rate of progression-free sur vival, 21%).91 of human tumors,18 making them especially at- Other chemotherapeutic agents that are used for tractive targets for angiogenesis inhibitors.29 Al- recurrent gliomas include nitrosoureas, carbo- though older antiangiogenic agents such as tha- platin, procarbazine, irinotecan, and etoposide. lidomide had only modest activity,101 newer and Carmustine wafers have modest activity, increas- more potent angiogenesis inhibitors show prom- ing the median survival by approximately 8 weeks ising activity. In preliminary studies, treatment in patients with recurrent glioblastomas.92 with the combination of bevacizumab and irino- tecan was associated with a low incidence of hem- INVESTIGATIONAL THERAPIES orrhage and response rates of 57 to 63% among patients with malignant gliomas (Fig. 5E through Targeted Molecular Therapies 5H).102,103 Some of the improvement that is seen The improved understanding of the molecular on radiographic images may be artifactual, caused pathogenesis of malignant gliomas has allowed by reduced vascular permeability and decreased a more rational use of targeted molecular thera- contrast enhancement as a result of the inhibi- pies (Fig. 3).18,20,21 Particular interest has focused tion of VEGF. However, this regimen also has on inhibitors that target receptor tyrosine kinases antitumor activity, as evidenced by the fact that it such as EGFR,93 PDGFR,94 and VEGFR,52 as well increased the 6-month rate of progression-free as on signal-transduction inhibitors targeting survival to 46% among patients with recurrent mTOR,95,96 farnesyltransferase,97 and PI3K (Ta- glioblastomas,102,103 as compared wit h a 6-mont h ble 2). Single agents have only modest activity, rate of progression-free survival of 21% for pa- with response rates of 0 to 15% and no prolonga- tients who were receiving treatment with temozo- tion of 6-month progression-free survival.3,20,21 lomide.91 Recently, a large, randomized phase II These disappointing results are due to several fac- trial of bevacizumab alone and bevacizumab with tors. Most malignant gliomas have coactivation of irinotecan was completed. Preliminary results con- multiple tyrosine kinases,98 as well as redundant firmed the safety of bevacizumab and showed an signaling pathways, thus limiting the activity of increase in the 6-month rate of progression-free single agents. In addition, many of these agents survival to 35.1% for patients receiving bevacizu-

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Table 2. Selected Investigational Treatments for Malignant Gliomas.*

Type of Treatment Example Convection-enhanced surgical delivery of pharmacologic Cintredekin besudotox agent Drugs to overcome resistance to TMZ Dose-dense TMZ MGMT inhibitors O6-benzylguanine PARP inhibitors BSI-201, ABT-888 New chemotherapies RTA744, ANG1005 Antiangiogenic therapies Anti-αvβ5 integrins Cilengitide Anti-hepatocyte growth factor AMG-102 Anti-VEGF Bevacizumab, aflibercept (VEGF-Trap) Anti-VEGFR Cediranib, pazopanib sorafenib, sunitinib, vandetinib, vatalanib, XL184, CT-322 Other agents Thalidomide Targeted molecular therapies Akt Perifosine EGFR inhibitors Erlotinib, gefitinib, lapatinib, BIBW2992, nimotuzumab, cetuximab FTI inhibitors Tipifarnib, lonafarnib HDAC inhibitors Vorinostat, depsipeptide, LBH589 HSP90 inhibitors ATI3387 Met XL184 mTOR inhibitors Everolimus, sirolimus, temsirolimus, deforolimus PI3K inhibitors BEZ235, XL765 PKCβ Enzastaurin PDGFR inhibitors Dasatinib, imatinib, tandutinib Proteasome Bortezomib Raf Sorafenib Src Dasatinib TGF-β AP12009 Combination therapies Erlotinib plus temsirolimus, gefitinib plus everolimus, gefitinib plus sirolimus, sorafenib plus temsirolimus, erlotinib, or tipifarnib, pazopanib plus lapatinib Immunotherapies Dendritic cell and EGFRvIII peptide vaccines DCVax, CDX-110 Monoclonal antibodies 131I-anti-tenascin antibody Gene therapy Other therapies 131I-TM-601

* Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21 EGFR denotes epidermal growth factor receptor, FTI farnesyltransferase, HDAC histone deacetylase, HSP90 heat-shock protein 90, MGMT O6-methylguanine−DNA methyltransferase, mTOR mammalian target of rapamycin, PARP poly (ADP-ribose) polymerase, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositol 3-kinase, PKCβ protein kinase C β, TGF transforming growth factor, TMZ temozolomide, and VEGFR vascular endothelial growth factor receptor.

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A B E F

C D G H

Figure 5. MRI Scans Showing Responses to Targeted Agents. Panels A through D show MRI scans in a patient with a recurrent malignant glioma who was treated with a combi- nation of erlotinib (an inhibitor of epidermal growth factor receptor [EGFR]) and sirolimus (an inhibitor of the mam- RETAKE 1st malian target of rapamycin [mTOR]).ICM T1-weightedAUTHOR imageswen obtained after the administration of gadolinium show a re- duction in the size of the enhancingREG tumor F FIGURE from the 5a-hpretreatment image (Panel A) 2ndto the image obtained 2 months CASE 3rd after treatment (Panel B), with fluid-attenuatedTITLE inversion recovery (FLAIR) Revisedstudies showing a reduction of edema from the pretreatment image (PanelEMail C) to the post-treatmentLine image4-C (Panel D). Panels E through H show MRI scans Enon SIZE of a recurrent glioblastoma in a patient whoARTIST: was treatedmst withH/T a combinationH/T of bevacizumab and irinotecan. T1- weighted images obtained after theFILL administration of gadoliniumCombo show a reduction33p9 in the size of the enhancing tu- mor from the image obtained before treatment AUTHOR,(Panel E) PLEASEto the imageNOTE: obtained 7 months after treatment (Panel F) and an associated reduction of edema Figure from hasthe been pretreatment redrawn and FLAIR type has image been (Panelreset. G) to the post-treatment FLAIR Please check carefully. image (Panel H). JOB: 35905 ISSUE: 7-31-08

mab alone and 50.2% for patients receiving the cross the blood−tumor barrier more effectively, combination of bevacizumab and irinotecan.104 gene therapy,105 peptide and dendritic-cell vac - A phase II trial of the pan-VEGFR inhibitor ce- cines,106 radiolabeled monoclonal antibodies dira nib in patients with recurrent glioblastomas against the extracellular matrix protein tena- showed response rates in excess of 50% and pro- scin,107 synthetic chlorotoxins ( 131I-TM-601),108 longation of the 6-month rate of progression-free and infusion of radiolabeled drugs and target- survival to approximately 26%.52 These agents also ed toxins into the tumor and surrounding brain decrease peritumoral edema, potentially allowing by means of convection-enhanced delivery (Ta- for a reduction in corticosteroid requirements. ble 2).109 Since antiangiogenic agents may have synergistic activity with radiotherapy, there is increasing in- PROGNOSTIC FACTORS terest in combining them with radiotherapy and temozolomide in patients with newly diagnosed The most important adverse prognostic factors glioblastomas.29,70 As noted previously, glioma in patients with malignant gliomas are advanced stem cells produce VEGF39 and require a vascular age, histologic features of glioblastoma, poor Kar- niche for optimal function.40 A nt i a ng iogen ic a g e nt s nofsky performance status, and unresectable tu- may therefore also target glioma stem cells. mor.110 There are ongoing efforts to identify bio- logic and genetic alterations in the tumors that Other Therapies may provide additional prognostic information, as Other investigational therapies for malignant well as guidance in making decisions about opti- gliomas include chemotherapeutic agents that mal therapy.15,16,82

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Supported by grants from the National Institutes of Health SUMMARY (U01 CA062407, to Dr. Wen; and KO8 CA1240804, to Dr. Kesari), a Sontag Foundation Distinguished Scientist Grant (to Dr. Kesari), Recently, there has been important progress in and research support from the Elizabeth Atkins and Will Kraft the treatment of malignant gliomas111 and in our Brain Tumor Research Funds (to Dr. Wen) and the John Kenney Brain Tumor Research Fund (to Dr. Kesari). understanding of the molecular pathogenesis of Dr. Wen reports receiving speaking fees from Schering- these tumors and the critical role that stem cells Plough, serving as a consultant for AngioChem, and receiving research funding from Exelixis, Schering-Plough, Genentech, play in their development and resistance to treat- GlaxoSmithKline, Amgen, AstraZeneca, and Celgene. Dr. Kesari ment. As our understanding of the molecular cor- reports receiving consulting fees from Bristol–Myers Squibb, relates of response improves, it may be possible speaking fees from Enzon, and research funding from Adnexus. No other potential conf lict of interest relevant to this article was to select the most appropriate therapies on the reported. basis of the patient’s tumor genotype. These ad- We thank Drs. Andrew Norden and Elizabeth Claus for help- ful comments. vances provide real opportunities for the develop- This article is dedicated to the memories of Elizabeth Atkins, ment of effective therapies for malignant gliomas. Will Kraft, and John Kenney.

