KESARI - Recent Progress in Brain Tumors...Concurrent temozolomide 75 mg/m 2 6-12 cycles of...

UCSD Moores Cancer CenterNeuro-Oncology Program

Recent Progress in Brain Tumors

Juvenile Pilocytic AstrocytomaGlioblastoma Multiforme

Desmoplastic Infantile GangliogliomaDesmoplastic Variant AstrocytomaMedulloblastomaAtypical Teratoid Rhabdoid TumorDiffuse Intrinsic Pontine Glioma

Metastatic Brain CancerGlioblastoma Multiforme

Courtesy of Dr. John Crawford

“Brain Cancer for Life”

-Mutational analysis, microarray expression, epigenetic phenomenology

-Age-specific biology of brain cancer

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

Late EffectsLong 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 cancerPatients with cancer living longer and developing neurologic disorders due to nervous system relapse or toxicity from treatments

Overview

IntroductionClinical PresentationPrimary Brain TumorsMetastatic Brain TumorsLeptomeningeal MetastasesPrimary CNS LymphomaParaneoplastic Syndromes

Classification of Brain TumorsTumors of Neuroepithelial Tissue

Glial tumors (astrocytic, oligodendroglial, mixed)Neuronal and mixed neuronal-glial tumorsNeuroblastic tumorsPineal parenchymal tumorsEmbryonal tumors

Tumors of Peripheral NervesShwannomaNeurofibromaPerineuriomaMalignant peripheral nerve sheath tumor

Classification of Brain Tumors

Tumors of the meningesTumors of meningothelial cellsMesenchymal, non-meningothelial tumorsPrimary melanocytic tumorsTumors of uncertain histogenesis

Lymphomas and hematopoetic neoplasmsGerm cell tumorsTumors of Sella regionMetastatic tumors

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

Brain Cancer IncidenceBrain Cancer Incidence

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

Gliomas

Meningiomas

Pituitary Adenoma

Neurinoma

Medulloblastoma

CraniopharyngiomaHemangioma Sarcoma

Others

•55% Malignant Gliomas

•10% Low Grade Gliomas

•20% 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 tumorsCBTRUS: 39,550 new cases per year benign and malignant brain tumors ACS: 17,000 new cases year of malignant brain tumorsPrevalence: 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 tumors2nd leading cause of cancer-related death <34 yrs 4th leading cause of cancer-related death 35-54 yrsLoss of productive work yearsLoss of independenceProgressive physical and cognitive impairment

Overview


Clinical Presentation

For tumors within the brain parenchyma there are two classes of symptoms :

Increased intracranial pressureFocal 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/vomitingFocal 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 headacheChange in pattern of headacheHeadache with progressive courseAbnormal neurologic examHistory of seizuresKnown 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 SpecializationDominant (left for 90%)

LanguageSpeech Calculation

Non-Dominant (right)Spatial perception

Frontal Lobe

Inappropriate social behaviorCognitive deficitsContralateral WeaknessAbulia/aphasia (Broca’s)Frontal release signsSeizures“Depression”

Temporal Lobe

Fluent aphasia (Wernicke’s)Homonymous superior quadrantianopsiaShort term memory lossIrritability/Limbic system –judgment, emotionSeizures (olfactory, gustatory hallucinations)Hemiparesis (mass effect)

Parietal Lobe

Sensory deficit Contralateral neglect, R/L confusion (tumor in non-dominant hemisphere)DyslexiaDysgraphiaHomonymous inferior quadrantianopsia

Occipital Lobe

Loss of visual acuityVisual hallucinationsProsopagnosia –inability to recognize familiar/famous facesSeizures

Cerebellum

Gait ataxia with or without truncal ataxiaDysarthriaDysmetriaNystagmusMay have obstructive symptoms related to 4th

ventricle compression

Corpus Callosum

“Butterfly glioma”Progressive severe dementiaIncontinenceBilateral pyramidal symptoms

Imaging: CT scan

Primary screen for:Mass effect HemorrhageEdemaCalcification

Advantages:Rapid emergency access

Imaging: MRIT1 no contrast T1 with contrast FLAIR

Advantages: Multiplanar imaging, superior sensitivityOffers physiological information

MRI as primary diagnostic tool?

Glioblastoma Breast cancer

MR SpectroscopyCho

Cre NAA

Low grade glioma

Choline>Creatine• increase reflects tumor cellularity (turnover)N-acetyl aspartate (NAA)• neuronal marker depicts normal functional neurons

ChoHigh grade glioma

Cre NAA

Choline>>>Creatine• reflects high cellularityN-acetyl aspartate• loss of peak reflects tumor replacing normal brain

PET Scan

BCNU 2 cycles

1. Evaluate enhancement? TumorFDG? Scar? Radiation effect

2. Document disease progression

Indications:

Biopsy and CSF AnalysisStereotactic Biopsy

CT or MRI guided biopsyLow risk, high yield although sample variability is a problem in gliomas

Open Biopsy: CraniotomyMortality <5% in major centersIf localized tumor and likely will need resection, often maximal tumor removal at time of initial craniotomy

CSF AnalysisNot part of the workup of primary malignant tumor or solid tumor metastases (except medulloblastoma)Used to diagnose leptomeningeal metastasesUsually contraindicated when large cerebral masses present

Overview


Primary Brain Tumors: Etiology

Challenges to epidemiological studyUncommon form of cancerDiversity of histologic brain tumor typesLack of uniformly accepted classification systemVariable reliability of exposure assessment (cognitive impairment of subjects and remote exposures)

Genetic Syndromes: 1-5% of brain tumorsNFI and NFIILi-Fraumeni syndrome (P53 mutation)

RadiationIonizing radiation: meningiomas, nerve sheathElectromagnetic radiation?Radiofrequency radiation: ? Cellular telephones

Head trauma, Environmental toxins, Infections

Primary Brain Tumors: Etiology

Malignant Gliomas

Glioblastoma

Anaplastic Astrocytoma

Low grade astrocytoma

OligodendrogliomaEpendymoma

5-8 yrs

2-3 yrs

10-14 months

Two pathways to Glioblastoma

Low grade glioma (II)

•High cellularity•Cellular pleomorphism•Infiltrative

Non-enhancing mass

H&E

Anaplastic Astrocytoma (III)

Non-enhancing mass, heterogeneous

•High cellularity•Pleomorphism•Mitosis

T1 + gadH&E

Glioblastoma (IV)

Enhancing mass, cysticcomponents, variable necrosis

T1 + gad

•High cellularity•Pleomorphism•Microvascular prolif•Necrosis

H&E

OligodendrogliomaLow grade (II) Anaplastic (III)

High cellularity, classic “friedegg” appearance of cells

Increased cellularity, mitosis, 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 diagnosisMaximum tumor debulkingPreserve neurologic functionIncreases survival by 2-3 months

New techniques:Intraoperative MRIFunctional mapping

Intraoperative MRI

Radiation TherapyProlongs 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 WBRTDose 54-60 Gy in 180-200 cGy fractions

no benefit from hyperfractionation

No agent with documented radiosensitizationBrachytherapy

possibly prolong survival but increased risk of radiation necrosis

Stereotactic radiosurgeryused primarily for recurrent disease – good local control

80-90% patients recur within primary site

Adjuvant ChemotherapyLow grade astrocytoma

Likely role for chemotherapy but used in progressive cases

Anaplastic glioma (astrocytoma, oligo-astro, oligodendroglioma)

Procarbazine, CCNU and vincristineBCNUTemozolamide (Temodar)

GlioblastomaTemozolamide recently shown to be beneficial.

Oligodendrogliomas are chemosensitive subset of gliomas

Characteristic genetic profile includes loss of 1p and 19qExample: “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 BBBSide effects profile

10-20% severe nausea and vomiting3% myelosuppression

Profound thrombocytopenia

Single agent therapyRecurrent 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.

Maximal surgical resection

Involved-field RT +

Concurrent temozolomide 75 mg/m2

6-12 cycles of temozolomide150-200 mg/m2

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

Recent Progress:New Standard of Care for Glioblastoma

Recent Progress:New Standard of Care for Glioblastoma

*2005: Temodar: 1st new drug for brain tumor in decades

Oligodendroglioma PR after cycle 10

Oligodendroglioma MR after cycle 12

Astrocytoma PR after cycle 12

Astrocytoma PR 7 months after cycle 12

Chemotherapy for Low-grade Gliomas

New Targets

ThalidomideAnti-VEGF

Targeting specific genetic pathways

GleevecEGFR antagonists(Iressa, Tarceva)

Cell survival (anti-apoptosis)

DNA

Mode of Action of Tyrosine Kinase Inhibitors

MembraneExtracellular

Intracellular

R R

mTOR Inhibitor

Ras

Proliferation

Chemotherapy/radiotherapy resistance Angiogenesis

EGF/PDGF/IGF

Antibody

Raf

Mek

Erk

PI3K

AKT

mTOR

PTEN

ZarnestraSCH66336

CCI-779, RAD001, AP23573

TKI EGFR-Iressa,TarcevaPDGFR-Gleevec

VEGFR-PTK787FTI

RAF inhibitorBay 43-9006

Erlotonib/rapamycin Bevacizumab/CPT-11

Adult Brain Tumor:Targeted Therapeutics Responders

Adult Brain Tumor:Targeted Therapeutics Responders

*2009: Avastin 2nd new drug for brain tumor

10%30%

Pediatric Brain Tumors:Everolimus for Subependymal Giant Cell

Astrocytomas

*2012: Affinitor:3rd new drug for brain tumors

100%

Novocure device approvalNovocureTM 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-compatible ceramic cannula

tumor

Tocagen Patient 171

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

• Injection is started in the superior region of tumor

• Injection is completed in the inferior region of the tumor

Tumor regression after Toca 511 & Toca FC

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

Tocagen patient 177 July, 2013 September, 2013

Overview


Brain Metastases: A Growing Problem

Incidence: 25-40% of all cancer patientsSymptomatic 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 brain80% of metastases are supratentorialMedian 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 functionNumber of metastasesSize of each lesionLocation of each lesion

Whole Brain Radiation

Indications:Previously, standard Rx for all casesMultifocal disease (>3 lesions)SymptomaticNot amenable to surgery or radiosurgery

Breast cancer – 10 mets

Surgery for Metastases

Solitary or <3 metastasesSurgery + WBRT vs. WBRT alone2 randomized trials demonstrated survival benefit for addition of surgery, 1 did notAccepted “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.

ChemotherapySurgery, radiosurgery, radiation therapy do not result in cureSystemic therapy is treatment of choice but no active agents currently available

Disease resistance to potentially active agentsInability to cross blood brain barrierLack tumor-specific therapiesPts heavily pretreated with cytotoxic agents limits choice of drugs

Desperate need for new therapiesNeed 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


Leptomeningeal MetastasesIncreasing5-8% 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 radiationNHL: 5-29%1% -2% of primary brain tumorsMost patients (70%) have progressive systemic disease at presentation1/3 of patients have concurrent epidural spinal or brain metastasesMedian 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 monthsIntrathecal chemotherapy is standard treatment

Methotrexate, Thiotepa, Cytarabine

Craniospinal radiation too toxicRadiation to localized sites of symptomatic diseaseNeed for new systemic therapy – same issues as chemotherapy for brain metastases

Achieving adequate CSF levels of drugs

Overview


Primary CNS Lymphoma

2% of all intracranial tumorsIncreasing incidence over past 10 yearsHIV-relatedEBV-relatedMedian survival >40 months

Primary CNS Lymphoma

25-50% are multifocalCells can infiltrate spinal cord, CSF (~30%) uvea or vitreous of the eye (~10%)Histology: most are diffuse B cellStaging: must exclude systemic disease

CT chest, abdomen, pelvisCSF analysis (minimum 10 cc)Slit lamp eye examination

Primary CNS Lymphoma -Treatment

Surgery: Biopsy onlyRadiation therapy: Whole brain radiation is not standard for patients anymoreChemotherapy: High-dose methotrexate improves long-term survival

3.5 g/m2 is standard - ? Benefit from higher doseUnclear added benefit from other cytotoxic agents

Intrathecal therapy if CSF is positive – treat twice weekly until CSF clear x 3

MethotrexateAra-CThiotepa

PCNSL: Chemosensitive tumors

Overview


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 paraneoplasticsyndrome

Cellular immunity probably also plays an important role

Clinical Features of ParaneoplasticSyndrome

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 poorEspecially with anti-Yo positive patientsYo negative patients have slightly better prognosis

Therapy:Treatment of underlying cancerImmunosuppression

IVIGSteroidsCellcept, cytoxanPlasmapheresis (usually ineffective)

NPH-Hydrocephalus60yo 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

AcknowledgmentsAcknowledgments

NIHMcDonnell FoundationAmerican Brain Tumor AssociationSontag FoundationNational Brain Tumor FoundationAccelerate Brain Cancer Cure (ABC2)Boston Fire Department/John Kenney FoundationFlorence Family FundPatients and families

“Where Discoveries are Delivered”“Where Discoveries are Delivered”

ONCOLOGY Board Review Manual

Metastatic Brain Tumors

Volume 10, Part 4 October 2013

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www.turner-white.com Oncology Volume 10, Part 4 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2Case Presentation . . . . . . . . . . . . . . . . . . . . . . . . .3Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12Board Review Questions . . . . . . . . . . . . . . . . . . .12References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

Table of Contents

ONCOLOGY BOARD REVIEW MANUAL

Metastatic Brain Tumors

Series Editor:Arthur T. Skarin, MD, FACP, FCCPDistinguished Physician, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Contributors:Jai Grewal, MD Co-Medical Director, Long Island Brain Tumor Center at NSPC, Lake Success, NY

Harpreet Kaur Grewal, MD University of Texas Health Sciences Center at Houston, Houston, TX

Santosh Kesari, MD, PhD Director, Neuro-Oncology Program, Translational Neuro-Oncology Laboratories, Neurotoxicity Treatment Center, Moores Cancer Center, University of California San Diego Health System, La Jolla, CA

STATEMENT OF EDITORIAL PURPOSE

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 to the current practice of oncology.

