cloudfront.practiceupdate.netcloudfront.practiceupdate.net/putextbook/19703.pdf · 21. CENTRAL NERVOUS SYSTEM TUMORS. Ashwatha Narayana, MD, Lawrence Recht, MD, and Philip H. Gutin,

21CENTRAL NERVOUS SYSTEM TUMORS

Ashwatha Narayana, MD, Lawrence Recht, MD, and Philip H. Gutin, MD

Primary central nervous system (CNS) tumors accounted for an estimated 21,810 new cases diagnosed in the year 2008 in the United States,1 and for an estimated 13,810 deaths for the same year. The incidence of brain tumors has been slowly increasing at an average rate of 1.1% per year.2 However, the death rate has been decreasing over time, and the 5-year relative survival rate for primary brain tumors has improved from 24% during 1975 through 1977 to 35% during 1996 through 2003.1 There is an early peak of 2 to 3 per 100,000 in the annual age-specific inci-dence of primary brain tumors in children up to the age of 4 years. A decline occurs between 15 and 24 years, followed by a steady rise, reaching a plateau of 21 per 100,000 between 75 and 79 years of age.3 Several histopathologically different tumors arise in the brain, reflecting the diversity of phenotypically distinct cells within the CNS, that have a capacity for neoplastic transfor-mation.4 Malignant gliomas are considered first in this chapter. Many of the principles of brain tumor management are discussed in this section. Tumors that are most common in children but that are also seen in adult patients are reviewed in Chapter 54 and are only briefly presented here. The chapter closes with a discus-sion on the management of metastatic brain tumors, which con-stitute the most common type of brain tumor encountered.

MALIGNANT GLIOMA

Epidemiologic StatisticsMalignant gliomas make up 35% to 45% of primary brain

tumors, and of these, nearly 85% are glioblastoma multiforme (GBM).4 The incidence of anaplastic astrocytoma (AA) peaks in children younger than 10 years of age and then remains constant in each subsequent decade of life. In contrast, GBM is uncom-mon before the age of 20 years, whereas the rate of occurrence increases dramatically after the age of 40.3 The incidence of malig-nant gliomas has increased at least twofold among the elderly during the previous two decades.5

Current knowledge of the molecular biology and genetics of the astrocytic neoplasms has been well summarized.6 Two genetic pathways, a progression pathway and a de novo pathway, that lead to GBM development have been described (Fig. 21-1). Although primary and secondary GBMs are histologically indis-tinguishable, it is well accepted that distinct molecular aberra-tions and pathways lead to the formation of primary (de novo) versus secondary GBMs. Primary GBMs are thought to arise in a de novo manner, without any malignant precursor lesion. Ampli-fication of the epidermal growth factor receptor (EGFR) is

thought to be a critical event in the molecular cause of primary GBMs. Secondary GBMs, on the other hand, are thought to arise as a result of the malignant transformation of lower grade gliomas, with overexpression of platelet-derived growth factor, fibroblast growth factor–2, and cyclin-dependent kinase 4, as well as p53 mutations and loss of Rb playing major roles in such transformations. Loss of PTEN has been implicated in both path-ways, although it is much more common in the pathogenesis of primary GBM.

Several hereditary syndromes are associated with an increased risk of brain tumors (Fig. 21-2). Neurofibromatosis-1 is the most common familial tumor syndrome associated with brain tumors.7 With the exception of Turcot syndrome, all are inherited in an autosomal dominant pattern. In addition to the association between hereditary syndromes and brain tumors, certain families of brain tumor patients have aggregations of brain tumors and extraneural malignancies. Germ-line p53 mutations have been frequently identified in glioma patients with multifocal lesions, a different second primary malignancy, and a family history of cancer.

Although some environmental factors have been linked with brain tumor development, they do not appear to be responsible for most brain tumors.8 Apart from a predisposing genetic syn-drome that is present in less than 5% of patients with brain tumors, the only other firmly established cause is ionizing radia-tion. Radiation-induced gliomas have been reported, and 25% of such cases have arisen in children with acute lymphoblastic leukemia who received prophylactic cranial irradiation and chemotherapy.

AnatomyThe brain is divided into supratentorial and infratentorial

compartments by the tentorium cerebelli. The supratentorial compartment includes the cerebral hemispheres and the sellar, pineal, and diencephalic regions, whereas the infratentorial com-partment includes the midbrain, pons, medulla, and cerebellum. The cerebral hemispheres are connected by the corpus callosum and are divided into the frontal, parietal, occipital, and temporal lobes. The frontal lobes are concerned with behavior organiza-tion, planning and association, and speech; the parietal lobes with motor, sensory, and complex intellectual functions; the occipital lobes with vision; and the temporal lobes with behavior, memory, speech, emotion, and auditory-visual pathways.9 Most malignant gliomas arise in the cerebral hemispheres, and the lobar distribu-tion is directly related to the amount of white matter present in each region.