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Nat Clin Pract On- mor endothelia and by promoting pericyte 7. Inskip PD, Tarone RE, Hatch EE, et al. col 2007;4:362-74. recruitment. Am J Pathol 2003;162:1083- Cellular-telephone use and brain tumors. 18. Furnari FB, Fenton T, Bachoo RM, et 93. N Engl J Med 2001;344:79-86. al. Malignant astrocytic glioma: genetics, 29. Jain RK, di Tomaso E, Duda DG, Loef- 8. Linos E, Raine T, Alonso A, Michaud biology, and paths to treatment. Genes fler JS, Sorensen AG, Batchelor TT. Angio- D. Atopy and risk of brain tumors: a meta- Dev 2007;21:2683-710. genesis in brain tumours. Nat Rev Neuro- analysis. J Natl Cancer Inst 2007;99:1544- 19. Lee da Y, Gutmann DH. Cancer stem sci 2007;8:610-22. 50. cells and brain tumors: uprooting the bad 30. Ligon KL, Huillard E, Mehta S, et al. 9. Wrensch M, Wiencke JK, Wiemels J, et seeds. Expert Rev Anticancer Ther 2007;7: Olig2-regulated lineage-restricted path- al. 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Malmer B, Adatto P, Armstrong G, et ways to primary and secondary glioblas- genitors in adult white matter are driven al. GLIOGENE, an international consor- toma. Am J Pathol 2007;170:1445-53. to form malignant gliomas by platelet- tium to understand familial glioma. Can- 23. Watanabe K, Tachibana O, Sata K, derived growth factor-expressing retrovi- cer Epidemiol Biomarkers Prev 2007;16: Yonekawa Y, Kleihues P, Ohgaki H. Over- ruses. J Neurosci 2006;26:6781-90. 1730-4. expression of the EGF receptor and p53 33. Sanai N, Alvarez-Buylla A, Berger MS. 12. Louis DN, Ohgaki H, Wiestler OD, et mutations are mutually exclusive in the Neural stem cells and the origin of al. The 2007 WHO classification of tu- evolution of primary and secondary gliomas. N Engl J Med 2005;353:811-22.

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34. Stiles CD, Rowitch DH. Glioma stem ed patients: systematic review and meta- in the radiotherapy of glioblastoma. Neu- cells: a midterm exam. Neuron 2008;58: analysis of randomized controlled trials. rology 1980;30:907-11. 832-46. Mayo Clin Proc 2007;82:1052-9. 66. Selker RG, Shapiro WR, Burger P, et 35. Singh SK, Hawkins C, Clarke ID, et al. 52. Bat chelor T T, Sorensen AG, d i Tomaso al. The Brain Tumor Cooperative Group Identification of human brain tumour ini- E, et al. AZD2171, a pan-VEGF receptor NIH Trial 87-01: a randomized compari- tiating cells. Nature 2004;432:396-401. tyrosine kinase inhibitor, normalizes tu- son of surgery, external radiotherapy, and 36. Dirks PB. Brain tumor stem cells: mor vasculature and alleviates edema in carmustine versus surgery, interstitial ra- bringing order to the chaos of brain can- glioblastoma patients. Cancer Cell 2007; diotherapy boost, external radiation ther- cer. J Clin Oncol 2008;26:2916-24. 11:83-95. apy, and carmustine. Neurosurgery 2002; 37. Beier D, Hau P, Proescholdt M, et al. 53. Gerber DE, Grossman SA, Streiff MB. 51:343-55. CD133(+) and CD133(-) glioblastoma- Management of venous thromboembo- 67. Souhami L, Seiferheld W, Brachman D, derived cancer stem cells show differen- lism in patients with primary and meta- et al. Randomized comparison of stereo- tial growth characteristics and molecular static brain tumors. J Clin Oncol 2006;24: tactic radiosurgery followed by conven- profiles. Cancer Res 2007;67:4010-5. 1310-8. tional radiotherapy with carmustine to 38. Vescovi AL, Galli R, Reynolds BA. 54. Ruff RL, Posner JB. Incidence and conventional radiotherapy with carmus- Brain tumour stem cells. Nat Rev Cancer treatment of peripheral venous thrombo- tine for patients with glioblastoma multi- 2006;6:425-36. sis in patients with glioma. Ann Neurol forme: report of Radiation Therapy Oncol- 39. Bao S, Wu Q, Sathornsumetee S, et al. 1983;13:334-6. ogy Group 93-05 protocol. Int J Radiat Stem cell-like glioma cells promote tumor 55. Levin JM, Schiff D, Loeffler JS, Fine Oncol Biol Phys 2004;60:853-60. angiogenesis through vascular endotheli- HA, Black PM, Wen PY. Complications of 68. Tsao MN, Mehta MP, Whelan TJ, et al. al growth factor. Cancer Res 2006;66: therapy for venous thromboembolic dis- The American Society for Therapeutic Ra- 7843-8. ease in patients with brain tumors. Neu - diology and Oncology (ASTRO) evidence- 40. Calabrese C, Poppleton H, Kocak M, rology 1993;43:1111-4. based review of the role of radiosurgery et al. A perivascular niche for brain tumor 56. Lee AY, Levine MN, Baker RI, et al. for malignant glioma. Int J Radiat Oncol stem cells. Cancer Cell 2007;11:69-82. Low-molecular-weight heparin versus a Biol Phys 2005;63:47-55. 41. Bao S, Wu Q, McLendon RE, et al. coumarin for the prevention of recurrent 69. Stupp R, Hegi ME, Gilbert MR, Chakra- Glioma stem cells promote radioresistance venous thromboembolism in patients with varti A. Chemoradiotherapy in malignant by preferential activation of the DNA dam- cancer. N Engl J Med 2003;349:146-53. glioma: standard of care and future direc- age response. Nature 2006;444:756-60. 57. Meyers CA, Weitzner MA, Valentine tions. J Clin Oncol 2007;25:4127-36. 42. Liu G, Yuan X, Zeng Z, et al. Analysis AD, Levin VA. Methylphenidate therapy 70. Duda DG, Jain RK, Willett CG. Antian- of gene expression and chemoresistance improves cognition, mood, and function giogenics: the potential role of integrating of CD133+ cancer stem cells in glioblas- of brain tumor patients. J Clin Oncol this novel treatment modality with chemo- toma. Mol Cancer 2006;5:67. 1998;16:2522-7. radiation for solid cancers. J Clin Oncol 43. Salmaggi A, Boiardi A, Gelati M, et al. 58. Shaw EG, Rosdhal R, D’Agostino RB 2007;25:4033-42. Glioblastoma-derived tumorospheres iden- Jr, et al. Phase II study of donepezil in ir- 71. Keime-Guibert F, Chinot O, Taillan- tify a population of tumor stem-like cells radiated brain tumor patients: effect on dier L, et al. Radiotherapy for glioblasto- with angiogenic potential and enhanced cognitive function, mood, and quality of ma in the elderly. N Engl J Med 2007; multidrug resistance phenotype. Glia 2006; life. J Clin Oncol 2006;24:1415-20. 356:1527-35. 54:850-60. 59. Litofsky NS, Farace E, Anderson F Jr, 72. Roa W, Brasher PM, Bauman G, et al. 44. Dean M, Fojo T, Bates S. Tumour stem Meyers CA, Huang W, Laws ER Jr. Depres- Abbreviated course of radiation therapy in cells and drug resistance. Nat Rev Cancer sion in patients with high-grade glioma: older patients with glioblastoma multi- 2005;5:275-84. results of the Glioma Outcomes Project. forme: a prospective randomized clinical 45. Cha S. Update on brain tumor imag- Neurosurgery 2004;54:358-66. trial. J Clin Oncol 2004;22:1583-8. ing: from anatomy to physiology. AJNR 60. Asthagiri AR, Pouratian N, Sherman 73. Glantz M, Chamberlain M, Liu Q, Am J Neuroradiol 2006;27:475-87. J, Ahmed G, Shaffrey ME. Advances in Litofsky NS, Recht LD. Temozolomide as 46. Young GS. Advanced MRI of adult brain tumor surgery. Neurol Clin 2007; an alternative to irradiation for elderly pa- brain tumors. Neurol Clin 2007;25:947-73. 25:975-1003. tients with newly diagnosed malignant 47. Chen W. Clinical applications of PET 61. Stummer W, Pichlmeier U, Meinel T, gliomas. Cancer 2003;97:2262-6. in brain t umors. J Nucl Med 2007;48:1468- Wiestler OD, Zanella F, Reulen HJ. Fluo- 74. Randomized trial of procarbazine, 81. rescence-guided surgery with 5-aminole- lomustine, and vincristine in the adju- 48. Brandsma D, Stalpers L, Taal W, vulinic acid for resection of malignant vant treatment of high-grade astrocyto- Sminia P, van den Bent MJ. Clinical fea- glioma: a randomised controlled multi- ma: a Medical Research Council trial. tures, mechanisms, and management of centre phase III trial. Lancet Oncol 2006; J Clin Oncol 2001;19:509-18. pseudoprogression in malignant gliomas. 7:392-401. 75. Fine HA, Dear KB, Loeffler JS, Black Lancet Oncol 2008;9:453-61. 62. Lacroix M, Abi-Said D, Fourney D, et PM, Canellos GP. Meta-analysis of radia- 49. Wen PY, Schiff D, Kesari S, Drappatz J, al. A multivariate analysis of 416 patients tion therapy with and without adjuvant Gigas D, Doherty L. Medical management with glioblastoma multiforme: prognosis, chemotherapy for malignant gliomas in of patients with brain tumors. J Neuroon- extent of resection, and survival. J Neuro - adults. Cancer 1993;71:2585-97. col 2006;80:313-32. surg 2001;95:190-8. 76. Stewart LA. Chemotherapy in adult 50. Glantz MJ, Cole BF, Forsyth PA, et al. 63. Walker MD, Alexander E Jr, Hunt WE, high-grade glioma: a systematic review Practice parameter: anticonvulsant pro- et al. Evaluation of BCNU and/or radio- and meta-analysis of individual patient phylaxis in patients with newly diagnosed therapy in the treatment of anaplastic data from 12 randomised trials. Lancet brain tumors: report of the Quality Stan- gliomas: a cooperative clinical trial. J Neu- 2002;359:1011-8. dards Subcommittee of the American Acad- rosurg 1978;49:333-43. 77. Westphal M, Hilt D, Bortey E, et al. emy of Neurology. Neurology 2000;54: 64. Stupp R, Mason WP, van den Bent MJ, A phase 3 trial of local chemotherapy 1886-93. et al. Radiotherapy plus concomitant and with biodegradable carmustine (BCNU) 51. Green H, Paul M, Vidal L, Leibovici L. adjuvant temozolomide for glioblastoma. wafers (Gliadel wafers) in patients with Prophylaxis of Pneumocystis pneumonia N Engl J Med 2005;352:987-96. primary malignant glioma. Neuro Oncol in immunocompromised non-HIV-infect- 65. Hochberg FH, Pruitt A. Assumptions 2003;5:79-88.