PUBLISHING STAFF

PRESIDENT, GROUP PUBLISHERBruce M. White

SENIOR EDITORRobert Litchkofski

EXECUTIVE VICE PRESIDENTBarbara T. White

EXECUTIVE DIRECTOR OF OPERATIONS

Jean M. Gaul

NOTE FROM THE PUBLISHER:This publication has been developed with-out involvement of or review by the Amer-ican Board of Internal Medicine.

M e t a s t a t i c B r a i n T u m o r s

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


Metastatic Brain TumorsJai Grewal, MD, Harpreet Kaur Grewal, MD, and Santosh Kesari, MD, PhD

INTRODUCTION

Systemic cancer can affect the central nervous system in several different ways, including direct tumor metastasis and indirect remote effects. Intra-cranial metastasis can involve the skull, dura, and leptomeninges (arachnoid and pia mater), as well as the brain parenchyma. Of these, parenchymal brain metastases are the most common and have been found in as many as 24% of cancer patients in autopsy studies.1 It has been reported that metastatic brain tumors outnumber primary brain tumors 10 to 1.2

Metastasis to the brain generally occurs by he-matogenous dissemination, with tumor cells having a propensity to lodge and grow at the gray-white junction. The distribution of brain metastases is proportionate to the cerebral blood flow, with 80% occurring in the supratentorial region, 15% in the cerebellum, and 5% in the brainstem.1 Unlike pri-mary brain tumors, such as glioblastoma, brain metastases do not typically involve the corpus callosum or infiltrate across the midline. The most common primary histologies include lung, breast, melanoma, renal, and colon cancer, and tumors of unknown primary (Figure 1).3

Brain metastases can present with a variety of symptoms (Figure 2), including focal neurological deficits, headache, and seizures. The sudden onset of symptoms may be related to intracranial hemor-rhage associated with brain metastases. Given its relatively high incidence, lung cancer is the most common type of brain metastases to result in in-tracranial hemorrhage. However, other cancer pri-maries have, relative to their incidence, a very high propensity to spontaneously develop tumor-associ-ated intracranial hemorrhage; they are melanoma, renal cell carcinoma, choriocarcinoma, thyroid, and germ cell. Ultimately, any brain metastasis has the potential for spontaneous hemorrhage.

Often, the presentation of brain metastasis oc-curs in a patient with established malignancy, in which case a clinical and radiological diagnosis is usually sufficient. Magnetic resonance imaging (MRI) with gadolinium contrast is preferred over computed tomography (CT) alone due to greater sensitivity in identifying additional lesions. For ex-ample, in approximately one-third of cases present-ing with a single metastasis on CT, MRI will lead to the discovery of additional metastases (Figure 3).4

Occasionally, brain metastasis can occur as the presenting feature in a patient not known to have

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cancer. A thorough assessment is essential in iden-tifying the associated systemic malignancy and in determining which site of disease is safest for tissue diagnosis. In the differential diagnosis, conditions apart from metastatic disease need to be consid-ered (Table 1).

CASE PRESENTATION

INITIAL PRESENTATION AND EVALUATION

A 54-year-old woman presents with a left breast mass and is treated with a lumpec-

tomy and axillary lymph node dissection. Her tumor is negative for hormonal receptors (estro-gen receptor, progesterone receptor) and is also negative for HER2/neu (human epidermal growth factor receptor 2). She has positive lymph nodes and receives local radiation therapy and 8 cycles of adjuvant cyclophosphamide, methotrexate, and

5-fluorouracil. There are no other sites of meta-static disease at diagnosis.

Eight months after her diagnosis, she develops right-sided headaches. She has an excellent per-formance status. CT of the brain without contrast reveals a right parietal hypodensity with significant mass effect. MRI with gadolinium contrast does not reveal any additional lesions (Figure 4). There is no evidence of any active extracranial disease.

• What are important prognostic factors inbrain metastasis?

PROGNOSIS

Several factors have been validated as important prognostic factors in patients with brain metastasis. These include age, performance status, and extent of extracranial disease. These factors have been used to stratify patients into several prognostic

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

Lung40%

Breast 19%

Melanoma 10%

GI 7%

GU 7%

GYN 5%

Other 10%

Unknown 2%



categories, known as RPA (recursive partitioning analysis) classes.5 Discrete differences in survival have been demonstrated based upon this clas-sification (Table 2). Poor performance status sug-gests a poor outcome (RPA class 3) regardless of the other factors. The patient in this case is in the most favorable group, RPA class 1.

Recently these prognostic categories were updat-ed and a fourth prognostic element was incorporat-

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 3 months) in all histologies examined. In addition, performance status was found to be an important 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-tastasis.8 Elevated serum lactate dehydrogenase (LDH) also has been suggested as a predictor for developing brain metastasis.9 The role of HER2/neu receptor status is unclear,10 but the prognosis of patients with brain metastasis in the setting of HER2-positive disease may be more favorable due to better control of extracranial disease with trastuzumab.11 Features of breast cancer which may increase risk for developing brain metastasis

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

Figure 3. (A) Computed tomography of the brain reveals a sin-gle brain metastasis (arrow). (B) Magnetic resonance imaging with contrast reveals a second small site of metastasis in the contralateral hemisphere (arrow).

Headache

Cognitive

Weakness

Gait

Seizures

Speech

Vision

Percentage

6

12

18

21

30

32

49



include age less than 50 years, high-grade histol-ogy, expression of basal cytokeratin CK5/6, over-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 cancer with varying prognoses.13 Ongoing research is exploring the implications of these categories with regard to brain metastasis.

• What treatment options are available forbrain metastasis?

TREATMENT

SurgerySurgical resection is an important consideration

for a patient with favorable prognostic factors (RPA class 1 or 2) and a single brain metastasis in a sur-gically accessible area. Several studies suggest im-proved functional independence and overall survival if surgical resection is performed in addition to whole brain radiation therapy (WBRT),14–16 although one randomized study and a subsequent meta-analysis dispute this benefit.17,18 Resection for several metas-tases is less well-established than resection for sin-gle lesions, although it appears that resection of all intracranial metastases confers an outcome similar to resection of a single brain metastasis.19 Resection

of recurrent brain metastasis after initial treatment has also been shown to be feasible in retrospective analyses.20,21 Large tumor size, significant mass ef-fect, noneloquent tumor location, and the need for diagnostic tissue are also considerations in making a decision to perform an operation.

Whole Brain Radiation TherapyWBRT for brain metastases was described over

50 years ago by Chao and colleagues.22 This mo-dality, in contrast to the other local therapies, may address microscopic metastatic disease in the brain that is not yet clinically or radiographically evident. There is only one randomized study com-paring WBRT and supportive care (with corticoste-roids).23 In this study, 46 patients were randomized to either WBRT or supportive care; median survival was slightly longer in the group receiving WBRT (14 weeks versus 10 weeks). However, neither brain imaging with CT or MRI nor statistical analy-sis was performed. Rates of local recurrence are significantly higher in patients who have WBRT withheld and only receive local therapy (either sur-

Table 1. Differential Diagnosis of Brain Metastasis

DiseaseProcess 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-netic resonance imaging of the brain with contrast (A) at diagnosis and (B) after surgical resection.



gery or stereotactic radiosurgery; see below),24–27

although overall survival appears similar, likely because death often results from extracranial dis-ease. The effects of WBRT upon neurocognitive function and quality-of-life are conflicting; declines in neurocognitive function and quality-of-life have been attributed to poor tumor control28–30 as well as to WBRT itself.31 Acute radiation toxicity includes headaches, nausea, vomiting, fatigue, alopecia, ear fullness, dry mouth, and scalp irritation. Late toxicity from WBRT includes progressive cognitive impairment, ataxia, and urinary incontinence.32,33

Using smaller fraction size (3 Gy or less) decreas-es the likelihood of such complications in the sub-set of patients who survive for a prolonged period of time.

Prophylactic cranial irradiation (PCI) of approxi-mately 25 Gy of WBRT is considered standard of care in the treatment of chemotherapy-sensitive small-cell lung cancer (SCLC), as there is both a survival benefit and improved local control.34

A randomized study found that higher doses of PCI (36 Gy) for SCLC led to increased neurocognitive toxicity without benefit.35

A trial of PCI for locally advanced NSCLC re-vealed a decreased risk of brain metastasis with increased neurocognitive toxicity.36,37 This trial was closed prematurely due to poor accrual.

Stereotactic RadiosurgeryStereotactic radiosurgery (SRS) involves tech-

niques to precisely deliver high-dose radiation to a small area of brain in a single or small number of fractions. Theoretically, the surrounding tissue is spared most of the dose. Small spherical brain 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 given either as a single fraction (most commonly) or over a small number of fractions. Use of a head-frame may be a necessary part of the technique (eg, Gamma knife). A late and serious complica-tion of SRS is radionecrosis. Multiple studies have confirmed the ability of SRS to achieve local tumor control,38–42 even in radioresistant malignancies. SRS offers less morbidity than surgical resection in treating patients with multiple brain metastases, and it may be more cost effective.43 Whether there is an upper limit to the number of brain metastases that can be treated with SRS is unclear; it appears feasible to treat patients with more than 10 metas-tases.44 Randomized clinical trials evaluating surgi-cal resection, WBRT and SRS for brain metastasis are summarized in Table 3.14,15,17,24,26,27,38,42,45,46

Pharmacologic TherapyIn randomized trials, traditional chemotherapy

has demonstrated limited benefit in controlling metastatic brain tumors.47–50 There may be several reasons for this. Most important, the blood-brain barrier limits the penetration of chemotherapy into brain and brain tumor tissue. Additionally, because

Table 2. Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Prognostic Classification

RPAClass Criteria MedianSurvival(months)

1 KPS ≥70Age <65 yrControlled primary tumorNo extracranial disease

7.1

2 All other situations 4.2

3 KPS <70 2.3

KPS = Karnosky performance status.

Adapted from Gaspar L, Scott C, Rotman M, et al. Recursive partition-ing analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745–51.



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

Study ClinicalSituation

AllReceived

Randomized Intervention

N

Conclusions

Patchell et al (1990)14

Single brain metastasis

WBRT Surgical resection 48 Undergoing surgical resection prior to WBRT improved local control at original site of metastasis, overall survival, and functional independence

Vecht et al (1993)15


WBRT Surgical resection 63 Undergoing surgical resection prior to WBRT improved local control at original site of metastasis, overall survival, and functional independence,* particularly in patients with well-controlled extracranial disease

Mintz et al (1996)17


WBRT Surgical resection 84 Undergoing surgical resection prior to WBRT failed to dem-onstrate an improvement in overall survival or functional independence

Patchell et al (1998)24


Surgical resection

WBRT 95 The addition of WBRT following surgical resection de-creased the risk of intracranial relapse and risk of neuro-logic death, but did not improve overall survival or func-tional independence

Kondziolka et al (1999)42

2–4 brain metastases

WBRT SRS 27† Adding SRS to WBRT was well tolerated and improved local control, but did not improve overall survival

Andrews et al (2004)38

Unresectable 1–3 brain metastases (RTOG 9508)

WBRT SRS 333 In patients with a single unresectable brain metastasis, add-ing SRS to WBRT led to improved overall survival. The SRS group experienced improved performance status. In 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 et al (2006)26

1–4 small (<3 cm) brain metastasis

SRS WBRT 132 Omitting WBRT after SRS increased the risk of local recur-rence, but did not change overall survival. There were no significant differences in neurological function and toxicity between the 2 groups.

Muacevic et al (2008)45

Single resectable brain metastasis

– Resection + WBRT versus SRS alone

33† The group treated with SRS alone experienced an increased 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 et al (2011)27

1–3 brain metastases (EORTC 22952)

Either resection or SRS

WBRT 359 Omitting WBRT after local therapy (with either surgery or SRS) led to increased risk of intracranial relapse and neurologic death; however, there were no significant differ-ences in overall survival or functional independence. Sepa-rately published analysis demonstrated improved QOL in the group that did not receive WBRT.‡

Sperduto et al (2013)46

1–3 brain metastases (RTOG 0320)

WBRT and SRS

3-arm study of con-current/adjuvant: te-mozolomide versus erlotinib versus none

126† The study was underpowered to derive conclusions; how-ever, there was a suggestion of improved survival and im-proved time to CNS progression in the control group,* that 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.



brain metastasis can develop as a late feature in the course of cancer, the tumor may have already been treated with several chemotherapy regimens, leading to some degree of chemoresistance in the metastatic tissue.

However, systemic chemotherapy does play an important role in controlling extracranial disease. For example, patients with brain metastasis from HER2-positive breast cancer may have improved survival compared to patients with brain metasta-sis associated with HER2-negative disease due to the efficacy of agents such as trastuzumab in con-trolling extracranial disease.51 Trastuzumab itself has no significant penetration across the blood-brain barrier.52

Newer agents with better penetration into the cen-tral nervous system, such as temozolomide,46,53,54

capecitabine, lapatinib,55 and erlotinib,46 have been investigated as treatment options for brain metas-tasis, and as potential radiosensitizers. Many such agents are small-molecule compounds with rela-tively favorable toxicity profiles. The optimal role of chemotherapy in the treatment of brain metastasis is still evolving.

The histology of the primary tumor is an impor-tant consideration when selecting drug therapies. In patients with metastatic melanoma and brain metastasis, ipilumimab does not appear to con-tribute to toxicity and may warrant further explora-tion.56,57 Sorafenib may decrease the incidence of brain metastasis in patients with renal cell carci-noma.58

EGFR mutations predict response to therapy with anti-EFGR agents such as erlotinib. Systemic resistance may occur while the metastatic disease in the central nervous system remains sensitive;59

higher concentration of drug might be achievable in the central nervous system via weekly “pulsa-tile” dosing of erlotinib. Finally, in HER2-positive

breast cancer, responses are observed (objective response rate of 38%) with the combination of lapatinib plus capacitabine.55 Experimental thera-pies for brain metastasis include the placement of BCNU (bis-chloroethylnitrosourea)–impregnated wafers into the resection cavity at the time of sur-gery for single metastasis.60

Radiation SensitizersAnother approach in treating brain metastasis is

to utilize agents that may serve as a radiosensitizer. Agents tested in a randomized controlled fashion in-clude lonidamine,61 metronidazole,62 thalidomide,63

misonidazole,64 bromodeoxyuridine,65 gefitinib,54

and motexafin gadolinium.66 None of these agents has been shown to prolong overall survival in brain metastases, but motexafin gadolinium has been shown to improve time to neurological progression as well as neurocognitive function in the subset of patients with NSCLC.67,68 Based on the success of the concurrent use of temozolomide with radia-tion therapy in glioblastoma,69 temozolomide and erlotinib were separately tested as radiosensitiz-ers in a randomized controlled trial (RTOG-0320) for patients with 3 or fewer brain metastases from NSCLC. All arms of the study included SRS and WBRT. Patients were randomized to either temo-zolomide, erlotinib, or no chemotherapy during the period of radiotherapy and were allowed to con-tinue the drug as adjuvant therapy. Unfortunately, the study was terminated early due to poor accrual, and it appeared that overall survival was in fact worsened by adding 1 of the 2 agents compared with SRS/WBRT alone, although the study was underpowered to confirm this trend.46

Efaproxiral, an allosteric modifier of hemoglobin, demonstrated improved survival and quality of life when randomly assigned to 106 patients with breast cancer receiving WBRT and supplemental oxygen.70



Supportive CareIn 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-methasone consists of an intravenous bolus of 10 to 20 mg followed by 4 to 24 mg/day in divided 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-ticosteroids are often continued until tumor control is achieved with definitive treatment (eg, surgery or WBRT) and should then be tapered.