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Reliance on a pathologic classification of brain tumors is a requisite for treatment. Indeed, histopathologic examination is more important than anatomic staging in determining the clini-cal behavior and prognosis of these tumors. Tumor classification is based on histologic evidence of differentiation; however, expression of histologic features may vary widely within tumors of a given type, particularly diffuse gliomas. This regional hetero-geneity makes interpretation of small biopsy samples difficult; this is especially true of astrocytomas. Unfortunately, these dif-ficulties can have significant implications on the diagnosis and grading of these tumors.

Histologic grading is a means of predicting the biologic behav-ior of a neoplasm. In the clinical setting, tumor grade is a key factor influencing the choice of therapies, particularly determin-ing the use of adjuvant radiation and specific chemotherapy pro-tocols. The WHO classification of tumors of the nervous system includes a grading scheme that ranges across a wide variety of neoplasms rather than a strict histologic grading system.10 Grade I applies to lesions with low proliferative potential and the pos-sibility of cure following surgical resection alone. Neoplasms des-ignated grade II are generally infiltrative in nature and, despite low-level proliferative activity, often recur. Some type II tumors tend to progress to higher grades of malignancy, for example,

The brain is housed within the bony calvarium, made up of the frontal, ethmoid, parietal, sphenoid, temporal, and occipital bones. The posterior margin of the lesser wings of the sphenoid marks the anterior aspect of the lateral cerebral (Sylvian) fissure, the junction of the frontal and temporal lobes of the brain. The base of the skull can be approximated on the surface of the patient by a line, called the orbitomeatal or Reid baseline, which extends from the infraorbital rim to the external auditory meatus.9

Pathologic ConditionsNeuropathologists have not agreed on a uniform classification

system for brain tumors. However, the fourth edition of the World Health Organization (WHO) classification of tumors of the CNS, published in 2007, is based on the consensus of an international working group of pathologists and geneticists.10 It is the standard for the definition of brain tumors for clinical oncology and cancer research communities worldwide. Accord-ing to this classification, CNS tumors are classified as follows: (1) tumors of neuroepithelial tissue, (2) germ cell tumors, (3) tumors of cranial and paraspinal nerves, (4) tumors of the sellar region, (5) tumors of the meninges, (6) lymphomas and hemopoietic neoplasms, and (7) metastatic tumors (Table 21-1).

Glial progenitor cell

De novo pathway Secondary pathway

EGFR amplification(chrom. 7p12)

• Signal transduction activator

INK4A loss(chrom. 9q26)

• Disrupts p16INK4A pathway

HDM2 amplification(chrom. 12q14)

• Negative regulator of proliferation

PTEN loss(chrom. 10q24)


PDGFoverexpression


FGF2overexpression


p53 mutation• Disrupts p14ARF pathway

Low-grade glioma(WHO grade II)

CDK4 amplification(chrom. 12q13)

• Disrupts p14ARF pathway

Rb loss(chrom. 13q13)

• Disrupts p14ARF pathway

Anaplastic astrocytoma(WHO grade III)

PTEN loss(chrom. 10q24)

• AKT/mTOR activity enhanced

Secondary GBM(WHO grade IV)

Primary GBM(De novo pathway)

FIGURE 21-1 • Geneticsofgliomaspathway.

Chapter 21 CentralNervousSystemTumors 423Sectio

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infiltrative astrocytic tumors with cytologic atypia alone as grade II (diffuse astrocytoma), those also showing anaplasia and mitotic activity as grade III (AA), and tumors additionally showing microvascular proliferation or necrosis as WHO grade IV (Fig. 21-3). Necrosis may be of any type; perinecrotic palisading need not be present.

Clinical PresentationThe presenting symptoms and signs of brain tumors are

divided into those associated with a mass effect and increased intracranial pressure and those that are focal. The most common presenting symptom is headache, and approximately 20% of patients with supratentorial tumors present with seizures. Altera-tions in personality, mood, mental capacity, and concentration are frequently seen early in the clinical course.4 The focal neuro-

low-grade diffuse astrocytomas that transform to AA and glio-blastoma. Similar transformation occurs in oligodendroglioma and oligoastrocytoma. The designation WHO grade III is generally reserved for lesions with histologic evidence of malig-nancy, including nuclear atypia and brisk mitotic activity. The designation WHO grade IV is assigned to cytologically malignant, mitotically active, necrosis-prone neoplasms. Examples of grade IV neoplasms include glioblastoma, medulloblastoma, and lymphoma.