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78. Westphal M, Ram Z, Riddle V, Hilt D, patients treated in a single institution. 100. Haas-Kogan DA, Prados MD, Lam- Bortey E. Gliadel wafer in initial surgery J Clin Oncol 2005;23:8863-9. born KR, Tihan T, Berger MS, Stokoe D. for malignant glioma: long-term follow- 89. Yung WK, Prados MD, Yaya-Tur R, et Biomarkers to predict response to epider- up of a multicenter controlled trial. Acta al. Multicenter phase II trial of temozolo- mal growth factor receptor inhibitors. Neurochir (Wien) 2006;148:269-75. mide in patients with anaplastic astrocy- Cell Cycle 2005;4:1369-72. 79. van den Bent MJ. Anaplastic oligoden- toma or anaplastic oligoastrocytoma at 101. Fine HA, Wen PY, Maher EA, et al. droglioma and oligoastrocytoma. Neurol f irst relapse: Temodal Brain Tumor Group. Phase II trial of thalidomide and carmus- Clin 2007;25:1089-109. J Clin Oncol 1999;17:2762-71. [Erratum, tine for patients with recurrent high- 80. Jenkins RB, Blair H, Ballman KV, et J Clin Oncol 1999;17:3693.] grade gliomas. J Clin Oncol 2003;21:2299- al. A t(1;19)(q10;p10) mediates the com- 90. Wong ET, Hess KR, Gleason MJ, et 304. bined deletions of 1p and 19q and pre- al. Outcomes and prognostic factors in 102. Vredenburgh JJ, Desjardins A, Hern- dicts a better prognosis of patients with recurrent glioma patients enrolled onto don JE II, et al. Phase II trial of bevaci- oligodendroglioma. Cancer Res 2006;66: phase II clinical trials. J Clin Oncol 1999; zumab and irinotecan in recurrent malig- 9852-61. 17:2572-8. nant glioma. Clin Cancer Res 2007;13: 81. Cairncross JG, Ueki K, Zlatescu MC, 91. Yung WK, Albright RE, Olson J, et al. 1253-9. et al. Specific genetic predictors of che- A phase II study of temozolomide vs. pro- 103. Vredenburgh JJ, Desjardins A, Hern- motherapeutic response and survival in carbazine in patients with glioblastoma don JE II, et al. Bevacizumab plus irinote- patients with anaplastic oligodendro- multiforme at first relapse. Br J Cancer can in recurrent glioblastoma multiforme. gliomas. J Natl Cancer Inst 1998;90: 2000;83:588-93. J Clin Oncol 2007;25:4722-9. 1473-9. 92. Brem H, Piantadosi S, Burger PC, et 104. Cloughesy TF, Prados MD, Wen PY, 82. Ino Y, Betensky RA, Zlatescu MC, et al. Placebo-controlled trial of safety and et al. A phase II, randomized, non-com- al. Molecular subtypes of anaplastic oli- eff icacy of intraoperative controlled deliv- parative clinical trial of the effect of beva- godendroglioma: implications for patient ery by biodegradable polymers of chemo- cizumab (BV) alone or in combination management at diagnosis. Clin Cancer therapy for recurrent malignant gliomas: with irinotecan (CPT) on 6-month pro- Res 2001;7:839-45. the Polymer-brain Tumor Treatment Group. gression free survival (PFS6) in recurrent, 83. Ngo TT, Peng T, Liang XJ, et al. The Lancet 1999;345:1008-12. treatment-refractory glioblastoma (GBM). 1p-encoded protein stathmin and resis- 93. Rich JN, Reardon DA, Peery T, et al. J Clin Oncol 2008;26:Suppl:91s. abstract. tance of malignant gliomas to nitroso­ Phase II trial of gefitinib in recurrent 105. Fulci G, Chiocca EA. The status of ureas. J Natl Cancer Inst 2007;99:639- glioblastoma. J Clin Oncol 2004;22:133- gene therapy for brain tumors. Expert 52. 42. Opin Biol Ther 2007;7:197-208. 84. Cairncross G, Berkey B, Shaw E, et al. 94. Wen PY, Yung WK, Lamborn KR, et al. 106. Sampson JH, Archer GE, Mitchell DA, Phase III trial of chemotherapy plus ra- Phase I/II study of imatinib mesylate for Heimberger AB, Bigner DD. Tumor-specif- diotherapy compared with radiotherapy recurrent malignant gliomas: North Amer- ic immunotherapy targeting the EGFRvIII alone for pure and mixed anaplastic oligo- ican Brain Tumor Consortium Study 99-08. mutation in patients with malignant glio- dendroglioma: Intergroup Radiation Ther- Clin Cancer Res 2006;12:4899-907. ma. Semin Immunol (in press). apy Oncology Group Trial 9402. J Clin 95. Galanis E, Buckner JC, Maurer MJ, et 107. Reardon DA, Akabani G, Coleman Oncol 2006;24:2707-14. al. Phase II trial of temsirolimus (CCI-779) RE, et al. Salvage radioimmunotherapy 85. van den Bent MJ, Carpentier AF, Bran- in recurrent glioblastoma multiforme: with murine iodine-131-labeled antitenas- des AA, et al. Adjuvant procarbazine, lo- a North Central Cancer Treatment Group cin monoclonal antibody 81C6 for patients mustine, and vincristine improves pro- Study. J Clin Oncol 2005;23:5294-304. with recurrent primary and metastatic ma- gression-free survival but not overall 96. Chang SM, Wen P, Cloughesy T, et al. lignant brain tumors: phase II study re- survival in newly diagnosed anaplastic oli- Phase II study of CCI-779 in patients with sults. J Clin Oncol 2006;24:115-22. godendrogliomas and oligoastrocytomas: recurrent glioblastoma multiforme. In- 108. Mamelak AN, Rosenfeld S, Bucholz a randomized European Organisation for vest New Drugs 2005;23:357-61. R, et al. Phase I single-dose study of intra- Research and Treatment of Cancer phase 97. Cloughesy TF, Wen PY, Robins HI, et cavitary-administered iodine-131-TM-601 III trial. J Clin Oncol 2006;24:2715-22. al. Phase II trial of tipifarnib in patients in adults with recurrent high-grade glio- 86. Keles GE, Lamborn KR, Chang SM, with recurrent malignant glioma either ma. J Clin Oncol 2006;24:3644-50. Prados MD, Berger MS. Volume of residu- receiving or not receiving enzyme-induc- 109. Ferguson S, Lesniak MS. Convection al disease as a predictor of outcome in ing antiepileptic drugs: a North American enhanced drug delivery of novel therapeu- adult patients with recurrent supratento- Brain Tumor Consortium Study. J Clin tic agents to malignant brain tumors. rial glioblastomas multiforme who are Oncol 2006;24:3651-6. Curr Drug Deliv 2007;4:169-80. undergoing chemotherapy. J Neurosurg 98. Stommel JM, Kimmelman AC, Ying 110. Curran WJ Jr, Scott CB, Horton J, et 2004;100:41-6. H, et al. Coactivation of receptor tyrosine al. Recursive partitioning analysis of prog- 87. Butowski NA, Sneed PK, Chang SM. kinases affects the response of tumor cells nostic factors in three Radiation Therapy Diagnosis and treatment of recurrent high- to targeted therapies. Science 2007;318: Oncology Group malignant glioma trials. grade astrocytoma. J Clin Oncol 2006;24: 287-90. J Natl Cancer Inst 1993;85:704-10. 1273-80. 99. Mellinghoff IK, Wang MY, Vivanco I, et 111. Brem SS, Bierman PJ, Black PH, et al. 88. Combs SE, Thilmann C, Edler L, De- al. Molecular determinants of the response Central nervous system cancers. J Natl bus J, Schulz-Ertner D. Efficacy of frac- of glioblastomas to EGFR kinase inhibi- Compr Canc Netw 2008;6:456-504. tionated stereotactic reirradiation in re- tors. N Engl J Med 2005;353:2012-24. [Er- Copyright © 2008 Massachusetts Medical Society. current gliomas: long-term results in 172 ratum, N Engl J Med 2006;354:884.]