Seizures can occur in patients with brain me-tastasis. However, anticonvulsants should be re-served for patients who have actually experienced a seizure.71 Anticonvulsants that do not induce hepatic enzymes, such as levetiracetam, valpro-ate, gabapentin, and pregabalin, are less likely to interact with chemotherapy and are preferred.

CASE 1 CONTINUED

The single metastasis is surgically resected without significant neurological sequelae

(Figure 4). The pathological review is consistent with metastatic breast cancer. The patient then receives WBRT to a total dose of 30 Gy in 15 fractions. She receives surveillance brain MRI with gadolinium every 3 months. She remains

clinically and radiologically stable 6 months after the completion of WBRT. After the eighth month, she reports impaired balance and urinary incon-tinence. Contrast MRI of the brain reveals sulcal enhancement within the cerebellum. MRI of the spine shows leptomeningeal enhancement near the conus medullaris (Figure 5). Lumbar puncture is performed; cerebrospinal fluid (CSF) analysis reveals elevated protein (121 mg/dL) and the pres-ence of malignant cells on CSF cytology. These cells are consistent with the primary cancer cells.

• What is the significance of these findings?

LEPTOMENINGEAL METASTASIS

The clinical, radiological, and laboratory find-ings are suggestive of leptomeningeal metastasis (LM). LM refers to infiltration of the leptomeninges (arachnoid and pia mater) with neoplastic cells. Synonyms for this condition include neoplastic

Figure 5. (A) Sulcal enhancement of the cerebellum (arrows) on brain magnetic resonance imaging (MRI), consistent with lepto-meningeal metastasis. (B) Leptomeningeal metastasis on lumbar spine MRI with enhancement near the conus medullaris (arrows).



meningitis, meningeal carcinomatosis, and lepto-meningeal disease. The presence of malignant cells on CSF cytology is considered the diagnostic gold standard for this condition and is highly specific; however, a single negative cytology does not nec-essarily exclude the diagnosis. Three serial lumbar punctures for CSF analysis has a sensitivity of ap-proximately 90%.72 CSF protein is commonly elevat-ed. When unequivocal evidence of LM is noted on MRI, a radiographic diagnosis of LM may be made without CSF.

Simultaneous involvement of multiple levels of the neuroaxis is a clinical hallmark of LM. Cerebral, cra-nial nerve, and spine involvement are common and

each may be associated with a specific set of signs and symptoms (Table 4).73 Elevated intracranial pres-sure may result in headache, nausea, vomiting, and confusion. Hematological malignancies are frequent-ly associated with LM, as are many types of solid malignancies and primary brain tumors (Table 5).74

The disease process may be diffuse or nodular. Diffuse LM may be difficult to detect on MRI. Nodu-lar LM can cause symptoms due to mass effect and can result in spinal cord compression. Use of intra-CSF chemotherapy may have limited benefit for bulky leptomeningeal tumors greater than 2 mm in size due to limited penetration of drug.75–77 MRI findings in LM are noted in Table 6.78,79

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.



The prognosis of LM is poor and survival is typically less than 6 months. However, a small subset of pa-tients with LM (including those with breast cancer) may experience prolonged survival of 1 year or greater.

• What treatment options are available for pa-tients with LM?

Treatment options for patients with LM are pallia-tive and include intrathecal chemotherapy, sys-temic chemotherapy, and radiotherapy.

ChemotherapyIntra-CSF chemotherapy can be delivered via lum-

bar puncture (intrathecal) or via a ventricular catheter connected to a reservoir placed under the scalp (Ommaya reservoir). While complications are pos-

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 flow study (cisternogram) may be performed prior to delivering intrathecal chemotherapy to identify any sites of obstruction to CSF flow; these areas may be treated with focal radiotherapy to restore normal flow patterns.80 Agents which may be ad-ministered into CSF for LM are listed in Table 7. Arachnoiditis, a common acute complication of intra-CSF chemotherapy, may present within 72 hours of drug administration as headache, nausea, and vomit-ing, and is treated with systemic cortico-steroids.

Systemic chemotherapy may play a role in treat-ing LM as well as managing the extracranial ma-lignancy (Table 8).81 Supportive care for patients with LM includes CSF shunting,82 corticosteroids, and anticonvulsants.

Radiation therapy can also be used to palliate LM. The extent of the central nervous system

Table 5. Malignancies Associated with Leptomeningeal Metastasis

Malignancy Frequency(%)

Non-CNS solid tumors

Lung

SCLC 15

NSCLC 1

Breast 5

Melanoma 5

Gastrointestinal 1

Head and neck 1

Hematologic malignancies

Leukemia 5–15

Lymphoma 6

Primary CNS tumors

PCNSL 42

Glioma 14

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

Table 6. Magnetic Resonance Imaging Findings in Leptomeningeal Metastasis

Finding Frequency(%)

Brain

Parenchymal volume loss 93

Sulcal (pial) enhancement 57

Enhancing nodules 36

Ependymal enhancement 21

Communicating hydrocephalus 7

Spine

Cauda equina nerve root thickening 20

Lineal pial enhancement 32

Enhancing subarachnoid nodules Not reported

Adapted from Chamberlain MC, Sandy AD, Press GA. Leptomeningeal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. Neurology 1990;40(3 Pt 1):435–8; and Col-lie DA, Brush JP, Lammie GA, et al. Imaging features of leptomeningeal metastases. Clin Radiol 1999;54:765–71.



treated may vary and can range from very limited radiation therapy to irradiation of the entire neu-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-hood of response to other therapies.

CASE CONTINUED

Treatment consisted of radiation therapy to the caudal equina area with improvement in

urinary incontinence. Following radiation therapy, in-trathecal liposomal cytarabine was administered via an Ommaya reservoir with clearing of CSF cytology after 3 doses. The patient remained neurologically stable, but developed new lung metastases which were unresponsive to salvage treatment and result-ed in significant functional impairment. She decided to pursue comfort care and died shortly thereafter.

CONCLUSION

Metastatic disease to the central nervous sys-tem is an issue that has become more significant

as patients survive longer with cancer. Brain me-tastases and leptomeningeal metastases are 2 types of central nervous system metastases which require careful selection of treatment modalities for each individual patient. The prognosis is generally poor for both conditions, but prognostic factors have been identified which help to stratify patients and determine the appropriateness of available therapies. In addition to treatment of malignancy, management of neurological complications is im-portant in managing these patients. More effec-tive therapies for these conditions are essential, as they represent a critical obstacle to the overall progress of cancer treatment.

Table 7. Agents That Have Been Administered into Cerebrospinal Fluid for Leptomeningeal Metastasis

Methotrexate

Cytarabine (ara-C)

Liposomal cytarabine (DepoCyt)

Thiotepa

Topotecan

Trastuzumab*

Rituximab*

Interleukin-2

*Perissinotti AJ, Reeves DJ. Role of intrathecal rituximab and trastu-zumab in the management of leptomeningeal carcinomatosis. Ann Pharmacother 2010;44:1633–40.

Table 8. Chemotherapy Options in Leptomeningeal Metastasis.

Drug CSF–PlasmaRatio(%)

Antimetabolites

Methotrexate 3

6-Mercaptopurine 25

Cytarabine 20

Capecitabine* Unknown

Alkylating agents

Thiotepa >90

Temozolomide† 20

*Rogers LR, Remer SE, Tejwani S. Durable response of breast cancer leptomeningeal metastasis to capecitabine monotherapy. Neuro Oncol 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, intrathecal chemotherapy, and symptom management in the treatment of leptomeningeal metastasis. Curr Oncol Rep 2003;5:29–40.

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Go to www.turner-white.com and select Oncologyfrom the drop-down menu of specialties.



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50. Ushio Y, Arita N, Hayakawa T, et al. Chemotherapy of brain metastases from lung carcinoma: a controlled randomized study. Neurosurgery 1991;28:201–5.

51. Kirsch DG, Loeffler JS. Brain metastases in patients with breast cancer: new horizons. Clin Breast Cancer



2005;6:115–24.52. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin

Oncol 2000;18:2349–51.53. Gamboa-Vignolle C, Ferrari-Carballo T, Arrieta O, et al.

Whole-brain irradiation with concomitant daily fixed-dose temozolomide for brain metastases treatment: a ran-domised phase II trial. Radiother Oncol 2012;102:187–91.

54. Pesce GA, Klingbiel D, Ribi K, et al. Outcome, quality of life and cognitive function of patients with brain metasta-ses from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolo-mide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03). Eur J Cancer 2012;48:377–84.

55. Lin NU, Eierman W, Greil R, et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topo-tecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol. 2011;105:613–20.

56. Weber JS, Amin A, Minor D, et al. Safety and clinical activ-ity of ipilimumab in melanoma patients with brain metas-tases: retrospective analysis of data from a phase 2 trial. Melanoma Res 2011;21:530–4.

57. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13:459–65.

58. Massard C, Zonierek J, Gross-Goupil M, et al. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol 2010;21:1027–31.

59. Grommes C, Oxnard GR, Kris MG et al. "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364–9.

60. Ewend MG, Brem S, Gilbert M, et al. Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and pro-vides excellent local control. Clin Cancer Res 2007;13:3637–41.

61. DeAngelis LM, Currie VE, Kim JH, et al. The combined use of radiation therapy and lonidamine in the treatment of brain metastases. J Neurooncol 1989;7:241–7.

62. Eyre HJ, Ohlsen JD, Frank J, et al. Randomized trial of ra-diotherapy versus radiotherapy plus metronidazole for the treatment metastatic cancer to brain. A Southwest Oncol-ogy Group study. J Neurooncol 1984;2:325–30.

63. Knisely JP, Berkey B, Chakravarti A, et al. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys 2008;71:79–86.

64. Komarnicky LT, Phillips TL, Martz K, et al. A randomized phase III protocol for the evaluation of misonidazole com-

bined with radiation in the treatment of patients with brain metastases (RTOG-7916). Int J Radiat Oncol Biol Phys 1991;20:53–8.

65. Phillips TL, Scott CB, Leibel SA, et al. Results of a ran-domized comparison of radiotherapy and bromodeoxy-uridine with radiotherapy alone for brain metastases: report of RTOG trial 89-05. Int J Radiat Oncol Biol Phys 1995;33:339–48.

66. Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain me-tastases. J Clin Oncol 2003;21:2529–36.

67. Mehta MP, Shapiro WR, Phan SC, et al. Motexafin gado-linium combined with prompt whole brain radiotherapy pro-longs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial. Int J Radiat Oncol Biol Phys 2009;73:1069–76.

68. Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gado-linium: results of a randomized phase III trial. J Clin Oncol 2004;22:157–65.

69. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblas-toma. N Engl J Med 2005;352:987–96.

70. Scott C, Suh J, Stea B, et al. Improved survival, quality of life, and quality-adjusted survival in breast cancer pa-tients treated with efaproxiral (Efaproxyn) plus whole-brain radiation therapy for brain metastases. Am J Clin Oncol 2007;30:580–7.

71. Glantz MJ, Cole BF, Forsyth PA, et al. Practice param-eter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1886–93.

72. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759–72.

73. DeAngelis LM, Boutros D. Leptomeningeal metastasis. Cancer Invest 2005;23:145–54.

74. Kesari S, Batchelor TT. Leptomeningeal metastases. Neu-rol Clin 2003;21:25–66.

75. Benjamin JC, Moss T, Moseley RP, et al. Cerebral distri-bution of immunoconjugate after treatment for neoplastic meningitis using an intrathecal radiolabeled monoclonal antibody. Neurosurgery 1989;25:253–8.

76. Burch PA, Grossman SA, Reinhard CS. Spinal cord penetration of intrathecally administered cytarabine and methotrexate: a quantitative autoradiographic study. J Natl Cancer Inst 1988;80:1211–6.

77. Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous



meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int 2013 May 2;4(Suppl 4):S265–88.

78. Chamberlain MC, Sandy AD, Press GA. Leptomenin-geal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. Neurology 1990;40(3 Pt 1):435–8.

79. Collie DA, Brush JP, Lammie GA, et al. Imaging features of leptomeningeal metastases. Clin Radiol 1999;54:765–71.

80. Chamberlain MC, Kormanik PA. Prognostic significance

of 111indium-DTPA CSF flow studies in leptomeningeal metastases. Neurology 1996;46:1674–7.

81. Berg SL, Chamberlain MC. Systemic chemotherapy, intra-thecal chemotherapy, and symptom management in the treatment of leptomeningeal metastasis. Curr Oncol Rep 2003;5:29–40.

82. Omuro AM, Lallana EC, Bilsky MH, DeAngelis LM. Ven-triculoperitoneal shunt in patients with leptomeningeal metastasis. Neurology 2005;64:1625–7.

review article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 359;5 www.nejm.org july 31, 2008492

Medical Progress

Malignant Gliomas in AdultsPatrick Y. Wen, M.D., and Santosh Kesari, M.D., Ph.D.

From the Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital; and the Center for Neuro-Oncology, Dana−Farber Cancer In-stitute — both in Boston. Address reprint requests to Dr. Wen at the Center for Neuro- Oncology, Dana−Farber/Brigham and Women’s Cancer Center, SW430D, 44 Binney St., Boston, MA 02115, or at [email protected].