Astrocytic gliomas, which are the most common primary brain tumors, arise from astrocytes, the supporting cells of the brain and spinal cord. The cytoplasmic processes that extend from the astrocytes contain a characteristic filamentous protein, glial fibrillary acidic protein (GFAP), which provides an immunohis-tochemical marker for these tumors. The WHO defines diffusely

Syndrome(OMIM)

Nervous systemtumors

Tumors of otherorgans and apparatus

Inheritance Gene Locus

Neurofibromatosis type 1

Neurofibromatosis type 2

Familial schwannomatosis

Familial posterior fossa brain tumor

Tuberous sclerosis

von Hippel-Lindau

Li-Fraumeni

Neurofibroma, optic glioma, plexiform neurofibroma, neurofibrosarcoma, as trocytoma, meningioma, Schwannoma, meningioma, ependymoma, astrocytoma, neurofibroma (occasional)

Schwannoma

Glioblastoma multiforme (or other astrocytomas)

Rhabdoid tumor

Ependymoma, giant cell astrocytoma, retinal astrocytoma

Cerebellar hemangioblastoma, spinal cord hemangioblastoma

Astrocytoma,glioblastomamutiforme

Familial glioma

Hypothalamic tumor, rhabdomyosarcoma duodenal carcinoid, somatostatinoma, parathyroid adenoma, pheochromocytoma Juvenile posterior subcapsular lenticular capacities, juvenile cortical cataract, retinal hamartoma, occasional cafe-au- lait spots, NF2 plaques, mononeuropathy

Usual onset less than 2 years of age

Multiple bilateral renal angiomyolipoma, myocardial rhabdomyoma, renal carcinoma, renal cysts, pacial angiofibroma, gingival fibromaPulmonary, adenal, liver hemangiomas; pancreatic and renal hemangioblastoma; bilateral papillary cystadenoma of the epididymis; renal cell carcinoma; hypernephroma; paraganglioma; pheochromocytoma; pancreatic cancer; adenocarcinoma of ampulla of Vater

Rhabdomyosarcoma, soft tissue sarcoma, osteosarcoma; breast cancer; leukemia; melanoma

AD

AD

AD

AD

AD

AD

AD? AR?

NF1 17q11

NF2

?

?

SNF5/INI1

TSC1 TSC2

VHL

TP53

17q11

22q12

?

9q34 16p133

3p26-p25

17p13

FIGURE 21-2 • Hereditarysyndromesassociatedwithbraintumors.


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logic symptoms and signs observed with supratentorial brain tumors are summarized in Table 21-2.

Routes of SpreadMalignant gliomas form as an expansile mass that conforms to

the barriers of the cortical convolutions, deep nuclear structures, and adjacent myelinated nerve fibers.11 Microscopic examination typically shows a gradient of infiltrating tumor cells that decreases with the distance from the periphery of the mass. As they enlarge, malignant gliomas extend directly into adjacent lobes, infiltrate throughout the ipsilateral cerebral hemisphere, and disseminate along anatomically defined nerve fiber pathways. In some cases, individual cells, facilitated by the accompanying edema, may infiltrate for long distances from the main tumor mass. Multi-centric gliomas are found in less than 5% of patients. Dissemina-tion by seeding through the cerebrospinal fluid pathways occurs in approximately 10% of cases, but is usually a late event, often appearing at a time when its effects are inconsequential compared with those of the recurrent primary tumor mass. Metastases rarely arise outside the CNS.

Diagnostic StudiesMagnetic resonance imaging (MRI) is the modality of choice

for diagnosis and evaluation of intracranial neoplasms. It is the ideal modality for initial preoperative diagnosis, including tumor extent, treatment planning, and image-guided therapies because of its multiplanar capability, anatomic detail, and superior reso-lution.12,13 The ability to characterize tissue allows for improved

Table 21-1 WorldHealthOrganizationClassificationofPrimaryCentralNervousSystemTumors