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ONCOLOGY Board Review Manual

Volume 10, Part 2 August 2013

Primary Brain Tumors

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STATEMENT OF EDITORIAL PURPOSE Primary Brain Tumors

The Hospital Physician Oncology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in oncology. Each manual reviews a topic essential Series Editor: to the current practice of oncology. Arthur T. Skarin, MD, FACP, FCCP Distinguished Physician, Dana-Farber Cancer Institute, PUBLISHING STAFF Harvard Medical School, Boston, MA

PRESIDENT, GROUP PUBLISHER Contributors: Bruce M. White Jai Grewal, MD Long Island Brain Tumor Center at NSPC, Great Neck, NY SENIOR EDITOR Robert Litchkofski Harpreet Kaur Grewal, MD University of Texas Health Sciences Center at Houston, Houston, TX EXECUTIVE VICE PRESIDENT Barbara T. White Santosh Kesari, MD, PhD Director, Neuro-Oncology Program, Translational Neuro- Oncology Laboratories, Neurotoxicity Treatment Center, EXECUTIVE DIRECTOR OF OPERATIONS Moores Cancer Center, University of California San Diego Jean M. Gaul Health System, La Jolla, CA

Table of Contents

Introduction ...... 2 Case Presentation ...... 2 NOTE FROM THE PUBLISHER: This publication has been developed with- Conclusion ...... 17 out involvement of or review by the Amer- Board Review Questions ...... 17 ican Board of Internal Medicine. References ...... 17

www.turner-white.com Oncology Volume 10, Part 2 1 Primary Brain Tumors ONCOLOGY BOARD REVIEW MANUAL

Primary Brain Tumors

Jai Grewal, MD, Harpreet Kaur Grewal, MD, and Santosh Kesari, MD, PhD

INTRODUCTION tumors are rarely metastatic outside the central nervous system, with some exceptions (embryo- Primary central nervous system tumors are rela- nal tumors, malignant meningiomas). Tumors are tively rare, but they can cause significant morbidity. graded from I to IV based on histological grading They are also among the most lethal of all neo- and prognosis, with grade IV being the most ag- plasms. Brain tumors are the second most com- gressive. Notable features of selected nervous mon cause of death due to intracranial disease, system tumors are shown in Table 3. Gliomas second only to stroke. The estimated annual inci- account for 78% of all primary malignant central dence of primary brain tumors is approximately 21 nervous system tumors,1 and glioblastoma (WHO per 100,000 individuals in the United States.1 The grade IV) is the most common malignant primary incidence of brain tumors varies by gender, age, brain tumor in adults. Despite advances in the field race, ethnicity, and geography and has increased of oncology, the prognosis of these aggressive tu- over time.2 Gliomas and germ cell tumors are more mors remains poor. common in men, whereas meningiomas are twice This review focuses on the evaluation and man- as common in women. The only validated environ- agement of primary brain tumors, in particular glio- mental risk factor for primary brain tumors is expo- blastoma (the most common malignant brain tumor sure to ionizing radiation. Other etiologies include in adults), and highlights new advances in treatment inherited cancer syndromes and primary central options. Management of common complications as- nervous system lymphoma associated with AIDS.3 sociated with brain tumors will also be discussed. Approximately 5% to 10% of gliomas are associ- ated with a family history.4 Inherited cancer syn- CASE PRESENTATION dromes involving brain tumors are listed in Table 1. Primary brain tumors are classified according to A 40-year-old right-handed nonsmoking the World Health Organization 2007 classification,5 man presents to the emergency depart- as shown in Table 2. The TNM staging system is ment (ED) with the sudden onset of right-sided not used for primary brain tumors. Primary brain weakness. His family reports that he has had

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2 Hospital Physician Board Review Manual www.turner-white.com Primary Brain Tumors

Table 1. Genetic Syndromes Associated with Nervous System Tumors Nervous Syndrome System Skin Other Locus Gene Protein Function Neurofibromatosis Neurofibroma, Café-au-lait, Iris hamarto- 17q11 NF1 Neurofibromin Tumor suppressor type 1 MPNST, optic nerve axillary freck- mas, osseous gene, ras GTPase- glioma, astrocy- ling lesions, pheo- activating protein toma chromocytoma, regulates cell prolif- leukemia eration and differen- tiation Neurofibromatosis Bilateral vestibular None Posterior lens 22q12 NF2 Merlin or Tumor suppressor type 2 schwannomas, opacities, reti- schwannomin gene, binds to actin, peripheral schwan- nal hamartoma regulating mem- nomas, meningio- brane cytoskeleton mas, meningioan- giomatosis, spinal ependymoma, as- trocytoma, glial hamartins, cerebral calcifications Tuberous sclerosis Subependymal Angiofibroma Cardiac rhab- 9q34 TSC1, Hamartin (TSC Tumor suppressor giant cell astro- (adenoma domyoma, (TSC1), TSC2 1), tuberin genes, tuberin- cytoma, cortical sebaceum), renal an- 16p13 (TSC2) harmartin complex glioneuronal ham- subungual fi- giomyolipoma, (TSC2) suppresses activa- artomas (tubers), bromas pulmonary 60% spo- tion of the mTOR ependymal hamar- lymphangioma- radic pathway (which in- tomas (candle gut- tosis creases proliferation terings) and cell growth) von Hippel-Lindau Cerebrellar and None Renal cell 3p25 VHL pVHL Tumor suppressor spinal cord heman- carcinoma, gene, role in protein gioblastoma pheochromo- degradation and an- cytoma, renal giogenesis angiomatosis, cysts of kidney and pancreas, cyst adenoma of epididymis Li-Fraumeni Diffuse astrocy- None Bone and soft 17p13 TP53 p53 Tumor suppressor toma, medulloblas- tissue sar- gene, promotes toma, supratentorial coma, breast apoptosis in cells with PNET cancer DNA damage (continued on page 4)

progressive difficulty speaking over the last 3 to 4 onds, the shaking stopped but he could not hold weeks. He has had particular trouble with finding anything in his right hand. Examination reveals an the right word. One hour prior to presentation to the alert man with expressive aphasia, who is other- ED, he had been preparing lunch when he noticed wise cognitively intact and follows commands. He that his right arm was shaking. After about 30 sec- is noted to make frequent paraphasic errors. Nam- www.turner-white.com Oncology Volume 10, Part 2 3 Primary Brain Tumors

Table 1. Genetic Syndromes Associated with Nervous System Tumors (continued) Nervous Syndrome System Skin Other Locus Gene Protein Function Cowden Dysplastic ganglio- Multiple trichi- Oral mucosa fi- 10q23 PTEN PTEN Tumor suppressor cytoma of the cer- lemmoma, fi- broma, hamar- gene, expression ebellum (Lhermitte- broma tomatous colon causes cell cycle ar- Duclos) polyps, thyroid rest and apoptosis, tumors, breast regulates PI3K/Akt cancer pathway Turcot Medulloblastoma, Café-au-lait Colorectal 5q21, APC, APC, hMLH1, APC-tumor suppres- glioblastoma polyps or carci- 3p21, hMLH1, hPMS2 sor gene regulating noma 7p22w hPMS2 β-catenin, hMLH1, hPMS2-mismatch repair proteins Gorlin Medulloblastoma Nevoid basal Jaw kerato- 9q22 PTCH1 Ptc1 Tumor suppressor, (desmoplastic) cell carcino- cysts, ovarian suppresses smooth- mas, palmar fibroma ened-mediated cell and plantar pits proliferation APC = adenomatous polyposis coli; hMLH1 = human MutL homolog; hPMS2 = human postmeiotic segregation increased 2; MPNST = malignant peripheral nerve sheath tumor; mTOR = mammalian target of rapamycin; PI3K = phosphoinositide-3-kinase, PTCH = Drosophila patched homolog 1; PTEN = phosphatase and tensin homolog.