N Engl J Med 2008;359:492-507.Copyright © 2008 Massachusetts Medical Society.

Malignant gliomas account for approximately 70% of the 22,500new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year.1-3 Although relatively uncommon, malig-

nant gliomas are associated with disproportionately high morbidity and mortality. Despite optimal treatment, the median survival is only 12 to 15 months for patients with glioblastomas and 2 to 5 years for patients with anaplastic gliomas. Recently, there have been important advances in our understanding of the molecular patho-genesis of malignant gliomas and progress in treating them. This review summa-rizes the diagnosis and management of these tumors in adults and highlights some areas under investigation.

EPIDEMIOL O GIC FE AT UR ES

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.9The 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

Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by SANTOSH KESARI MD on July 30, 2008 .

Medical Progress

n engl j med 359;5 www.nejm.org july 31, 2008 493

no identified genetic cause. Recently, an interna-tional consortium, GLIOGENE, was established to study the genetic basis of familial gliomas.11

PATHOL O GIC A L FE AT UR ES

Malignant gliomas are histologically heteroge-neous and invasive tumors that are derived from glia. The World Health Organization (WHO) clas-sifies astrocytomas on the basis of histologic fea-tures into four prognostic grades: grade I (pilo-cytic astrocytoma), grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma).1 Grade III and IV tumors are con-sidered malignant gliomas. Anaplastic astrocy-tomas are characterized by increased cellularity, nuclear atypia, and mitotic activity. Glioblastomas also contain areas of microvascular proliferation, necrosis, or both (Fig. 1 and 2). Uncommon glio-blastoma variants include gliosarcomas, which contain a prominent sarcomatous element; giant-cell glioblastomas, which have multinucleated giant cells; small-cell glioblastomas, which are associated with amplification of the epidermal growth factor receptor (EGFR); and glioblasto-mas with oligodendroglial features, which may be associated with a better prognosis than standard glioblastomas.1,12 Oligodendrogliomas are divided by the WHO into two grades: well-differentiated oligodendrogli omas and oligoastrocytomas (WHO grade II), and anaplastic oligodendrogliomas and anaplastic oligoastrocytomas (WHO grade III) (Fig. 1). All of these tumors may contain perinu-clear halos (Fig. 2C) and a delicate network of branching blood vessels (chicken-wire pattern).1

Malignant gliomas typically contain both neo-plastic and stromal tissues, which contribute to their histologic heterogeneity and variable out-come. Molecular studies such as gene-expression profiling potentially allow for better classification of these tumors and separation of the tumors into different prognostic groups.13-17

MOLECUL A R PATHO GENESIS

Recently, there has been important progress in our understanding of the molecular pathogenesis of malignant gliomas, and especially the importance of cancer stem cells.18,19 Malignant transforma-tion in gliomas results from the sequential accu-mulation of genetic aberrations and the deregu-lation of growth-factor signaling pathways (Fig. 1

and 3).18,22 Glioblastomas can be separated into two main subtypes on the basis of biologic and genetic differences.18,22 Primary glioblastomas typ-ically occur in patients older than 50 years of age and are characterized by EGFR amplification and mutations, loss of heterozygosity of chromosome 10q, deletion of the phosphatase and tensin ho-mologue on chromosome 10 (PTEN), and p16 de-letion. Secondary glioblastomas are manifested in younger patients as low-grade or anaplastic astro-cytomas and transform over a period of several years into glioblastomas. These tumors, which are much less common than primary glioblastomas, are characterized by mutations in the p53 tumor-suppressor gene,23 overexpression of the platelet-derived growth factor receptor (PDGFR), abnor-malities in the p16 and retinoblastoma (Rb) pathways, and loss of heterozygosity of chromo-some 10q.18,24 Secondary glioblastomas have tran-scriptional patterns and aberrations in the DNA copy number that differ markedly from those of primary glioblastomas.18,22 Despite their genetic differences, primary and secondary glioblastomas are morphologically indistinguishable and respond similarly to conventional therapy, but they may re-spond differently to targeted molecular therapies.

High-grade oligodendrogliomas are character-ized by the loss of chromosomes 1p and 19q (in 50 to 90% of patients).1 Progression from low-grade to anaplastic oligodendroglioma is associ-ated with defects in PTEN, Rb, p53, and cell-cycle pathways.1

Deregulated Growth Factor Signaling

The most common defects in growth-factor sig-naling involve EGFR and PDGFR (Fig. 3).18 Am-plification of EGFR occurs almost exclusively in primary glioblastomas and is seen in approximate-ly 40 to 50% of patients with that type of tumor. About half of the tumors with EGFR amplifica-tion express a constitutively autophosphorylated variant of EGFR, known as EGFRvIII, that lacks the extracellular ligand-binding domain (exons 2 through 7).14,18 This characteristic variant has become an important therapeutic target for ki-nase inhibitors, immunotoxins, and peptide vac-cines.3,18 Recently, activating mutations in the ex-tracellular domain of EGFR have been identified.25

PDGF signaling is a key regulator of glial devel-opment,26 and both ligand and receptors are fre-quently expressed in gliomas, creating an auto-crine loop that stimulates proliferation of the




tumor.18 Growth factor–receptor signaling, through intermediate signal-transduction generators, re-sults in the activation of transcriptional programs for survival, proliferation, invasion, and angio-genesis. Common signal-transduction pathways activated by these growth factors are the Ras– mitogen-activated protein (MAP) kinase path-way, which is involved in proliferation and cell-cycle progression, and the phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian target of rapa-mycin (mTOR) pathways, which are involved in the inhibition of apoptosis and cellular proliferation (Fig. 3).18 PTEN, a tumor-suppressor gene that neg-atively regulates the PI3K pathway, is inactivated in 40 to 50% of patients with glio blastomas.18,27

Many of the above pathways lead to the up-regulation of vascular endothelial growth factor (VEGF) and angiogenesis.28,29 EGFR, PDGFR, and VEGF-receptor (VEGFR) pathways also play an

important role in the normal development of the nervous system by promoting the proliferation of multipotent stem cells. Other developmental path-ways that contribute to the biologic features of gliomas are those involving sonic hedgehog, wing-less, Notch, CXC chemokine receptor 4 (CXCR4), and bone morphogenetic proteins.19 In addition, oligodendrocyte transcription factor 2 (Olig2), a developmentally regulated, lineage-restricted neural transcription factor, is a universal marker of diffuse gliomas and stem cells that may be a prerequisite for early transformation.30 Drugs that target these pathways are under active in-vestigation as treatment for gliomas.

Role of Stem Cells in Pathogenesis and Resistance to Therapy

Although the genetic and signaling pathways in-volved in the development of malignant gliomas

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P16Ink4a/P14ARF loss RB mutated (~65%)p53 mutated PTEN lossLOH 9p, 10qCDK4/EGFR/MYC amplifiedVEGF overexpressed

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Figure 1. Pathways in the Development of Malignant Gliomas.

Genetic and chromosomal alterations involved in the development of the three main types of malignant gliomas (primary and secondary glioblastomas and anaplastic oligodendroglioma) are shown. Oligodendrocyte transcription factor 2 (Olig2) (blue) and vascular endo-thelial growth factor (VEGF) (red) are expressed in all high-grade gliomas. Median lengths of survival (asterisks) are shown. A slash indicates one or the other or both. DCC denotes deleted in colorectal carcinoma, EGFR epidermal growth factor receptor, LOH loss of heterozygosity, MDM2 murine double minute 2, PDGF platelet-derived growth factor, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositol 3-kinase, PTEN phosphatase and tensin homologue, and RB retinoblastoma.


Medical Progress


have been relatively well characterized, the cellu-lar origins of these tumors are unknown. The adult nervous system harbors neural stem cells that are capable of self-renewal, proliferation, and

differentiation into distinctive mature cell types.31

There is increasing evidence that neural stem cells, or related progenitor cells, can be transformed into cancer stem cells and give rise to malignant gliomas

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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) (Panel B, hematoxylin and eosin). Panels C and D show the histologic features of an anaplastic oligodendroglioma, including the typical perinuclear halo (“fried egg”) appearance (Panel C, hematoxy-lin and eosin) and diffuse Olig2 staining (Panel D, brown color). The proliferation index can be quantified by immunohis-tochemical analysis with the use of Ki67 staining (Panel E, black color), and heterogeneous EGFR amplification by colori-metric in situ hybridization showing more than two signals (brown spots in nuclei) in almost all tumor cells (Panel F). (Courtesy of Ali G. Saad, M.D., Department of Pathology, Brigham and Women’s Hospital.)




by escaping the mechanisms that control prolif-eration and programmed differentiation (Fig. 4).32-36 These stem cells are identified by several immunocytochemical markers, such as CD133, a glycoprotein also known as prominin 1.26,32,35,37

Although stem cells account for only a minority of the cells within malignant gliomas, they ap-pear to be critical for generating these tumors.36,38

Recent studies suggest that glioma stem cells pro-duce VEGF and promote angiogenesis in the tu-mor microenvironment.39 In addition, tumor stem cells appear to require a vascular niche for opti-mal function.40 These observations raise the pos-sibility that antiangiogenic therapy may inhibit the functioning of glioma stem cells.

There is growing evidence that glioma stem cells may contribute to the resistance of malig-nant gliomas to standard treatments (Fig. 4). Radioresistance in stem cells generally results from the preferential activation of DNA-damage-response pathways,41 whereas chemoresistance re-sults partly from the overexpression of O6-meth-ylguanine−DNA methyltransferase (MGMT), the up-regulation of multidrug resistance genes, and the inhibition of apoptosis.42-44 Therapeutic strat-egies that effectively target stem cells and over-come their resistance to treatment will be neces-sary if malignant gliomas are to be completely eradicated (Fig. 4). A better understanding of the biologic differences between normal and cancer stem cells will be required to develop selective therapies that spare normal brain cells.

DI AGNOSIS

Clinical Presentation

Patients with malignant gliomas may present with a variety of symptoms, including headaches, sei-zures, focal neurologic deficits, confusion, mem-ory loss, and personality changes. Although the classic headaches that are suggestive of increased intracranial pressure are most severe in the morn-ing and may wake the patient from sleep, many patients experience headaches that are indistin-guishable from tension headaches. When severe, the headaches may be associated with nausea and vomiting.

Imaging

The diagnosis of malignant gliomas is usually suggested by magnetic resonance imaging (MRI) or computed tomography. These imaging studies

typically show a heterogeneously enhancing mass with surrounding edema. Glioblastomas frequent-ly have central areas of necrosis and more exten-sive peritumoral edema than that associated with anaplastic gliomas.45 Functional MRI may help define the relationship of speech and motor ar-eas to the tumor and aid in the planning of sur-gery. Diffusion-weighted imaging, diffusion ten-sor imaging, dynamic contrast-enhanced MRI to measure vessel permeability, and perfusion im-aging to measure relative cerebral blood volume are increasingly used as diagnostic aids and as a means of monitoring the response to therapy.46

Figure 3 (facing page). Major Signaling Pathways in Malignant Gliomas and the Corresponding Targeted Agents in Development for Glioblastoma.

RTK inhibitors that target epidermal growth factor (EGF) receptor include gefitinib, erlotinib, lapatinib, BIBW2992, and vandetanib; those that target platelet-derived growth factor (PDGF) receptor include ima-tinib, dasatinib, and tandutinib; those that target vas-cular endothelial growth factor (VEGF) receptor include cediranib, pazopanib, sorafenib, sunitinib, vata-lanib, vandetanib, and XL184. EGF receptor antibodies include cetuximab and panitumumab. Farnesyl trans-ferase inhibitors include lonafarnib and tipifarnib; HDAC inhibitors include depsipeptide, vorinostat, and LBH589; PI3K inhibitors include BEZ235 and XL765; mTOR inhibitors include sirolimus, temsirolimus, everolimus, and deforolimus; and VEGF receptor inhib-itors include bevacizumab, aflibercept (VEGF-trap), and CT-322. Growth factor ligands include EGF, PDGF, IGF, TGF, HGF/SF, VEGF, and FGF. Stem-cell pathways include SHH, wingless family, and Notch. Akt denotes murine thymoma viral oncogene homologue (also known as protein kinase B), CDK cyclin-dependent ki-nase, ERK extracellular signal-regulated kinase, FGF fi-broblast growth factor, FTI farnesyl transferase inhibi-tors, GDP guanine diphosphate, Grb 2 growth factor receptor-bound protein 2, GTP guanine triphosphate, HDAC histone deacetylase, HGF/SF hepatocyte growth factor/scatter factor, IGF insulin-like growth factor, MEK mitogen-activated protein kinase kinase, mTOR mammalian target of rapamycin, NF1 neurofibromin 1, PIP2 phosphatidylinositol (4,5) biphosphate, PIP3 phosphatidylinositol 3,4,5-triphosphate, PI3K phos-phatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, PTEN phosphatase and tensin ho-mologue, RAF v-raf 1 murine leukemia viral oncogene homologue 1, RAS rat sarcoma viral oncogene homo-logue, RTK receptor tyrosine kinase inhibitor, SHH sonic hedgehog, SOS son of sevenless, Src sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue, TGF transforming growth factor family, and TSC1 and 2 tu-berous sclerosis gene 1 and 2. Red text denotes inhibi-tors. Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21


Medical Progress


Proton magnetic resonance spectroscopy detects the levels of metabolites and may help differenti-ate a tumor from necrosis or benign lesions. In patients with malignant gliomas, this imaging technique typically shows an increase in the cho-

line peak (reflecting increased membrane turn-over) and a decrease in the N-acetyl aspartate peak (reflecting decreased neuronal cellularity), as com-pared with the findings in unaffected areas of the brain.45,46 Positron-emission tomography that uses




isotopes such as 18F-fluorodeoxyglucose, 18F-flu-oro-l-thymidine, 11C-methionine, and 3,4-dihy-droxy-6-18F-fluoro-l-phenylalanine is being eval-uated for its usefulness in diagnosis and in monitoring the response to therapy.47

In up to 40% of cases, the MRI studies that

are performed in the first month after radiothera-py show increased enhancement.48 In 50% of these cases, the increased enhancement reflects a tran-sient increase in vessel permeability as a result of radiotherapy, a phenomenon termed “pseudopro-gression,” which improves with time.48 Differen-

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).