MajorClassificationofTumors WHOGrade

Astrocytic TumorsPilocyticastrocytoma I

Diffuseastrocytoma II

Anaplasticastrocytomas III

Glioblastoma IV

Gliosarcoma IV

Oligodendroglial TumorsOligodendroglioma II

Anaplasticoligodendroglioma III

Oligoastrocytic TumorsOligoastrocytoma II

Anaplasticoligoastrocytoma III

Ependymal TumorsEpendymoma II

Anaplasticependymoma III

Choroid Plexus TumorsChoroidplexuspapilloma II

Atypicalchoroidplexuspapilloma III

Tumours of the pineal regionPineocytoma I

Pineoblastoma IV

Neuronal and Mixed Neuronalglial TumorsAnaplasticganglioglioma III

Tumors of the Pineal RegionPineocytoma I

Pineoblastoma IV

Embryonal TumorsMedulloblastoma IV

CNSprimitiveneuroectodermaltumors(PNETs)

IV

Tumors of the Cranial and Paraspinal NervesSchwannoma I

Neurofibroma I

Meningeal TumorsMeningeoma I

Anaplasticmeningioma II

Hemangioblastoma I

Tumors of the Sellar RegionCraniopharyngioma I

Pituicytoma I

A

B

FIGURE 21-3 • Pathologicconditionsofmalignantglioma.A,Anaplasticastrocytomashowinghypercellularityandpleomorphicnuclei.Tumornecrosisisabsent.(Hematoxylinandeosin;originalmagnification×250.)B,Glioblastomamultiformewiththehallmarkfeaturesofnecrosiswithperipheralpseudopalisadingofneoplasticnuclei.(Hematoxylinandeosin;originalmagnification×250.)


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assessment of fatty, hemorrhagic, cystic, necrotic, and vascular components, as well as mass effect and location. In malignant gliomas, on T1-weighted sequence enhanced with gadolinium contrast, the tumor appears as an irregular, ringlike configuration that may surround a central area of necrosis (Fig. 21-4). On T2-weighted fluid-attenuation image recovery (FLAIR) images, the changes that reflect edema extend beyond the boundaries of contrast enhancement that may harbor microscopic extension. In fact, tumor may even be found in normal-appearing brain beyond the T2-weighted abnormality.

Imaging studies are performed within the first 48 hours after surgical resection to determine the presence of residual tumor and to provide a baseline for subsequent treatment. Enhance-ment resulting from surgical trauma may be indistinguishable from residual tumor even after a complete surgical resection. Postsurgical enhancement develops as early as the fifth postop-erative day, peaks after 2 weeks, and may persist for months.14 Corticosteroids, which act to re-establish the blood-brain barrier, also have a profound effect on the area of enhancement, and diminution in the area of enhancement may be due to cortico-steroids alone. To determine a radiographic response to therapy, patients should be on the same or a lower dose of corticosteroids than the dose at the time of the pretreatment scan.

Lacking with conventional MRI is an assessment of physiologic and functional information about the tumor. The gadolinium enhancement, as seen on T1-weighted MRI, reflects regions where there has been a breakdown of the blood-brain barrier. This may not be a reliable indicator of high-grade tumor because of the presence of nonenhancing tumor or contrast-enhancing necrosis.15 Similarly, T2-defined volume either over-estimates or underestimates the microscopic or nonenhancing disease in a majority of patients. New MRI techniques, such as MR perfusion, MR diffusion, MR spectroscopy (MRS), and func-tional MRI (fMRI), can provide further physiologic characteriza-tion of the tumor related to hemodynamics, cellularity, and metabolism, respectively, and may be used to assess response to therapy.16

MRS is a noninvasive method to evaluate the malignancy of gliomas based on metabolite levels such as N-acetylaspartate (NAA), choline (Cho) compounds, total creatine (Cr), and lactate (Lac), or metabolite ratios such as Cho/NAA and Cho/Cr (Fig. 21-5). Spectroscopy also holds great promise in aiding target definition for radiotherapy treatment planning and evaluation of response to therapy and tumor recurrence.17 With the advantage of measuring tumor regional variations in abnormalities of metabolite levels, MRS has recently been used as an in vivo molecular imaging technique that assists in targeting and predicts response to radiation therapy for patients with brain gliomas.

In addition to MRS, brain fMRI has gained potential in clinical application recently as it can image the eloquent cortices, such as the motor cortex, the Broca area, the Wernicke area, and the visual cortex, which are difficult to identify on anatomic MRI. Incorporation of fMRI information into the radiotherapy treat-ment process can possibly allow a radiation oncologist to prop-erly plan and deliver an adequate radiation dose while avoiding damage to the adjacent functional cortices in the treatment of gliomas.18

Dynamic MRI techniques can be used to measure important features of tumor vascularity in vivo, including the density and permeability of capillaries. Increased vessel numbers lead to higher regional cerebral (i.e., tumor) blood volume, which can be measured relative to healthy brain tissue by perfusion MRI techniques. Thus, relative cerebral blood volume provides analy-