ing and repetition are impaired. Motor examination Headache is a presenting symptom in approxi- reveals significant weakness in his right hand. mately 48% of newly diagnosed brain tumors.6 It Deep tendon reflexes are more brisk on the entire is often dull, non-throbbing, and intermittent. Su- right side. The right plantar response is upgoing. pratentorial masses can result in frontal headache. Coordination testing on the right side is hampered Posterior fossa masses cause headache in oc- by weakness, but is intact on the left side. The re- cipital and cervical areas. Early morning headache mainder of the examination is unremarkable. is considered a classic presentation because of increased intracranial pressure (ICP) in the recum- • What are the common presenting features of bent position. However, this classic presentation a brain tumor? occurs in a minority of patients.6 Seizures are the presenting feature of brain CLINICAL FEATURES OF BRAIN TUMORS tumors in approximately one-third of cases. They Symptoms from a brain tumor can be focal occur due to irritation of the brain parenchyma. or generalized. The most common presenting There is evidence that blood–brain-barrier failure symptoms in patients with brain tumor include may be an etiological factor contributing to the de- headaches, seizures, cognitive impairment, per- velopment of seizures.7 sonality changes, and focal neurological defi- Low-grade tumors, particularly oligodendroglio- cits. Focal signs and symptoms reflect the lo- mas, have a relatively greater tendency to present cation of the tumor within the central nervous with seizures (over 70% in some series).8,9 Even system. if seizures do not occur at presentation, they may

4 Hospital Physician Board Review Manual www.turner-white.com Primary Brain Tumors

Table 2. Abbreviated 2007 World Health Organization Classification of Brain Tumors Tumors of neuroepithelial tissue Tumors of the pineal region Astrocytic tumors Pineocytoma Pilocytic astrocytoma Pineal parenchymal tumor of intermediate differentiation Subependymal giant cell astrocytoma Pineoblastoma Pleomorphic xanthoastrocytoma Embryonal tumors Diffuse astrocytoma Medulloblastoma Anaplastic astrocytoma CNS primitive neuroectodermal tumor Glioblastoma CNS neuroblastoma Gliomatosis cerebri Atypical teratoid/rhabdoid tumor Oligodendroglial tumors Tumors of cranial and paraspinal nerves Oligodendroglioma Schwannoma Anaplastic oligodendroglioma Neurofibroma Oligoastrocytic (mixed) tumors Malignant peripheral nerve sheath tumor Oligoastrocytoma Tumors of the meninges Anaplastic oligoastrocytoma Meningioma (15 variants) Ependymal tumors Hemangioblastoma Subependymoma Hemangiopericytoma Myxopapillary ependymoma Primary CNS lymphoma Ependymoma Germ cell tumors Anaplastic ependymoma Germinoma Choroid plexus tumors Embryonal carcinoma Choroid plexus papilloma Yolk-sac tumor Choroid plexus carcinoma Choriocarcinoma Neuronal and mixed neuronal-glial tumors Teratoma Dysplastic gangliocytoma of cerebellum Mixed germ cell tumor Dysembryoplastic neuroepithelial tumor Tumors of the sellar region Gangliocytoma Craniopharyngioma Ganglioglioma Granular cell tumor of the neurohypophysis Anaplastic ganglioglioma Metastatic tumors Central neurocytoma Paraganglioma

CNS = central nervous system. Adapted from Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO classification of tumours of the central nervous system. Lyon, France: IARC; 2007.

occur later in 40% to 60% of patients with brain resection, there may be a marked improvement tumors. Seizures tend to be partial with possible in seizure frequency (or even complete seizure secondary generalization; seizure semiology will resolution) if the active seizure focus has been correlate with the tumor location within the brain. removed. Conversely, worsening of seizure type or Seizure frequency varies among patients. In pa- seizure frequency (or even status epilepticus) may tients who have experienced an extensive surgical herald radiologic tumor progression.10

www.turner-white.com Oncology Volume 10, Part 2 5 Primary Brain Tumors

Table 3. Notable Features of Selected Central and Peripheral Nervous System Tumors Tumor Clinical Radiologic Pathologic Central Nervous System Oligodendroglioma Often present with seizures Calcifications “Fried egg” appearance 1p and 19q chromosomal dele- tions Diffuse low-grade astrocytoma May present with seizures or Nonenhancing diffuse area of T2 Low mitotic activity subtle symptoms signal Positive for p53, associated with Gyral expansion IDH1/2 mutations Ependymoma Peak age 15 yr Majority are in fourth ventricle or Perivascular pseudorosettes May present as obstructive spinal cord hydrocephalus Enhancing May spread via CSF pathways Meningioma Most common primary CNS tumor Diffuse contrast enhancement EMA-positive (40%) Dural tail sign Desmosomes More common in women Locations: convexity, parasagittal, Progesterone receptors Pregnancy may promote growth sphenoid wing, spinal, cavernous Many variants sinus Primary CNS lymphoma May shrink or disappear (tran- Diffuse contrast enhancement Most B-cell siently) with corticosteroids Periventricular lesions Perivascular cuffing May be associated with HIV Restricted diffusion on DWI CD20+ (B-cell type) Glioblastoma Most common adult malignant pri- Ring-enhancing, irregular, necrot- Vascular proliferation mary tumor ic-appearing mass(es) Necrosis Peak age 55, median survival Pseudopalisadating arrangement 14.6 mo of tumor cells Chemotherapy shown to prolong survival in RCT Medulloblastoma Peaks in first and third decades Posterior fossa enhancing mass Small, round blue cells (on H&E of life May seed via CSF pathways stain) May present with obstructive hy- (“drop metastases”) Homer-Wright rosettes (character- drocephalus or cerebellar signs istic of all PNETs) Ependymoblastoma First 5 years of life Supratentorial enhancing mass True rosettes Prognosis poor with possible CSF seeding Gangliocytoma/ganglioglioma First 2 decades of life Temporal lobe mass Gangliocytoma: only neoplastic Intractable complex-partial sei- neuronal cells zures Ganglioglioma: mixed neoplastic neuronal and glial cells; eosino- philic granular bodies Dysembryoplastic neuroepithelial Second and third decades of life Medial temporal lobe Neuronal and glial elements Tumor Rarely regrows after surgical re- section Choroid plexus papilloma In adults tumor of choroid plexus Children: lateral ventricle more likely to be metastatic Adults: fourth ventricle (continued on page 7)

6 Hospital Physician Board Review Manual www.turner-white.com Primary Brain Tumors

Table 3. Notable Features of Selected Central and Peripheral Nervous System Tumors (continued) Tumor Clinical Radiologic Pathologic Peripheral Nervous System Neuroblastoma First decade of life Sympathetic chain in chest or Similar to medulloblastomas May present with “dancing eyes” abdomen May form “flourettes” (opsoclonus-myoclonus) Neurofibromas Associated with NF1 Dorsal spinal nerve roots Hyperplasia of Schwann cells Schwannomas Tinnitis, hearing loss Cerebropontine angle mass Antoni A and B Bilateral schwannomas Verocay bodies May be associated with NF2

CNS = central nervous system; CSF = cerebrospinal fluid; DWI = diffusion-weighted imaging; EMA = epithelial membrane antigen; H&E = hematoxylin and eosin; RCT = randomized controlled trial; NF1 = neurofibromatosis 1; NF2 = neurofibromatosis 2; PNET = primitive neuroectodermal tumor.