Medical Progress


tiating this transient effect from true progres-sion of the cancer can be challenging initially, even with advanced imaging techniques.

TR E ATMEN T

General Medical Management

Much of the care of patients with malignant gliomas involves general medical management. The most common problems include seizures, per-itumoral edema, venous thromboembolism, fa-tigue, and cognitive dysfunction.49 Patients who present with seizures should be treated with an-tiepileptic drugs. Since antiepileptic drugs that induce hepatic cytochrome P-450 enzymes, such as phenytoin and carbamazepine, increase the me-tabolism of many chemotherapeutic agents, anti-epileptic drugs that do not induce these enzymes, such as levetiracetam, are generally preferred. The use of prophylactic antiepileptic drugs in patients with malignant gliomas who have never had a seizure is controversial. The American Academy of Neurology issued a practice guideline indicating that there is no evidence that prophylactic anti-epileptic drugs are beneficial and advises against the routine use of antiepileptic drugs in patients with brain tumors who have not had seizures.50

Corticosteroids such as dexamethasone are fre-quently used to treat peritumoral edema. Cush-ing’s syndrome and corticosteroid myopathy may develop in patients who require prolonged treat-ment with high doses of corticosteroids. Patients with brain tumors who receive corticosteroids are at increased risk for Pneumocystis jiroveci pneumoni-tis, and prophylactic antibiotic therapy should be considered,49 although a recent meta-analysis did not show a benefit from this approach.51 As the rate of survival among patients with malignant glioma improves, long-term complications from treatment with corticosteroids, including osteo-porosis and compression fractures, are becoming increasingly evident, and preventive measures, such as treatment with vitamin D, calcium sup-plements, and bisphosphonates, should be con-sidered. Novel therapies such as corticotropin-releasing factor, bevacizumab (a humanized VEGF monoclonal antibody), and VEGFR inhibitors de-crease peritumoral edema and may reduce the need for corticosteroids.49,52

Patients with malignant gliomas are at in-creased risk for venous thromboembolism from leg and pelvic veins, with a cumulative incidence

of 20 to 30%.49,53 The risk of intratumoral hem-orrhage associated with anticoagulation therapy in patients with gliomas who have venous throm-boembolism is low,49,54 whereas inferior vena cava filters are associated with high complication rates.55 Unless a patient with malignant glioma and venous thromboembolism has an intracere-bral hemorrhage or other contraindications, it is generally safe to provide anticoagulation therapy for the venous thromboembolism. Low-molecular-weight heparin may be more effective and safer than warfarin.56

Patients with malignant gliomas frequently ex-perience fatigue and may benefit from treatment with modafinil or methylphenidate.57 Methyl-phenidate may also help abulia, and donepezil58

and memantine may reduce memory loss, although evidence supporting these approaches remains limited. Depression is underdiagnosed in patients with malignant gliomas, and antidepressants and psychiatric support are often invaluable.59

Specific Therapy for Newly Diagnosed Malignant Gliomas

The standard therapy for newly diagnosed malig-nant gliomas involves surgical resection when fea-sible, radiotherapy, and chemotherapy (Table 1). Malignant gliomas cannot be completely eliminat-ed surgically because of their infiltrative nature, but patients should undergo maximal surgical resection whenever possible. Surgical debulking reduces the symptoms from mass effect and pro-vides tissue for histologic diagnosis and molecu-lar studies. Advances such as MRI-guided neuro-navigation, intraoperative MRI, functional MRI, intraoperative mapping,60 and fluorescence-guid-ed surgery61 have improved the safety of surgery and increased the extent of resection that can be achieved. The value of surgery in prolonging sur-vival is controversial, but patients who undergo extensive resection probably have a modest sur-vival advantage.60-62 Stereotactic biopsies should be performed only in patients who have inoper-able tumors that are located in critical areas.

Radiotherapy is the mainstay of treatment for malignant gliomas. The addition of radiotherapy to surgery increases survival among patients with glioblastomas from a range of 3 to 4 months to a range of 7 to 12 months.63,64 Conventional ra-diotherapy consists of 60 Gy of partial-field exter-nal-beam irradiation delivered 5 days per week in fractions of 1.8 to 2.0 Gy. After standard radio-




therapy, 90% of the tumors recur at the original site.65 Strategies to increase the radiation dose to the tumor with the use of brachytherapy 66 and stereotactic radiosurgery 67,68 have failed to im-prove survival. Newer chemotherapeutic agents,69

targeted molecular agents,20 and antiangiogenic agents70 may enhance the effectiveness of radio-therapy.

Patients who are older than 70 years of age have a worse prognosis than younger patients and rep-resent a particular challenge. Among these pa-tients, radiotherapy produces a modest benefit in median survival (29.1 weeks) as compared with supportive care (16.9 weeks).71 Since older pa-tients often tolerate radiotherapy less well than younger patients, an abbreviated course of radio-therapy (40 Gy in 15 fractions over a period of 3 weeks)72 or chemotherapy with temozolomide (an oral alkylating agent with good penetration of the blood–brain barrier) alone73 may be con-sidered, since the outcomes with these approach-es are similar to the outcomes with conventional radiotherapy regimens.

Chemotherapy is assuming an increasingly im-portant role in the treatment of malignant gliomas. Although early studies of adjuvant chemotherapy for malignant gliomas with the use of nitroso-ureas failed to show a benefit,63,74 two meta-analyses have suggested that adjuvant chemother-

apy results in a modest increase in survival (a 6 to 10% increase in the 1-year survival rate).75,76

The European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) conducted a phase III trial comparing radiotherapy alone (60 Gy over a period of 6 weeks) with radiotherapy and concomitant treatment with temozolomide (75 mg per square meter of body-surface area per day for 6 weeks), followed by adjuvant temozolomide therapy (150 to 200 mg per square meter per day for 5 days every 28 days for 6 cycles), in patients with newly diagnosed glioblastomas.64 As reported by Stupp et al., the combination of radiotherapy and temozolomide had an acceptable side-effect profile and, as compared with radiotherapy alone, increased the median survival (14.6 months vs. 12.1 months, P<0.001).64 In addition, the survival rate at 2 years among the patients who received radiotherapy and temozolomide was significantly greater than the rate among the patients who received radiotherapy alone (26.5% vs. 10.4%),64

establishing radiotherapy with concomitant and adjuvant temozolomide as a useful combination for newly diagnosed glioblastomas.

MGMT is an important repair enzyme that con-tributes to resistance to temozolomide. In a com-panion study to the EORTC–NCIC study reported by Stupp et al., tumor specimens from the pa-

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 grade III)

Maximal surgical resection, with the following options after surgery (no ac-cepted standard treatment): radiotherapy, plus concomitant and adjuvant TMZ or adjuvant TMZ alone†

Anaplastic oligodendrogliomas and anaplastic oligoastrocy-tomas (WHO grade III)

Maximal surgical resection, with the following options after surgery (no ac-cepted standard treatment): radiotherapy alone, TMZ or PCV with or with-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.


Medical Progress


tients were examined for epigenetic silencing of the MGMT gene.15 MGMT promoter methylation silences the gene, thus decreasing DNA repair ac-tivity and increasing the susceptibility of the tu-mor cells to temozolomide. Patients with glioblas-toma and MGMT promoter methylation (45% of the total) who were treated with temozolomide had a median survival of 21.7 months and a 2-year survival rate of 46%. In contrast, patients without MGMT promoter methylation who were treated with temozolomide had a significantly shorter median survival of only 12.7 months and a 2-year survival rate of 13.8%.15 Currently, temozolomide is used in the treatment of glioblastomas regard-less of MGMT promoter methylation status. How-ever, if the importance of MGMT promoter methy-lation is confirmed by the results of an ongoing study by the Radiation Therapy Oncology Group (RTOG 0525), patients with unfavorable MGMT methylation status may be selected for other treatments in future investigations. Studies of dose-intensive temozolomide regimens to deplete MGMT and of combinations of temozolomide with inhibitors of MGMT, such as O6-benzylgua-nine, and inhibitors of other repair enzymes, such as poly-(ADP-ribose)-polymerase, are in progress.

Another chemotherapeutic approach involves the implantation of biodegradable polymers con-taining carmustine (Gliadel Wafers, MGI Pharma) into the tumor bed after resection of the tumor. The aim of treatment with these polymers, which release carmustine gradually over the course of several weeks, is to kill residual tumor cells. In a randomized, placebo-controlled trial that inves-tigated the use of these polymers in patients with newly diagnosed malignant gliomas, median sur-vival increased from 11.6 months to 13.9 months (P = 0.03).77 This survival advantage was main-tained at 2 and 3 years.78

Therapy for Anaplastic Gliomas

Anaplastic astrocytomas are treated with radio-therapy and either concurrent and adjuvant temo-zolomide (as for glioblastomas) or adjuvant temo-zolomide alone. Currently, there are no findings from controlled trials that support the use of con-current temozolomide in patients with anaplastic astrocytomas.

Anaplastic oligodendrogliomas and anaplas-tic oligoastrocytomas are an important subgroup of malignant gliomas that are generally more re-sponsive to therapy than are pure astrocytic tu-mors.79 A codeletion of chromosomes 1p and

19q,79 mediated by an unbalanced translocation of 19p to 1q,80 occurs in 61 to 89% of patients with anaplastic oligodendrogliomas and 14 to 20% of patients with anaplastic oligoastrocytomas. Tu-mors in patients with the 1p and 19q codeletion are particularly sensitive to chemotherapy with PCV — procarbazine, lomustine (CCNU), and vin-cristine — with response rates of up to 100%, as compared with response rates of 23 to 31% among patients without the deletion of chromosomes 1p and 19q.81,82 The reason for the increased chemo-sensitivity of tumors in patients with the 1p and 19q codeletion is unclear. One study suggested that 1p loss is associated with decreased levels of stathmin and an increased sensitivity to nitroso-ureas.83 The status of chromosomes 1p and 19q, rather than standard histologic assessment, is now used as an eligibility criterion in studies involv-ing patients with anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, reflecting a par-adigm shift in the design of clinical trials for pa-tients with these tumors.

Two large phase III studies of PCV chemother-apy with radiotherapy, as compared with radio-therapy alone, in patients with newly diagnosed anaplastic oligodendrogliomas or anaplastic oli-goastrocytomas, have been reported.84,85 In both studies, the addition of chemotherapy to radio-therapy increased the time to tumor progression by 10 to 12 months but did not improve overall survival (median, 3.4 and 4.9 years).84,85 The fail-ure of chemotherapy to increase survival may be partly explained by the fact that patients who ini-tially received radiotherapy alone subsequently re-ceived chemotherapy when they had a relapse, so that most patients in both groups eventually re-ceived chemotherapy. In both studies, patients with the codeletion of 1p and 19q had improved survival as compared with those without the code-letion of 1p and 19q. Although most studies involving patients with anaplastic oligodendro-gliomas or anaplastic oligoastrocytomas were con-ducted with PCV chemotherapy, temozolomide is likely to have similar activity and less toxicity79; however, studies directly comparing the two regi-mens have not been performed.

Therapy for Recurrent Malignant Gliomas

Despite optimal treatment, nearly all malignant gliomas eventually recur. For glioblastomas, the median time to progression after treatment with radiotherapy and temozolomide is 6.9 months.64 If the tumor is symptomatic from mass effect, re-




operation may be indicated (Table 1). However, sur-gery performed in selected patients results in only limited prolongation of survival.86

The usefulness of radiotherapy for recurrent malignant gliomas is controversial.87 Although some reports have suggested that fractionated ste-reotactic reirradiation88 and stereotactic radiosur-gery68 may be beneficial, selection bias may have influenced these results.

The value of conventional chemotherapy for re-current malignant gliomas is modest. In general, chemotherapy is more effective for anaplastic gliomas than for glioblastomas.79,87 Temozolo-mide was evaluated in a phase II study involving patients with recurrent anaplastic gliomas who had previously been treated with nitrosoureas; the study showed a 35% response rate. The 6-month rate of progression-free survival was 46%,89 com-paring favorably with the 31% rate of progression-free survival at 6 months for therapies that were reported to be ineffective.90 In contrast, temozolo-mide has only limited activity in patients with recurrent glioblastomas (response rate, 5.4%; 6-month rate of progression-free survival, 21%).91

Other chemotherapeutic agents that are used for recurrent gliomas include nitrosoureas, carbo-platin, procarbazine, irinotecan, and etoposide. Carmustine wafers have modest activity, increas-ing the median survival by approximately 8 weeks in patients with recurrent glioblastomas.92

IN V ES TIG ATIONA L THER A PIES

Targeted Molecular Therapies

The improved understanding of the molecular pathogenesis of malignant gliomas has allowed a more rational use of targeted molecular thera-pies (Fig. 3).18,20,21 Particular interest has focused on inhibitors that target receptor tyrosine kinases such as EGFR,93 PDGFR,94 and VEGFR,52 as well as on signal-transduction inhibitors targeting mTOR,95,96 farnesyltransferase,97 and PI3K (Ta-ble 2). Single agents have only modest activity, with response rates of 0 to 15% and no prolonga-tion of 6-month progression-free survival.3,20,21 These disappointing results are due to several fac-tors. Most malignant gliomas have coactivation of multiple tyrosine kinases,98 as well as redundant signaling pathways, thus limiting the activity of single agents. In addition, many of these agents

have poor penetration across the blood−tumor bar-rier. There has been considerable interest in iden-tifying molecular features of the tumor that pre-dict a response, so that patients who are most likely to benefit can be selected for a particular treatment. EGFR inhibitors appear to be more ef-fective in patients who have tumors with EGFRvIII mutations and intact PTEN than in patients who do not have these molecular changes99; patients who have tumors with increased activity of the PI3K–Akt pathway, as indicated by an increase in phosphorylated Akt, generally do not have a re-sponse.100 Current experimental strategies to in-crease the effectiveness of targeted molecular ther-apies include the use of a single agent targeted against several kinases, combinations of agents that inhibit complementary targets such as EGFR and mTOR (Table 2 and Fig. 5A through 5D), and targeted agents combined with radiotherapy and chemotherapy.3,18,20,21

Antiangiogenic Agents

Malignant gliomas are among the most vascular of human tumors,18 making them especially at-tractive targets for angiogenesis inhibitors.29 Al-though older antiangiogenic agents such as tha-lidomide had only modest activity,101 newer and more potent angiogenesis inhibitors show prom-ising activity. In preliminary studies, treatment with the combination of bevacizumab and irino-tecan was associated with a low incidence of hem-orrhage and response rates of 57 to 63% among patients with malignant gliomas (Fig. 5E through 5H).102,103 Some of the improvement that is seen on radiographic images may be artifactual, caused by reduced vascular permeability and decreased contrast enhancement as a result of the inhibi-tion of VEGF. However, this regimen also has antitumor activity, as evidenced by the fact that it increased the 6-month rate of progression-free survival to 46% among patients with recurrent glioblastomas,102,103 as compared with a 6-month rate of progression-free survival of 21% for pa-tients who were receiving treatment with temozo-lomide.91 Recently, a large, randomized phase II trial of bevacizumab alone and bevacizumab with irinotecan was completed. Preliminary results con-firmed the safety of bevacizumab and showed an increase in the 6-month rate of progression-free survival to 35.1% for patients receiving bevacizu-


Medical Progress


Table 2. Selected Investigational Treatments for Malignant Gliomas.*

Type of Treatment Example

Convection-enhanced surgical delivery of pharmacologic agent

Cintredekin besudotox

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.




mab alone and 50.2% for patients receiving the combination of bevacizumab and irinotecan.104

A phase II trial of the pan-VEGFR inhibitor ce-dira nib in patients with recurrent glioblastomas showed response rates in excess of 50% and pro-longation of the 6-month rate of progression-free survival to approximately 26%.52 These agents also decrease peritumoral edema, potentially allowing for a reduction in corticosteroid requirements. Since antiangiogenic agents may have synergistic activity with radiotherapy, there is increasing in-terest in combining them with radiotherapy and temozolomide in patients with newly diagnosed glioblastomas.29,70 As noted previously, glioma stem cells produce VEGF39 and require a vascular niche for optimal function.40 Antiangiogenic agents may therefore also target glioma stem cells.

Other Therapies

Other investigational therapies for malignant gliomas include chemotherapeutic agents that

cross the blood−tumor barrier more effectively, gene therapy,105 peptide and dendritic-cell vac-cines,106 radiolabeled monoclonal antibodies against the extracellular matrix protein tena-scin,107 synthetic chlorotoxins (131I-TM-601),108

and infusion of radiolabeled drugs and target-ed toxins into the tumor and surrounding brain by means of convection-enhanced delivery (Ta-ble 2).109

PRO GNOS TIC FAC T OR S

The most important adverse prognostic factors in patients with malignant gliomas are advanced age, histologic features of glioblastoma, poor Kar-nofsky performance status, and unresectable tu-mor.110 There are ongoing efforts to identify bio-logic and genetic alterations in the tumors that may provide additional prognostic information, as well as guidance in making decisions about opti-mal therapy.15,16,82

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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-malian target of rapamycin [mTOR]). T1-weighted images obtained after the administration of gadolinium show a re-duction in the size of the enhancing tumor from the pretreatment image (Panel A) to the image obtained 2 months after treatment (Panel B), with fluid-attenuated inversion recovery (FLAIR) studies showing a reduction of edema from the pretreatment image (Panel C) to the post-treatment image (Panel D). Panels E through H show MRI scans of a recurrent glioblastoma in a patient who was treated with a combination of bevacizumab and irinotecan. T1-weighted images obtained after the administration of gadolinium show a reduction in the size of the enhancing tu-mor from the image obtained before treatment (Panel E) to the image obtained 7 months after treatment (Panel F) and an associated reduction of edema from the pretreatment FLAIR image (Panel G) to the post-treatment FLAIR image (Panel H).


Medical Progress


SUMM A R Y

Recently, there has been important progress in the treatment of malignant gliomas111 and in our understanding of the molecular pathogenesis of these tumors and the critical role that stem cells play in their development and resistance to treat-ment. As our understanding of the molecular cor-relates of response improves, it may be possible to select the most appropriate therapies on the basis of the patient’s tumor genotype. These ad-vances provide real opportunities for the develop-ment of effective therapies for malignant gliomas.

Supported by grants from the National Institutes of Health (U01 CA062407, to Dr. Wen; and KO8 CA1240804, to Dr. Kesari), a Sontag Foundation Distinguished Scientist Grant (to Dr. Kesari), and research support from the Elizabeth Atkins and Will Kraft Brain Tumor Research Funds (to Dr. Wen) and the John Kenney Brain Tumor Research Fund (to Dr. Kesari).

Dr. Wen reports receiving speaking fees from Schering-Plough, serving as a consultant for AngioChem, and receiving research funding from Exelixis, Schering-Plough, Genentech, GlaxoSmithKline, Amgen, AstraZeneca, and Celgene. Dr. Kesari reports receiving consulting fees from Bristol–Myers Squibb, speaking fees from Enzon, and research funding from Adnexus. No other potential conflict of interest relevant to this article was reported.

We thank Drs. Andrew Norden and Elizabeth Claus for help-ful comments.

This article is dedicated to the memories of Elizabeth Atkins, Will Kraft, and John Kenney.

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ONCOLOGY Board Review Manual

Primary Brain Tumors

Volume 10, Part 2 August 2013

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2Case Presentation . . . . . . . . . . . . . . . . . . . . . . . . .2Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17Board Review Questions . . . . . . . . . . . . . . . . . . .17References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Table of Contents


Primary Brain Tumors

Series Editor:Arthur T. Skarin, MD, FACP, FCCPDistinguished Physician, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Contributors:Jai Grewal, MDLong Island Brain Tumor Center at NSPC, Great Neck, NY

Harpreet Kaur Grewal, MD University of Texas Health Sciences Center at Houston, Houston, TX

Santosh Kesari, MD, PhDDirector, Neuro-Oncology Program, Translational Neuro-Oncology Laboratories, Neurotoxicity Treatment Center, Moores Cancer Center, University of California San Diego Health System, La Jolla, CA

STATEMENT OF EDITORIAL PURPOSE

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 to the current practice of oncology.

PUBLISHING STAFF

PRESIDENT, GROUP PUBLISHERBruce M. White

SENIOR EDITORRobert Litchkofski

EXECUTIVE VICE PRESIDENTBarbara T. White

EXECUTIVE DIRECTOR OF OPERATIONS

Jean M. Gaul

NOTE FROM THE PUBLISHER:This publication has been developed with-out involvement of or review by the Amer-ican Board of Internal Medicine.

P r i m a r y B r a i n T u m o r s



Primary Brain TumorsJai Grewal, MD, Harpreet Kaur Grewal, MD, and Santosh Kesari, MD, PhD

INTRODUCTION

Primary central nervous system tumors are rela-tively rare, but they can cause significant morbidity. They are also among the most lethal of all neo-plasms. Brain tumors are the second most com-mon cause of death due to intracranial disease, second only to stroke. The estimated annual inci-dence of primary brain tumors is approximately 21 per 100,000 individuals in the United States.1 The incidence of brain tumors varies by gender, age, race, ethnicity, and geography and has increased over time.2 Gliomas and germ cell tumors are more common in men, whereas meningiomas are twice as common in women. The only validated environ-mental risk factor for primary brain tumors is expo-sure to ionizing radiation. Other etiologies include inherited cancer syndromes and primary central nervous system lymphoma associated with AIDS.3

Approximately 5% to 10% of gliomas are associ-ated with a family history.4 Inherited cancer syn-dromes involving brain tumors are listed in Table 1.

Primary brain tumors are classified according to the World Health Organization 2007 classification,5

as shown in Table 2. The TNM staging system is not used for primary brain tumors. Primary brain

tumors are rarely metastatic outside the central nervous system, with some exceptions (embryo-nal tumors, malignant meningiomas). Tumors are graded from I to IV based on histological grading and prognosis, with grade IV being the most ag-gressive. Notable features of selected nervous system tumors are shown in Table 3. Gliomas account for 78% of all primary malignant central nervous system tumors,1 and glioblastoma (WHO grade IV) is the most common malignant primary brain tumor in adults. Despite advances in the field of oncology, the prognosis of these aggressive tu-mors remains poor.

This review focuses on the evaluation and man-agement of primary brain tumors, in particular glio-blastoma (the most common malignant brain tumor in adults), and highlights new advances in treatment options. Management of common complications as-sociated with brain tumors will also be discussed.

CASE PRESENTATION

A 40-year-old right-handed nonsmoking man presents to the emergency depart-

ment (ED) with the sudden onset of right-sided weakness. His family reports that he has had

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.



progressive difficulty speaking over the last 3 to 4 weeks. He has had particular trouble with finding the right word. One hour prior to presentation to the ED, he had been preparing lunch when he noticed that his right arm was shaking. After about 30 sec-

onds, the shaking stopped but he could not hold anything in his right hand. Examination reveals an alert man with expressive aphasia, who is other-wise cognitively intact and follows commands. He is noted to make frequent paraphasic errors. Nam-

Table 1. Genetic Syndromes Associated with Nervous System Tumors

SyndromeNervous System

Skin

Other

Locus

Gene

Protein Function

Neurofibromatosis type 1

Neurofibroma, MPNST, optic nerve glioma, astrocy-toma

Café-au-lait, axillary freck-ling

Iris hamarto-mas, osseous lesions, pheo-chromocytoma, leukemia

17q11 NF1 Neurofibromin Tumor suppressor gene, ras GTPase-activating protein regulates cell prolif-eration and differen-tiation

Neurofibromatosis type 2

Bilateral vestibular schwannomas, peripheral schwan-nomas, meningio-mas, meningioan-giomatosis, spinal ependymoma, as-trocytoma, glial hamartins, cerebral calcifications

None Posterior lens opacities, reti-nal hamartoma

22q12 NF2 Merlin or schwannomin

Tumor suppressor gene, binds to actin, regulating mem-brane cytoskeleton

Tuberous sclerosis Subependymal giant cell astro-cytoma, cortical glioneuronal ham-artomas (tubers), ependymal hamar-tomas (candle gut-terings)

Angiofibroma (adenoma sebaceum), subungual fi-bromas

Cardiac rhab-domyoma, renal an-giomyolipoma, pulmonary lymphangioma-tosis

9q34 (TSC1), 16p13 (TSC2) 60% spo-radic

TSC1, TSC2

Hamartin (TSC 1), tuberin (TSC2)

Tumor suppressor genes, tuberin-harmartin complex suppresses activa-tion of the mTOR pathway (which in-creases proliferation and cell growth)

von Hippel-Lindau Cerebrellar and spinal cord heman-gioblastoma

None Renal cell carcinoma, pheochromo-cytoma, renal angiomatosis, cysts of kidney and pancreas, cyst adenoma of epididymis

3p25 VHL pVHL Tumor suppressor gene, role in protein degradation and an-giogenesis

Li-Fraumeni Diffuse astrocy-toma, medulloblas-toma, supratentorial PNET

None Bone and soft tissue sar-coma, breast cancer

17p13 TP53 p53 Tumor suppressor gene, promotes apoptosis in cells with DNA damage(continued on page 4)



ing and repetition are impaired. Motor examination reveals significant weakness in his right hand. Deep tendon reflexes are more brisk on the entire right side. The right plantar response is upgoing. Coordination testing on the right side is hampered by weakness, but is intact on the left side. The re-mainder of the examination is unremarkable.

• What are the common presenting features ofa brain tumor?

CLINICAL FEATURES OF BRAIN TUMORS

Symptoms from a brain tumor can be focal or generalized. The most common presenting symptoms in patients with brain tumor include headaches, seizures, cognitive impairment, per-sonality changes, and focal neurological defi-cits. Focal signs and symptoms reflect the lo-cation of the tumor within the central nervous system.

Headache is a presenting symptom in approxi-mately 48% of newly diagnosed brain tumors.6 It is often dull, non-throbbing, and intermittent. Su-pratentorial masses can result in frontal headache. Posterior fossa masses cause headache in oc-cipital and cervical areas. Early morning headache is considered a classic presentation because of increased intracranial pressure (ICP) in the recum-bent position. However, this classic presentation occurs in a minority of patients.6

Seizures are the presenting feature of brain tumors in approximately one-third of cases. They occur due to irritation of the brain parenchyma. There is evidence that blood–brain-barrier failure may be an etiological factor contributing to the de-velopment of seizures.7

Low-grade tumors, particularly oligodendroglio-mas, have a relatively greater tendency to present with seizures (over 70% in some series).8,9 Even if seizures do not occur at presentation, they may

Table 1. Genetic Syndromes Associated with Nervous System Tumors (continued)

SyndromeNervous System

Skin

Other

Locus

Gene

Protein

Function

Cowden Dysplastic ganglio-cytoma of the cer-ebellum (Lhermitte-Duclos)

Multiple trichi-lemmoma, fi-broma

Oral mucosa fi-broma, hamar-tomatous colon polyps, thyroid tumors, breast cancer

10q23 PTEN PTEN Tumor suppressor gene, expression causes cell cycle ar-rest and apoptosis, regulates PI3K/Akt pathway

Turcot Medulloblastoma, glioblastoma

Café-au-lait Colorectal polyps or carci-noma

5q21, 3p21, 7p22w

APC, hMLH1, hPMS2

APC, hMLH1, hPMS2

APC-tumor suppres-sor gene regulating β-catenin, hMLH1, hPMS2-mismatch repair proteins

Gorlin Medulloblastoma (desmoplastic)

Nevoid basal cell carcino-mas, palmar and plantar pits

Jaw kerato-cysts, ovarian fibroma

9q22 PTCH1 Ptc1 Tumor suppressor, suppresses smooth-ened-mediated cell 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.



occur later in 40% to 60% of patients with brain tumors. Seizures tend to be partial with possible secondary generalization; seizure semiology will correlate with the tumor location within the brain. Seizure frequency varies among patients. In pa-tients who have experienced an extensive surgical

resection, there may be a marked improvement in seizure frequency (or even complete seizure resolution) if the active seizure focus has been removed. Conversely, worsening of seizure type or seizure frequency (or even status epilepticus) may herald radiologic tumor progression.10

Table 2. Abbreviated 2007 World Health Organization Classification of Brain TumorsTumorsofneuroepithelialtissue 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 TumorsofcranialandparaspinalnervesOligodendroglioma Schwannoma

Anaplastic oligodendroglioma Neurofibroma

Oligoastrocytic (mixed) tumors Malignant peripheral nerve sheath tumor

Oligoastrocytoma TumorsofthemeningesAnaplastic oligoastrocytoma Meningioma (15 variants)

Ependymal tumors Hemangioblastoma

Subependymoma Hemangiopericytoma

Myxopapillary ependymoma PrimaryCNSlymphomaEpendymoma Germ cell tumorsAnaplastic 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 TumorsofthesellarregionGangliocytoma Craniopharyngioma

Ganglioglioma Granular cell tumor of the neurohypophysis

Anaplastic ganglioglioma Metastatic tumorsCentral 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.