Altered mental status is a presenting feature in CASE CONTINUED 15% to 20% of cases.11 Tumors associated with Computed tomography (CT) of the brain elevated ICP, gliomatosis cerebri, and those located shows a left frontal hypodensity with sur- in the frontal lobes are more likely to be associ- rounding mass effect. This is followed by magnetic ated with altered mental status at presentation. The resonance imaging (MRI) of the brain, which re- severity can range from mild inattention to deep veals a heterogeneous mass in the left frontal lobe. coma. The lesion is hypointense on T1-weighted imaging Focal neurological deficits such as aphasia, and hyperintense on T2-weighted imaging with hemiparesis, sensory loss, and visual field loss extensive surrounding edema. There is associated may also occur at presentation and correlate mass effect. Post-gadolinium T1-weighted imaging with tumor location. Aphasia is associated with reveals an irregularly shaped ring-enhancing mass involvement of the dominant hemisphere (usu- with necrosis (see Figure 1 for imaging findings ally the left), while sensorimotor and visual defi- from a similar case). Due to the patient’s recent cits can occur if the tumor affects the corre- seizure and evidence of mass effect, intravenous sponding pathways within the central nervous levetiracetam and dexamethasone are initiated. system. The time course of symptoms often correlates • What is the work-up of a patient with a pos- with the growth rate of the neoplasm. Symptoms sible brain tumor? may gradually progress over time. In the case pre- sented, the patient comes to medical attention after NARROWING THE DIFFERENTIAL DIAGNOSIS an acute event. Careful history taking revealed that A patient suspected of possibly having a brain neurological symptoms had been apparent for sev- tumor should undergo a thorough general and eral weeks before this. Patients with slow-growing neurological evaluation. Often, a noncontrast head tumors may have less pronounced symptoms than CT is the initial imaging study. It is favored due patients with fast growing masses of similar size and to its wide availability and short imaging time. location. It is helpful in the rapid diagnosis of intracranial www.turner-white.com Oncology Volume 10, Part 2 7 Primary Brain Tumors

Figure 1. Magnetic resonance imaging (MRI) and pathologic features of an anaplastic glioma (A–D) and glioblastoma (E–H). Axial T1- weighted images (A, E) show no definite abnormality in the case of low-grade glioma and marked hypodensity in the case of glioblas- toma; axial T1-weighted post-gadolinium images (B, F) show no enhancement in the case of low-grade glioma and marked heteroge- neous enhancement in the case of glioblastoma; axial fluid-attenuated inversion recovery MRI images (C, G) show T2 hyperintensity within and surrounding the tumor, more so in glioblastoma; and pathologic specimens from low-grade glioma (D) and glioblastoma (H) show characteristic features. Low-grade tumors are moderately hypercellular and composed of well-differentiated astrocytes that infiltrate into normal brain. Modest nuclear atypia is present, but mitoses, necrosis, and vascular proliferation are absent. Glioblastoma shows very high cellularity, marked nuclear atypia, vascular proliferation, many mitoses, and geographic necrosis with pseudopalisad- ing. (Adapted with permission from Norden AD, Kesari S. Cancer neurology: Primary and metastatic brain tumors. Hospital Physician Neurology Board Review Manual. Wayne [PA]: Turner White Communications; 2006:10[Pt 3]:1–16).

hemorrhage, in identifying mass effect, and for presence of enhancement on administration of visualization of calcifications and bony destruc- gadolinium indicates the breakdown of the blood- tion. Patients with contraindication to MRI may brain barrier and suggests a high-grade neoplasm. benefit from a subsequent contrast-enhanced Low- and high-grade gliomas usually show poorly head CT evaluation. defined margins, heterogeneous areas of hemor- An MRI of the brain with gadolinium contrast rhage and necrosis, and significant surrounding is usually the test of choice, and often follows a vasogenic edema. These findings are usually head CT scan. An MRI provides greater anatomic less prominent in low-grade lesions. Calcifications and pathologic detail than a CT scan. On MRI, within the mass (better seen on CT) are generally tumors generally appear as a hypointense area suggestive of a more indolent (lower grade) neo- on T1-weighted imaging with corresponding hyper- plasm, such as an oligodendroglioma and cranio- intensity on T2-weighted imaging (Figure 1). The pharyngioma.

8 Hospital Physician Board Review Manual www.turner-white.com Primary Brain Tumors

With certain tumors (eg, medulloblastoma), imag- ing of the spine is required to exclude drop metasta- ses. Leptomeningeal metastasis may be evident on MRI as abnormal meningeal enhancement or tumor nodules within the cerebrospinal fluid (CSF) flow pathways. CSF cytology is considered the gold stan- dard for this diagnosis; however, lumbar puncture may be contraindicated if there is significant mass effect on imaging. A systemic evaluation should be considered to exclude metastatic cancer presenting as brain metastasis. This includes testicular, breast, and prostate exams, and imaging of the chest, ab- domen and pelvis. Of these, CT of the chest has the highest yield.12 A lesion that is more accessible to biopsy than the CNS mass may become evident. Additional diagnostic studies, such as bone marrow biopsy, positron emission tomography (PET), or Figure 2. Magnetic resonance spectroscopy in a patient with tumor markers, may be useful if brain metastasis or glioblastoma from (A) the area of abnormal enhancement and lymphoma is suspected. An abscess or demyelinat- (B) normal brain. Voxel placement is shown. The spectrum corre- ing lesion might be distinguished based on clinical sponding to the area of tumor (C) reveals an increased ratio of choline and imaging features. For most primary central (thick hollow arrows) to creatine (thick solid arrows) and decreased N-acetylaspartate (thin arrows) when compared with the contralat- nervous system neoplasms, tissue diagnosis with eral, unaffected brain (D). This is suggestive of increased cell mem- biopsy or resection is necessary. Occasionally, such brane turnover and neuronal destruction, respectively. as in the case of diffuse intrinsic brainstem gliomas, a presumptive diagnosis is made based on imaging and clinical findings, as biopsy in this area carries significant risk. imaging), in which illustration of the white matter tracts Newer imaging techniques provide additional in- associated with a tumor may be helpful in surgical formation about a suspicious mass. Magnetic reso- planning. Also, MR perfusion is an evolving technique nance spectroscopy (MRS) may demonstrate an which may help differentiate between tumor recur- elevated ratio of choline to creatine in tumors due rence and treatment effects (eg, radiation necrosis). to increased cell membrane turnover (Figure 2). Neuronal loss due to infiltration of tumor results in • What is the initial management of a patient decreased levels of N-acetylaspartate (NAA). Multi- found to have a mass lesion? voxel technique can evaluate different regions of the tumor to determine where high-grade features are INITIAL MANAGEMENT more likely to be found on biopsy; this can be help- Seizures ful in surgical planning.13 Other MR techniques with The patient’s symptoms of shaking of the right potential utility include tractography (diffusion tensor arm followed by hand weakness are suggestive www.turner-white.com Oncology Volume 10, Part 2 9 Primary Brain Tumors

Seizure

Stabilize patient

New-onset seizure Known seizure disorder

Evaluate for new intracranial pathol- Evaluate for exacerbating factors: ogy and significant toxic-metabolic AED noncompliance, worsening derangements; determine whether intracranial pathology, seizure is provoked toxic-metabolic insults

History: witness, recent fever, infection, headache, head trauma, medications, brain irradiation

Physical examination: vital signs, consciousness, Todd’s paralysis, myoclonus, asterixis, new neurologic deficits

Fluctuating/impaired Investigations: neuroim- consciousness, aging, laboratory studies, myoclonus EEG, CSF analysis

New toxic- Stat EEG New structural brain lesion(s) metabolic insults

Further evaluation Correct toxic-metabolic Electrographic seizures of lesion; consider derangements as best dexamethasone, AEDs, as possible neurologic consultation

Management of status Definitive therapy for epilepticus intracranial pathology

Figure 3. An approach to seizures in patients with brain tumors. AEDs = antiepileptic drugs; CSF = cerebrospinal fluid; EEG = electro- encephalography. (Adapted with permission from Grewal J, Grewal HK, Forman AD. Seizures and epilepsy in cancer: etiologies, evaluation, and management. Curr Onc Rep 2008;10:64–72.)

of a seizure and Todd’s paralysis. An approach to seizure, initiation of an antiepileptic drug (AED) for management of the patient with seizures is outlined secondary prophylaxis of seizures is warranted. in Figure 3. Because the patient experienced a Although AEDs may not completely prevent all

10 Hospital Physician Board Review Manual www.turner-white.com Primary Brain Tumors seizures, data show that they can reduce seizure ICP. Corticosteroids are the mainstay for manage- generalization.14 Traditionally, anticonvulsants such ment of cerebral edema. The most commonly as phenytoin, phenobarbital, and valproic acid used corticosteroid is dexamethasone. It has high have been used as first-line agents, particularly potency, a long half-life, and minimal mineralocor- in the acute setting. A major drawback of using ticoid effect. A typical regimen consists of an initial these older AEDs is the relative frequency of in- dose of 10 mg intravenously followed by 4 mg teractions with chemotherapeutic agents that are every 6 hours; however, a lower dose may produce used in the treatment of brain tumors.15,16 Enzyme- similar benefit.20 Once definitive therapy has been inducing AEDs such as phenytoin, phenobarbital, delivered and clinical improvement is seen, the and carbamazepine may increase the clearance dose is gradually tapered to avoid serious long- and reduce the clinical efficacy of corticosteroids term side effects such as gastric ulcers, cataracts, and antineoplastic agents that are metabolized by osteoporosis, hyperglycemia, adrenal suppres- the cytochrome P450 system. sion, muscle wasting, weight gain, and Cushing’s Newer AEDs such as levetiracetam, lacosamide, syndrome. and pregabalin have fewer adverse effects and do not have significant interactions with chemo- CASE CONTINUED therapeutic agents. Therefore, they are preferred The patient undergoes a CT scan of the over older AEDs in the brain tumor (and systemic chest, abdomen, and pelvis, which does cancer) population. Intravenous formulations of not reveal a systemic malignancy. A neurosurgical levetiracetam and lacosamide are available. In the consultation is obtained and the patient receives setting of refractory seizures or status epilepticus, a subtotal resection. The pathology is consistent acute treatment with classical AEDs should be with glioblastoma, exhibiting a pseudopalisading strongly considered. pattern, microvascular proliferation, and necrosis Primary prophylaxis of seizures is not recom- (Figure 1). The patient is counseled regarding his mended by the American Academy of Neurol- diagnosis and treatment options. A plan is made ogy guidelines for brain tumor patients who have to administer outpatient external-beam radiation never had a seizure.17 Clinical trials to determine therapy (EBRT) with concurrent chemotherapy. the efficacy of prophylactic anticonvulsants in this The radiation therapy consists of a total dose of situation have not yet demonstrated a benefit that 59.4 Gy delivered in 33 fractions of 1.8 Gy each. outweighs the risks.18,19 Therefore, anticonvulsants Oral concurrent temozolomide (TMZ) is adminis- should be reserved for brain tumor patients who tered daily at 75 mg/m2 for 42 consecutive doses have demonstrated a tendency to have seizures. (over 6 weeks). It should be mentioned that many of these newer anticonvulsants are not FDA-approved for use as • What treatment options are recommended for monotherapy or treatment of status epilepticus. a patient with newly diagnosed glioblastoma?