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” appearance1p and 19q chromosomal dele-tions

Diffuse low-grade astrocytoma May present with seizures or subtle symptoms

Nonenhancing diffuse area of T2 signalGyral expansion

Low mitotic activity Positive for p53, associated with IDH1/2 mutations

Ependymoma Peak age 15 yr May present as obstructive hydrocephalus

Majority are in fourth ventricle or spinal cord EnhancingMay spread via CSF pathways

Perivascular pseudorosettes

Meningioma Most common primary CNS tumor (40%) More common in womenPregnancy may promote growth

Diffuse contrast enhancementDural tail signLocations: convexity, parasagittal,sphenoid wing, spinal, cavernous sinus

EMA-positiveDesmosomesProgesterone receptorsMany variants

Primary CNS lymphoma May shrink or disappear (tran-siently) with corticosteroidsMay be associated with HIV

Diffuse contrast enhancementPeriventricular lesions Restricted diffusion on DWI

Most B-cellPerivascular cuffingCD20+ (B-cell type)

Glioblastoma Most common adult malignant pri-mary tumor Peak age 55, median survival 14.6 mo Chemotherapy shown to prolong survival in RCT

Ring-enhancing, irregular, necrot-ic-appearing mass(es)

Vascular proliferationNecrosisPseudopalisadating arrangement of tumor cells

Medulloblastoma Peaks in first and third decades of life May present with obstructive hy-drocephalus or cerebellar signs

Posterior fossa enhancing massMay seed via CSF pathways (“drop metastases”)

Small, round blue cells (on H&E stain)Homer-Wright rosettes (character-istic of all PNETs)

Ependymoblastoma First 5 years of lifePrognosis poor

Supratentorial enhancing mass with possible CSF seeding

True rosettes

Gangliocytoma/ganglioglioma First 2 decades of lifeIntractable complex-partial sei-zures

Temporal lobe mass Gangliocytoma: only neoplastic neuronal cellsGanglioglioma: mixed neoplastic neuronal and glial cells; eosino-philic granular bodies

Dysembryoplastic neuroepithelial Tumor

Second and third decades of lifeRarely regrows after surgical re-section

Medial temporal lobe Neuronal and glial elements

Choroid plexus papilloma In adults tumor of choroid plexus more likely to be metastatic

Children: lateral ventricleAdults: fourth ventricle

(continued on page 7)



Altered mental status is a presenting feature in 15% to 20% of cases.11 Tumors associated with elevated ICP, gliomatosis cerebri, and those located in the frontal lobes are more likely to be associ-ated with altered mental status at presentation. The severity can range from mild inattention to deep coma.

Focal neurological deficits such as aphasia, hemiparesis, sensory loss, and visual field loss may also occur at presentation and correlate with tumor location. Aphasia is associated with involvement of the dominant hemisphere (usu-ally the left), while sensorimotor and visual defi-cits can occur if the tumor affects the corre-sponding pathways within the central nervous system.

The time course of symptoms often correlates with the growth rate of the neoplasm. Symptoms may gradually progress over time. In the case pre-sented, the patient comes to medical attention after an acute event. Careful history taking revealed that neurological symptoms had been apparent for sev-eral weeks before this. Patients with slow-growing tumors may have less pronounced symptoms than patients with fast growing masses of similar size and location.

CASE CONTINUED

Computed tomography (CT) of the brain shows a left frontal hypodensity with sur-

rounding mass effect. This is followed by magnetic resonance imaging (MRI) of the brain, which re-veals a heterogeneous mass in the left frontal lobe. The lesion is hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging with extensive surrounding edema. There is associated mass effect. Post-gadolinium T1-weighted imaging reveals an irregularly shaped ring-enhancing mass with necrosis (see Figure 1 for imaging findings from a similar case). Due to the patient’s recent seizure and evidence of mass effect, intravenous levetiracetam and dexamethasone are initiated.

• What is the work-up of a patient with a pos-sible brain tumor?

NARROWING THE DIFFERENTIAL DIAGNOSIS

A patient suspected of possibly having a brain tumor should undergo a thorough general and neurological evaluation. Often, a noncontrast head CT is the initial imaging study. It is favored due to its wide availability and short imaging time. It is helpful in the rapid diagnosis of intracranial

Table 3. Notable Features of Selected Central and Peripheral Nervous System Tumors (continued)

Tumor Clinical Radiologic Pathologic

PeripheralNervousSystem

Neuroblastoma First decade of lifeMay present with “dancing eyes” (opsoclonus-myoclonus)

Sympathetic chain in chest or abdomen

Similar to medulloblastomasMay form “flourettes”

Neurofibromas Associated with NF1 Dorsal spinal nerve roots Hyperplasia of Schwann cells

Schwannomas Tinnitis, hearing lossBilateral schwannomas May be associated with NF2

Cerebropontine angle mass Antoni A and BVerocay bodies

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.



hemorrhage, in identifying mass effect, and for visualization of calcifications and bony destruc-tion. Patients with contraindication to MRI may benefit from a subsequent contrast-enhanced head CT evaluation.

An MRI of the brain with gadolinium contrast is usually the test of choice, and often follows a head CT scan. An MRI provides greater anatomic and pathologic detail than a CT scan. On MRI, tumors generally appear as a hypointense area on T1-weighted imaging with corresponding hyper-intensity on T2-weighted imaging (Figure 1). The

presence of enhancement on administration of gadolinium indicates the breakdown of the blood-brain barrier and suggests a high-grade neoplasm. Low- and high-grade gliomas usually show poorly defined margins, heterogeneous areas of hemor-rhage and necrosis, and significant surrounding vasogenic edema. These findings are usually less prominent in low-grade lesions. Calcifications within the mass (better seen on CT) are generally suggestive of a more indolent (lower grade) neo-plasm, such as an oligodendroglioma and cranio-pharyngioma.

Figure1.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).



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 tumor markers, may be useful if brain metastasis or lymphoma is suspected. An abscess or demyelinat-ing lesion might be distinguished based on clinical and imaging features. For most primary central nervous system neoplasms, tissue diagnosis with biopsy or resection is necessary. Occasionally, such 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.

Newer imaging techniques provide additional in-formation about a suspicious mass. Magnetic reso-nance spectroscopy (MRS) may demonstrate an elevated ratio of choline to creatine in tumors due to increased cell membrane turnover (Figure 2). Neuronal loss due to infiltration of tumor results in decreased levels of N-acetylaspartate (NAA). Multi-voxel technique can evaluate different regions of the tumor to determine where high-grade features are more likely to be found on biopsy; this can be help-ful in surgical planning.13 Other MR techniques with potential utility include tractography (diffusion tensor

imaging), in which illustration of the white matter tracts associated with a tumor may be helpful in surgical planning. Also, MR perfusion is an evolving technique which may help differentiate between tumor recur-rence and treatment effects (eg, radiation necrosis).

• What is the initial management of a patientfound to have a mass lesion?

INITIAL MANAGEMENT

SeizuresThe patient’s symptoms of shaking of the right

arm followed by hand weakness are suggestive

Figure2.Magnetic resonance spectroscopy in a patient with glioblastoma from (A) the area of abnormal enhancement and (B) normal brain. Voxel placement is shown. The spectrum corre-sponding to the area of tumor (C) reveals an increased ratio of choline (thick hollow arrows) to creatine (thick solid arrows) and decreased N-acetylaspartate (thin arrows) when compared with the contralat-eral, unaffected brain (D). This is suggestive of increased cell mem-brane turnover and neuronal destruction, respectively.



of a seizure and Todd’s paralysis. An approach to management of the patient with seizures is outlined in Figure 3. Because the patient experienced a

seizure, initiation of an antiepileptic drug (AED) for secondary prophylaxis of seizures is warranted. Although AEDs may not completely prevent all

Figure3. 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.)

Seizure

Stabilize patient

New-onset seizure Known seizure disorder

Evaluate for new intracranial pathol-ogy and significant toxic-metabolic derangements; determine whether

seizure is provoked

Evaluate for exacerbating factors: AED noncompliance, worsening

intracranial pathology, 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 consciousness,

myoclonus

Investigations: neuroim-aging, laboratory studies,

EEG, CSF analysis

Stat EEG New structural brain lesion(s)

New toxic- metabolic insults

Electrographic seizuresFurther evaluation of lesion; consider

dexamethasone, AEDs, neurologic consultation

Correct toxic-metabolic derangements as best

as possible

Management of status epilepticus

Definitive therapy for intracranial pathology



seizures, data show that they can reduce seizure generalization.14 Traditionally, anticonvulsants such as phenytoin, phenobarbital, and valproic acid have been used as first-line agents, particularly in the acute setting. A major drawback of using these older AEDs is the relative frequency of in-teractions with chemotherapeutic agents that are used in the treatment of brain tumors.15,16 Enzyme-inducing AEDs such as phenytoin, phenobarbital, and carbamazepine may increase the clearance and reduce the clinical efficacy of corticosteroids and antineoplastic agents that are metabolized by the cytochrome P450 system.

Newer AEDs such as levetiracetam, lacosamide, and pregabalin have fewer adverse effects and do not have significant interactions with chemo-therapeutic agents. Therefore, they are preferred over older AEDs in the brain tumor (and systemic cancer) population. Intravenous formulations of levetiracetam and lacosamide are available. In the setting of refractory seizures or status epilepticus, acute treatment with classical AEDs should be strongly considered.

Primary prophylaxis of seizures is not recom-mended by the American Academy of Neurol-ogy guidelines for brain tumor patients who have never had a seizure.17 Clinical trials to determine the efficacy of prophylactic anticonvulsants in this situation have not yet demonstrated a benefit that outweighs the risks.18,19 Therefore, anticonvulsants should be reserved for brain tumor patients who have demonstrated a tendency to have seizures. It should be mentioned that many of these newer anticonvulsants are not FDA-approved for use as monotherapy or treatment of status epilepticus.

Cerebral EdemaCerebral edema in the setting of brain tumors

is vasogenic, and vasogenic edema increases the

ICP. Corticosteroids are the mainstay for manage-ment of cerebral edema. The most commonly used corticosteroid is dexamethasone. It has high potency, a long half-life, and minimal mineralocor-ticoid effect. A typical regimen consists of an initial dose of 10 mg intravenously followed by 4 mg every 6 hours; however, a lower dose may produce similar benefit.20 Once definitive therapy has been delivered and clinical improvement is seen, the dose is gradually tapered to avoid serious long-term side effects such as gastric ulcers, cataracts, osteoporosis, hyperglycemia, adrenal suppres-sion, muscle wasting, weight gain, and Cushing’s syndrome.

CASE CONTINUED

The patient undergoes a CT scan of the chest, abdomen, and pelvis, which does

not reveal a systemic malignancy. A neurosurgical consultation is obtained and the patient receives a subtotal resection. The pathology is consistent with glioblastoma, exhibiting a pseudopalisading pattern, microvascular proliferation, and necrosis (Figure 1). The patient is counseled regarding his diagnosis and treatment options. A plan is made to administer outpatient external-beam radiation therapy (EBRT) with concurrent chemotherapy. The radiation therapy consists of a total dose of 59.4 Gy delivered in 33 fractions of 1.8 Gy each. Oral concurrent temozolomide (TMZ) is adminis-tered daily at 75 mg/m2 for 42 consecutive doses (over 6 weeks).

• What treatment options are recommended fora patient with newly diagnosed glioblastoma?

TREATMENT OF GLIOBLASTOMA

Based on the results of a phase III randomized, controlled trial,21 the standard of care for a patient



with newly diagnosed glioblastoma involves maxi-mal safe surgical resection followed by the combi-nation of EBRT and concurrent chemotherapy with daily TMZ. The patient is then assessed clinically and by MRI approximately 3 to 4 weeks following the completion of this treatment. If the tumor does not progress, chemoradiation is followed by at least 6 cycles of adjuvant TMZ on days 1 through 5 of a 28-day cycle.

SurgeryThe extent of tumor removal by surgery depends

on tumor location (especially proximity to eloquent brain), general health of the patient, and the pres-ence of mass effect. While a biopsy poses minimal risk to the patient and is well tolerated, it allows for pathological evaluation of only a small portion of the tumor. The pathological grade may change nearly half the time if resection is performed after biopsy.22

Class I data do not exist regarding the issue of whether extensive surgical debulking provides a survival benefit. One small randomized study23

did find a small but statistically significant benefit of craniotomy and resection over biopsy alone. A number of larger retrospective studies do suggest

a survival benefit for initial,24–26 recurrent,27 and multiple28 resections for glioblastoma. At the time of initial resection, the data suggest a possible survival benefit for patients with an extent of resection of 78% or greater.26 In one study, the morbidity from gross total resection was not significantly increased over biopsy or subtotal resection, and the risk at the time of initial surgery did not differ from the risk at reoperation.29 Carmustine (BCNU)-impregnated wafers can be placed into a tumor resection cavity 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

A prospective, randomized, phase III clinical trial utilizing 5-aminolevulinic acid for intraoperative visualization of tumor under fluoroscopic light was completed.31 Improved progression-free survival was seen in the group in which this technique was utilized. Preoperative imaging (such as functional MRI), intraoperative MRI, and other techniques (such as awake surgery) may help safely increase the extent of resection.32,33 A list of primary brain tumors potentially curable by surgical resection is outlined in Table 4.

Radiation TherapyEBRT is the most important type of radiation

therapy used in treating infiltrating tumors such as glioblastoma.34 While whole brain radiation therapy (WBRT) has been used in the past, data show that a more focused approach spares some of the toxicity of WBRT without a loss of efficacy.35,36

A typical dose would be approximately 60 Gy to the tumor evident on imaging with a 2-cm margin. Clear survival advantages have been demonstrat-ed in several studies at 50 to 60 Gy, but above 60 Gy there is a marked increase in toxicity.37,38 It is unknown whether the benefit observed with TMZ

Table 4. Tumors Treated by Surgical Resection

Pilocytic astrocytomaPleomorphic xanthoastrocytomaSubependymal giant cell astrocytomaSubependymomaMyxopapillary ependymomaParaganglioma of the filum terminaleDysplastic gangliocytoma of the cerebellumDysembryoplastic neuroepithelial tumorGangliogliomaCentral neurocytomaMeningiomaHemangioblastoma



in glioblastoma is predominantly due to a radio-sensitization effect, from the use of an effective alkylating agent, or both.39

ChemotherapyTemozolomide is a member of the class of drugs

known as imidotetrazines. It was developed as a less toxic alternative to precursor compounds and exhibited excellent penetration into the central nervous system.40,41 In 1999, it was first approved in the United States for recurrent anaplastic as-trocytoma.42 Following the positive results of an international phase III trial for glioblastoma,21 con-current TMZ and radiation therapy has become the standard of care for patients with newly diagnosed glioblastoma. This multicenter, randomized, con-trolled trial compared the efficacy and safety of TMZ administered concurrently and following ra-diation therapy (RT) with RT alone in patients with newly diagnosed glioblastoma. TMZ combined with RT was more effective than RT alone, and the combined treatment was well tolerated. Median overall survival time (OS) was 14.6 months in the TMZ plus RT group as compared to 12.1 months in the RT alone group. Based on the results of this study, the FDA approved TMZ in 2005 for the treatment of adult patients with newly diagnosed glioblastoma. TMZ has 100% oral bioavailability and readily crosses the blood-brain barrier. It acts by methylating the O6 position of guanine in DNA. Mispairing of thymidine with the O6-methylguanine results in DNA strand breakage and cell death.

TMZ is given orally at a daily dose of 75 mg/m2

for 6 weeks along with radiation therapy. Patients completing chemoradiation without disease pro-gression may proceed to receive adjuvant TMZ at 150 to 200 mg/m2 on days 1 through 5 of a 28-day cycle. Although the trial limited adjuvant TMZ to 6 cycles,21 in clinical practice patients have been

treated longer if there is no disease progression. Patients may receive Pneumocystis carinii pro-phylaxis during the concurrent phase of treatment. Adverse effects include myelosuppression, nau-sea, vomiting, anorexia, constipation, and fatigue. Hepatitis B reactivation has also been reported with the use of TMZ.43,44

Bevacizumab is a novel humanized monoclonal antibody targeting vascular endothelial growth fac-tor (VEGF). This pathway is important for tumor angiogenesis. The use of bevacizumab for newly diagnosed disease is being evaluated in clinical trials and therefore is not considered standard of care at present.

• What are the most important molecular mark-ers in brain tumors?

MOLECULAR MARKERS IN BRAIN TUMORS

Identifying subsets of patients who may be more likely to respond to a particular therapy is an im-portant focus of brain tumor research. This is com-monly done in the case of many other malignan-cies, such as testing for estrogen, progesterone, and HER2/neu receptors in breast cancer.

Anaplastic oligodendrogliomas have been re-ported to have a favorable response to chemo-therapy (and radiation) if they are associated with 1p and 19q chromosomal co-deletions.45 Two pro-spective, randomized, controlled trials evaluated the potential benefit of adding PCV chemotherapy (procarbazine, lomustine, vincristine) to radiation therapy alone as initial therapy.46,47 The long-term analysis for both studies confirmed the importance of 1p and 19q co-deletions as favorable indepen-dent prognostic factors.48,49

Patients with glioblastoma associated with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation experienced greater ben-



efit from TMZ.50 The MGMT repair enzyme is one mechanism by which tumor cells repair DNA dam-age from alkylating agents such as TMZ. MGMT promoter methylation suggests decreased avail-ability of this enzyme and alkylating chemotherapy may be more likely to lead to cell death.

Overexpression, amplification, or mutations of the epidermal growth factor receptor (EGFR) are common in glioblastoma.51 Several EGFR inhibitors have been approved for other malignan-cies, but unfortunately clinical trials have failed to demonstrate a benefit in malignant glioma.52 One interesting mutation results in a constitutively ac-tive receptor, the EGFRvIII. The co-expression of EGFRvIII and phosphatase and tensin homolog (PTEN) seems to predict sensitivity of recurrent GBM to EGFR inhibitors.53 While found in other cancers, EFGRvIII is not found in normal human tissue. The unique protein structure is the target of a cancer vaccine in clinical trials for glioblastoma.54

Other novel experimental therapies include small-molecule targeted agents, oncolytic viruses,55,56

and dendritic-cell immunotherapies.57

Discovered in 2008, mutations of the isoci-trate dehydrogenase glycolytic enzyme (IDH1 and IDH2) are commonly found in low-grade and sec-ondary high-grade gliomas.58 These mutations appear to occur early in the development of glio-mas and change the function of IDH to produce 2-hydroxyglutarate, a potential oncometabolite. When compared with wild-type IDH, the presence of IDH1 and IDH2 mutations is associated with im-proved prognosis in glioma.

Significant work is being performed using mi-croarray technology and sophisticated analysis to identify gene expression patterns that may have prognostic signficance.59,60 One such analysis stratified tumors into 3 groups: proneural, mesen-chymal, and proliferative,59 with tumors exhibiting

the proneural signature correlated with improved prognosis. It was noted that at recurrence, tumors tended to exhibit more of the mesenchymal pat-tern, which was correlated with a poorer prognosis.

CASE CONTINUED

Four weeks after the patient completed concurrent chemoradiation, an MRI of

the brain was obtained. This revealed increased contrast enhancement and surrounding edema. The patient was clinically unchanged. Surgical re-operation was deemed risky. The patient was continued on adjuvant TMZ with a shorter inter-val of MRI tumor surveillance (4-week intervals). By the third scan following chemoradiation, there was marked reduction in the size of the contrast-enhancing lesion, measuring approximately 50% of the pre-radiation size. The early MRI changes were attributed to a transient post-treatment phe-nomenon known as pseudoprogression. MRI sur-veillance was changed to 8-week intervals (after every 2 cycles of TMZ).

• What is the significance of transient radio-logic worsening after concurrent radiationand chemotherapy?

PSEUDOPROGRESSION

It is becoming increasingly evident that patients may experience transient radiological “progres-sion” early after the completion of chemoradiation with TMZ. This phenomenon has been labeled pseudoprogression.61–63 Patients may remain clini-cally stable in many of these cases. Up to half of all radiologic progression following chemoradia-tion may in fact fall under this category. The most significant consideration in a patient with possible pseudoprogression is whether to continue adju-vant TMZ, as a proportion of such patients have



been reported to experience an eventual response to therapy. Early radiation necrosis was found when these patients underwent re-operation.61

Close imaging surveillance is warranted if a patient with suspected pseudoprogression is continued on adjuvant TMZ. Patients who do not exhibit an improvement on follow-up imaging may have true progression and should be switched to alter-nate therapy. Pseudoprogression appears to be more common in glioblastoma patients expressing MGMT promoter methylation.64

• What are the neurologic complications ofradiation therapy?

Toxicity from RT can be divided into 3 types based on the amount of time that has elapsed since the completion of RT.65 Acute toxicity mani-fests as encephalopathy within days to weeks of therapy. The risk increases with higher dose, larger volume of brain irradiated, and poorer baseline cognitive status. The pathogenesis may involve breakdown of the blood-brain barrier, leading to cerebral edema. Corticosteroids may be used to prevent and manage acute toxicity. Early delayed toxicity usually occurs within a few weeks of treat-ment and is usually reversible. It may present as somnolence and neurologic deterioration. It usu-ally resolves spontaneously and may be managed with corticosteroids. Late radiation injury occurs months to years following therapy and is often ir-reversible. Radiation necrosis may be difficult to distinguish from tumor progression on imaging and can change similarly over time. If corticosteroids fail to control the necrotic process, surgical resec-tion may be warranted. Bevacizumab has been reported to be beneficial for radiation necrosis in a prospective randomized clinical trial.66 Cognitive im-pairment is one of the most frequent complications

in long-term survivors (more problematic in patients with low-grade tumors due to longer survival), and can range in severity.67 Deficits may involve atten-tion, learning, memory, processing speed, ability to multitask, and word-finding. Psychostimulants (eg, methylphenidate) in conjunction with serial neuro-psychological evaluations have been used to help patients remain functionally active.68

CASE CONTINUED

The patient remains clinically stable after 5 cycles of TMZ. Prior to completing his

sixth adjuvant cycle, he experiences the sudden onset of shortness of breath, tachycardia, and chest pain. Examination reveals a swollen and tender right calf. The patient is given 100% oxy-gen by mask and receives an emergent spiral CT arteriogram of the chest, which confirms extensive bilateral pulmonary embolism. A lower extremity Doppler ultrasound reveals deep vein thrombosis. The patient is admitted to the hospital and is initi-ated on low-molecular-weight heparin (LMWH). An inferior vena cava filter is not placed. Over the next 4 days, his symptoms improve and he is dis-charged home on the same anticoagulant. His wife is trained to subcutaneously administer the LMWH daily at home.

• What is the incidence and management ofvenous thromboembolism (VTE) in patientswith brain tumors?

Thromboembolic complications are very com-mon, occurring in 30% to 60% of malignant glioma patients.69–71 VTE is a frequent complication fol-lowing craniotomy for brain tumors. This increased risk is shared with other cancers, in particular, mul-tiple myeloma. However, the pathogenesis of VTE in glioblastoma is not completely understood. In



addition to typical risk factors such as immobility, it is possible that circulating factors produced by the tumor may be contributory, as these patients have altered hematologic profiles.72,73

Surveillance of thromboembolic complications is important. Intermittent pneumatic compression of the calf reduces the incidence of VTE during the perioperative period. A randomized, prospective, double-blind clinical trial showed that a multimo-dality approach with enoxaparin or unfractionated heparin in combination with graduated compres-sion stockings, intermittent pneumatic compres-sion, and surveillance venous ultrasonography of the legs was safe and effective in the primary prevention of VTE.74 Patients should be coun-seled regarding the risk of VTE and the impor-tance of notifying their physician of appropriate symptoms.

LMWH may be the therapy of choice for second-ary prevention of VTE. A randomized, controlled trial of LMWH versus warfarin reported a survival advantage for LMWH in patients with cancer.75 In-ferior vena cava interruption by a filter is indicated when oral anticoagulation is contraindicated or ineffective. Although filters are convenient for pa-tients at a high risk for bleeding, thrombosis may occur at or above the filter site and lead to pulmo-nary embolism or complete obstruction of venous return below the placement site.

CASE CONTINUED

The patient obtains a brain MRI after his sixth cycle of adjuvant TMZ and is found to

have tumor progression. On examination, his apha-sia appears to be worse. He is still ambulatory and is able to perform his own activities of daily living. He is offered participation in a clinical trial for re-current glioblastoma and receives an experimental therapy along with bevacizumab. He continues to

have neurologic deterioration and has radiologic progression. He does not wish to pursue additional therapy and is referred to hospice. He dies shortly thereafter, 10 months after his diagnosis.

• What is the management of tumor recurrence?

The majority of glioblastoma recurrences occur within 2 cm of the primary tumor site. Treatment op-tions for recurrent glioblastoma include re-operation, additional radiation, and additional chemotherapy. Referral for a clinical trial should also be a con-sideration in patients with adequate functional status. Surgical re-resection offers the opportunity to remove a significant tumor burden in selected patients. Carmustine (BCNU)-impregnated wafers may be placed into the surgical cavity and have shown benefit in recurrent high-grade glioma.76

Additional radiation may be delivered in several ways. Additional EBRT may be delivered but may cause significant toxicity from overlapping fields unless several years have elapsed from the initial radiation.77 Stereotactic radiosurgery (SRS) may be considered as a salvage option for a subgroup of patients with smaller lesions of recurrent glioblas-toma, and is well tolerated.78 Other radiotherapy options include brachytherapy with an implanted (GliaSite) balloon system.79

Standard recurrent high-grade glioma chemo-therapy options include nitrosoureas (carmustine, lomustine), irinotecan, carboplatin, cisplatin, and etoposide, often in combination. Bevacizumab is a humanized monoclonal antibody targeting VEGF. When compared with other agents, signifi-cant response rates have been reported both as monotherapy and in combination with other cyto-toxic agents.80 Based on this data, bevacizumab has received FDA approval as monotherapy for recurrent glioblastoma. However, the use of beva-



cizumab and its effect upon neuroimaging has led to the development of new imaging criteria to assess response to treatment, particularly in the setting of anti-angiogenic agents.81 Recently, a de-vice utilizing alternating electrical fields (NovoTTF, Novocure, Portsmouth, NH) worn on the head was approved by the FDA as monotherapy for recurrent glioblastoma.82

• What is the prognosis of glioblastoma?

The likelihood of a patient becoming a 2-year survivor increased from 10% with RT alone to 26% with the combination of radiation and TMZ.21

In subsequent long-term analysis, the likelihood of becoming a 5-year survivor after initial treat-ment with radiation and concurrent TMZ was 9.8% versus 1.9% with radiation alone.83 Validated prog-nostic factors which influence survival in glioblas-toma include age, performance status, extent of resection, and neurologic function.84 Other factors which might affect prognosis include mental status and tumor size.85 The role of molecular markers beyond MGMT and IDH1 in stratifying patients into prognostic categories is an important subject of research.

CONCLUSION

Glioblastoma represents one of the most ag-gressive central nervous system neoplasms in adults. Unfortunately, it is also the most common malignant primary central nervous system tumor. The advent of TMZ has increased survival and solidified the role of chemotherapy in treating this neoplasm. However, even with current standards of care, more research is needed to stratify pa-tients into prognostic categories and guide therapy. Novel therapies are on the horizon for this and

other cancers; patients and their caregivers should remain hopeful that research will lead to more ef-fective and less toxic therapies in the near future.

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