Cerebral Edema TREATMENT OF GLIOBLASTOMA Cerebral edema in the setting of brain tumors Based on the results of a phase III randomized, is vasogenic, and vasogenic edema increases the controlled trial,21 the standard of care for a patient www.turner-white.com Oncology Volume 10, Part 2 11 Primary Brain Tumors

Table 4. Tumors Treated by Surgical Resection a survival benefit for initial,24–26 recurrent,27 and Pilocytic astrocytoma multiple28 resections for glioblastoma. At the time of Pleomorphic xanthoastrocytoma initial resection, the data suggest a possible survival Subependymal giant cell astrocytoma benefit for patients with an extent of resection of Subependymoma 26 Myxopapillary ependymoma 78% or greater. In one study, the morbidity from Paraganglioma of the filum terminale gross total resection was not significantly increased Dysplastic gangliocytoma of the cerebellum over biopsy or subtotal resection, and the risk at Dysembryoplastic neuroepithelial tumor the time of initial surgery did not differ from the risk Ganglioglioma 29 Central neurocytoma at reoperation. Carmustine (BCNU)-impregnated Meningioma wafers can be placed into a tumor resection cavity Hemangioblastoma at the time of operation. They are FDA-approved for newly diagnosed malignant glioma, although in the associated clinical trial, statistical significance was not achieved in the glioblastoma subgroup.30 with newly diagnosed glioblastoma involves maxi- A prospective, randomized, phase III clinical trial mal safe surgical resection followed by the combi- utilizing 5-aminolevulinic acid for intraoperative nation of EBRT and concurrent chemotherapy with visualization of tumor under fluoroscopic light was daily TMZ. The patient is then assessed clinically completed.31 Improved progression-free survival and by MRI approximately 3 to 4 weeks following was seen in the group in which this technique was the completion of this treatment. If the tumor does utilized. Preoperative imaging (such as functional not progress, chemoradiation is followed by at MRI), intraoperative MRI, and other techniques least 6 cycles of adjuvant TMZ on days 1 through (such as awake surgery) may help safely increase 5 of a 28-day cycle. the extent of resection.32,33 A list of primary brain tumors potentially curable by surgical resection is Surgery outlined in Table 4. The extent of tumor removal by surgery depends on tumor location (especially proximity to eloquent Radiation Therapy brain), general health of the patient, and the pres- EBRT is the most important type of radiation ence of mass effect. While a biopsy poses minimal therapy used in treating infiltrating tumors such as risk to the patient and is well tolerated, it allows for glioblastoma.34 While whole brain radiation therapy pathological evaluation of only a small portion of the (WBRT) has been used in the past, data show tumor. The pathological grade may change nearly that a more focused approach spares some of half the time if resection is performed after biopsy.22 the toxicity of WBRT without a loss of efficacy.35,36 Class I data do not exist regarding the issue of A typical dose would be approximately 60 Gy to whether extensive surgical debulking provides a the tumor evident on imaging with a 2-cm margin. survival benefit. One small randomized study23 Clear survival advantages have been demonstrat- did find a small but statistically significant benefit ed in several studies at 50 to 60 Gy, but above 60 of craniotomy and resection over biopsy alone. A Gy there is a marked increase in toxicity.37,38 It is number of larger retrospective studies do suggest unknown whether the benefit observed with TMZ

12 Hospital Physician Board Review Manual www.turner-white.com Primary Brain Tumors in glioblastoma is predominantly due to a radio- treated longer if there is no disease progression. sensitization effect, from the use of an effective Patients may receive Pneumocystis carinii pro- alkylating agent, or both.39 phylaxis during the concurrent phase of treatment. Adverse effects include myelosuppression, nau- Chemotherapy sea, vomiting, anorexia, constipation, and fatigue. Temozolomide is a member of the class of drugs Hepatitis B reactivation has also been reported known as imidotetrazines. It was developed as with the use of TMZ.43,44 a less toxic alternative to precursor compounds Bevacizumab is a novel humanized monoclonal and exhibited excellent penetration into the central antibody targeting vascular endothelial growth fac- nervous system.40,41 In 1999, it was first approved tor (VEGF). This pathway is important for tumor in the United States for recurrent anaplastic as- angiogenesis. The use of bevacizumab for newly trocytoma.42 Following the positive results of an diagnosed disease is being evaluated in clinical international phase III trial for glioblastoma,21 con- trials and therefore is not considered standard of current TMZ and radiation therapy has become the care at present. standard of care for patients with newly diagnosed glioblastoma. This multicenter, randomized, con- • What are the most important molecular mark- trolled trial compared the efficacy and safety of ers in brain tumors? TMZ administered concurrently and following ra- diation therapy (RT) with RT alone in patients with MOLECULAR MARKERS IN BRAIN TUMORS newly diagnosed glioblastoma. TMZ combined Identifying subsets of patients who may be more with RT was more effective than RT alone, and likely to respond to a particular therapy is an im- the combined treatment was well tolerated. Median portant focus of brain tumor research. This is com- overall survival time (OS) was 14.6 months in the monly done in the case of many other malignan- TMZ plus RT group as compared to 12.1 months cies, such as testing for estrogen, progesterone, in the RT alone group. Based on the results of and HER2/neu receptors in breast cancer. this study, the FDA approved TMZ in 2005 for the Anaplastic oligodendrogliomas have been re- treatment of adult patients with newly diagnosed ported to have a favorable response to chemo- glioblastoma. TMZ has 100% oral bioavailability therapy (and radiation) if they are associated with and readily crosses the blood-brain barrier. It acts 1p and 19q chromosomal co-deletions.45 Two pro- by methylating the O6 position of guanine in DNA. spective, randomized, controlled trials evaluated Mispairing of thymidine with the O6-methylguanine the potential benefit of adding PCV chemotherapy results in DNA strand breakage and cell death. (procarbazine, lomustine, vincristine) to radiation TMZ is given orally at a daily dose of 75 mg/m2 therapy alone as initial therapy.46,47 The long-term for 6 weeks along with radiation therapy. Patients analysis for both studies confirmed the importance completing chemoradiation without disease pro- of 1p and 19q co-deletions as favorable indepen- gression may proceed to receive adjuvant TMZ at dent prognostic factors.48,49 150 to 200 mg/m2 on days 1 through 5 of a 28-day Patients with glioblastoma associated with O6- cycle. Although the trial limited adjuvant TMZ to methylguanine-DNA-methyltransferase (MGMT) 6 cycles,21 in clinical practice patients have been promoter methylation experienced greater ben- www.turner-white.com Oncology Volume 10, Part 2 13 Primary Brain Tumors efit from TMZ.50 The MGMT repair enzyme is one the proneural signature correlated with improved mechanism by which tumor cells repair DNA dam- prognosis. It was noted that at recurrence, tumors age from alkylating agents such as TMZ. MGMT tended to exhibit more of the mesenchymal pat- promoter methylation suggests decreased avail- tern, which was correlated with a poorer prognosis. ability of this enzyme and alkylating chemotherapy may be more likely to lead to cell death. CASE CONTINUED Overexpression, amplification, or mutations of Four weeks after the patient completed the epidermal growth factor receptor (EGFR) concurrent chemoradiation, an MRI of are common in glioblastoma.51 Several EGFR the brain was obtained. This revealed increased inhibitors have been approved for other malignan- contrast enhancement and surrounding edema. cies, but unfortunately clinical trials have failed to The patient was clinically unchanged. Surgical demonstrate a benefit in malignant glioma.52 One re-operation was deemed risky. The patient was interesting mutation results in a constitutively ac- continued on adjuvant TMZ with a shorter inter- tive receptor, the EGFRvIII. The co-expression of val of MRI tumor surveillance (4-week intervals). EGFRvIII and phosphatase and tensin homolog By the third scan following chemoradiation, there (PTEN) seems to predict sensitivity of recurrent was marked reduction in the size of the contrast- GBM to EGFR inhibitors.53 While found in other enhancing lesion, measuring approximately 50% cancers, EFGRvIII is not found in normal human of the pre-radiation size. The early MRI changes tissue. The unique protein structure is the target of were attributed to a transient post-treatment phe- a cancer vaccine in clinical trials for glioblastoma.54 nomenon known as pseudoprogression. MRI sur- Other novel experimental therapies include small- veillance was changed to 8-week intervals (after molecule targeted agents, oncolytic viruses,55,56 every 2 cycles of TMZ). and dendritic-cell immunotherapies.57 Discovered in 2008, mutations of the isoci- • What is the significance of transient radio- trate dehydrogenase glycolytic enzyme (IDH1 and logic worsening after concurrent radiation IDH2) are commonly found in low-grade and sec- and chemotherapy? ondary high-grade gliomas.58 These mutations appear to occur early in the development of glio- PSEUDOPROGRESSION mas and change the function of IDH to produce It is becoming increasingly evident that patients 2-hydroxyglutarate, a potential oncometabolite. may experience transient radiological “progres- When compared with wild-type IDH, the presence sion” early after the completion of chemoradiation of IDH1 and IDH2 mutations is associated with im- with TMZ. This phenomenon has been labeled proved prognosis in glioma. pseudoprogression.61–63 Patients may remain clini- Significant work is being performed using mi- cally stable in many of these cases. Up to half of croarray technology and sophisticated analysis to all radiologic progression following chemoradia- identify gene expression patterns that may have tion may in fact fall under this category. The most prognostic signficance.59,60 One such analysis significant consideration in a patient with possible stratified tumors into 3 groups: proneural, mesen- pseudoprogression is whether to continue adju- chymal, and proliferative,59 with tumors exhibiting vant TMZ, as a proportion of such patients have

14 Hospital Physician Board Review Manual www.turner-white.com Primary Brain Tumors been reported to experience an eventual response in long-term survivors (more problematic in patients to therapy. Early radiation necrosis was found with low-grade tumors due to longer survival), and when these patients underwent re-operation.61 can range in severity.67 Deficits may involve atten- Close imaging surveillance is warranted if a patient tion, learning, memory, processing speed, ability to with suspected pseudoprogression is continued multitask, and word-finding. Psychostimulants (eg, on adjuvant TMZ. Patients who do not exhibit methylphenidate) in conjunction with serial neuro- an improvement on follow-up imaging may have psychological evaluations have been used to help true progression and should be switched to alter- patients remain functionally active.68 nate therapy. Pseudoprogression appears to be more common in glioblastoma patients expressing CASE CONTINUED MGMT promoter methylation.64 The patient remains clinically stable after 5 cycles of TMZ. Prior to completing his • What are the neurologic complications of sixth adjuvant cycle, he experiences the sudden radiation therapy? onset of shortness of breath, tachycardia, and chest pain. Examination reveals a swollen and Toxicity from RT can be divided into 3 types tender right calf. The patient is given 100% oxy- based on the amount of time that has elapsed gen by mask and receives an emergent spiral CT since the completion of RT.65 Acute toxicity mani- arteriogram of the chest, which confirms extensive fests as encephalopathy within days to weeks of bilateral pulmonary embolism. A lower extremity therapy. The risk increases with higher dose, larger Doppler ultrasound reveals deep vein thrombosis. volume of brain irradiated, and poorer baseline The patient is admitted to the hospital and is initi- cognitive status. The pathogenesis may involve ated on low-molecular-weight heparin (LMWH). breakdown of the blood-brain barrier, leading to An inferior vena cava filter is not placed. Over the cerebral edema. Corticosteroids may be used to next 4 days, his symptoms improve and he is dis- prevent and manage acute toxicity. Early delayed charged home on the same anticoagulant. His wife toxicity usually occurs within a few weeks of treat- is trained to subcutaneously administer the LMWH ment and is usually reversible. It may present as daily at home. somnolence and neurologic deterioration. It usu- ally resolves spontaneously and may be managed • What is the incidence and management of with corticosteroids. Late radiation injury occurs venous thromboembolism (VTE) in patients months to years following therapy and is often ir- with brain tumors? reversible. Radiation necrosis may be difficult to distinguish from tumor progression on imaging and Thromboembolic complications are very com- can change similarly over time. If corticosteroids mon, occurring in 30% to 60% of malignant glioma fail to control the necrotic process, surgical resec- patients.69–71 VTE is a frequent complication fol- tion may be warranted. Bevacizumab has been lowing craniotomy for brain tumors. This increased reported to be beneficial for radiation necrosis in a risk is shared with other cancers, in particular, mul- prospective randomized clinical trial.66 Cognitive im- tiple myeloma. However, the pathogenesis of VTE pairment is one of the most frequent complications in glioblastoma is not completely understood. In www.turner-white.com Oncology Volume 10, Part 2 15 Primary Brain Tumors addition to typical risk factors such as immobility, it have neurologic deterioration and has radiologic is possible that circulating factors produced by the progression. He does not wish to pursue additional tumor may be contributory, as these patients have therapy and is referred to hospice. He dies shortly altered hematologic profiles.72,73 thereafter, 10 months after his diagnosis. Surveillance of thromboembolic complications is important. Intermittent pneumatic compression of • What is the management of tumor recurrence? the calf reduces the incidence of VTE during the perioperative period. A randomized, prospective, The majority of glioblastoma recurrences occur double-blind clinical trial showed that a multimo- within 2 cm of the primary tumor site. Treatment op- dality approach with enoxaparin or unfractionated tions for recurrent glioblastoma include re-operation, heparin in combination with graduated compres- additional radiation, and additional chemotherapy. sion stockings, intermittent pneumatic compres- Referral for a clinical trial should also be a con- sion, and surveillance venous ultrasonography sideration in patients with adequate functional of the legs was safe and effective in the primary status. Surgical re-resection offers the opportunity prevention of VTE.74 Patients should be coun- to remove a significant tumor burden in selected seled regarding the risk of VTE and the impor- patients. Carmustine (BCNU)-impregnated wafers tance of notifying their physician of appropriate may be placed into the surgical cavity and have symptoms. shown benefit in recurrent high-grade glioma.76 LMWH may be the therapy of choice for second- Additional radiation may be delivered in several ary prevention of VTE. A randomized, controlled ways. Additional EBRT may be delivered but may trial of LMWH versus warfarin reported a survival cause significant toxicity from overlapping fields advantage for LMWH in patients with cancer.75 In- unless several years have elapsed from the initial ferior vena cava interruption by a filter is indicated radiation.77 Stereotactic radiosurgery (SRS) may be when oral anticoagulation is contraindicated or considered as a salvage option for a subgroup of ineffective. Although filters are convenient for pa- patients with smaller lesions of recurrent glioblas- tients at a high risk for bleeding, thrombosis may toma, and is well tolerated.78 Other radiotherapy occur at or above the filter site and lead to pulmo- options include brachytherapy with an implanted nary embolism or complete obstruction of venous (GliaSite) balloon system.79 return below the placement site. Standard recurrent high-grade glioma chemo- therapy options include nitrosoureas (carmustine, CASE CONTINUED lomustine), irinotecan, carboplatin, cisplatin, and The patient obtains a brain MRI after his etoposide, often in combination. Bevacizumab sixth cycle of adjuvant TMZ and is found to is a humanized monoclonal antibody targeting have tumor progression. On examination, his apha- VEGF. When compared with other agents, signifi- sia appears to be worse. He is still ambulatory and cant response rates have been reported both as is able to perform his own activities of daily living. monotherapy and in combination with other cyto- He is offered participation in a clinical trial for re- toxic agents.80 Based on this data, bevacizumab current glioblastoma and receives an experimental has received FDA approval as monotherapy for therapy along with bevacizumab. He continues to recurrent glioblastoma. However, the use of beva-

16 Hospital Physician Board Review Manual www.turner-white.com Primary Brain Tumors cizumab and its effect upon neuroimaging has other cancers; patients and their caregivers should led to the development of new imaging criteria to remain hopeful that research will lead to more ef- assess response to treatment, particularly in the fective and less toxic therapies in the near future. setting of anti-angiogenic agents.81 Recently, a de- vice utilizing alternating electrical fields (NovoTTF, BOARD REVIEW QUESTIONS Novocure, Portsmouth, NH) worn on the head was Test your knowledge of this topic. Go to www.turner-white.com and select Oncology approved by the FDA as monotherapy for recurrent from the drop-down menu of specialties. glioblastoma.82

• What is the prognosis of glioblastoma? REFERENCES

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