Table 21-2 FocalSymptoms

AnatomicRegion

SymptomsorSignsorBoth

Frontallobe Personalitychange

Slowingofcontralateralhandmovements

Contralateralspastichemiplegia

Moodelevation

Difficultyinadaptingtonewsituations

Lossofinitiative

Dysphagia+lip,tongue,andhandmovements

Apraxia(ifdominantlobeinvolved)

Bifrontalinvolvement

Bilateralhemiparesis

Spasticbulbarpalsy

Impairmentofintellect

Labilityofmood

Dementia

Primitivegrasp,suck,andsnoutreflex

Temporallobe Impairmentofrecentmemory

Homonymousquadrantanopsia

Auditoryhallucination

Aggressivebehaviour

Non-dominantlobe

Minorperceptualproblem

Spatialdisorientation

Dominantlobe

Dysnomia

Impairedperceptionofverbalcommand

Fluent-Wernicke-likeaphasia

Parietallobe Mildhemiparesis

Mildtoseveresensoryloss

Homonymoushemianopsia

Visualinattention

Non-dominantlobe

Perceptualabnormalities

Anosognosia

Apraxiaforself-dressing

Dominantlobe

Alexia

Dysgraphia

Otherformsofapraxia

Occipitallobe Contralateralhomonymoushemianopsia

Visualaberrations

Bilateraloccipitalinvolvment

Corticalblindness

Thalamusorbasalgangliaorboth

Herniationsyndrome

Contralateralsensoryabnormalities

Intermittentcontralateralparesthesia

Neuropathicpainsyndrome

Contralateralintentiontremor

Semiballistic-likemovementdisorder

Hydrocephalusduetotrappingoflateralhornofventricle


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Beforesurgery

Aftersurgery

FIGURE 21-4 • Axialmagneticresonanceimageofhigh-gradeastrocytomaofrightfrontallobewithfluid-attenuationimagerecoverysequenceandT-weightedimagewithcontrast.

FIGURE 21-5 • Singlevoxelspectroscopyonapatientwithhigh-gradebrainstemglioma.

sis of capillary density in gliomas (Fig. 21-6). In adult astrocyto-mas, relative cerebral blood volumes correlate well with histopathologic grade and survival. A relative cerebral blood volume value of more than 1.75 is associated with the presence of high-grade tumor and with reduced survival in patients with gliomas.19

StagingThere is no accepted staging system for gliomas. The American

Joint Committee on Cancer (AJCC) proposed a staging scheme for primary brain tumors based on tumor (T) and metastasis (M) (dissemination within and rarely outside the CNS) as well as grade (G). Because this system was not generally adapted to clini-

cal use, it was removed from the 1997 AJCC staging manual and since then has not been used.

Prognostic FactorsA major contribution of the cooperative group brain tumor

studies has been the identification of pretreatment characteristics that affect the outcome in patients with malignant gliomas. A nonparametric recursive partitioning technique was applied to an analysis of 1578 patients accrued to three successive Radiation Therapy Oncology Group (RTOG) trials.20 Age, histologic appearance, Karnofsky performance status (KPS), mental status, duration of symptoms, neurologic functional class, extent of surgery, and radiation dose were identified as significant parti-


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A B C

D E F

FIGURE 21-6 • Perfusionimaginginapatientwithrecurrentglioblastoma.A-Frepresentimagestakenbeforeand10monthsaftertherapy,demonstratingdecreaseincontrastenhancementinT1images(BandD);rCBVinperfusionimaging(BandE)andKtransindiffusionimaging(CandF)sequences.

tioning covariates. As shown in Table 21-3, six patient classes were defined with median survival times ranging from 4.6 to 58.6 months and 2-year survival rates of 4% to 76%. These classes were used to define favorable (classes I and II, 12% of the patients evaluated), intermediate (classes III and IV, 43%), and poor (classes V and VI, 45%) prognosis subgroups. A subsequent reanalysis of the data in glioblastoma patients showed no statisti-cal difference between class V and VI with a median survival time of 7.5 months.21 This information is important for interpreting correctly the results of studies comparing different treatment regimens and for assessing the potential of new therapeutic methodologies.

Standard Therapeutic Approaches

SurgeryThe combination of surgery, radiation therapy, and chemo-

therapy represents the standard approach to the treatment of malignant gliomas. Generally, surgery is performed through an open craniotomy. The goals of surgery are to provide a histologic diagnosis, to alleviate intracranial hypertension and focal neuro-logic deficits resulting from a mass effect, and to permit rapid corticosteroid dose tapering.22 Furthermore, a large tumor mass left in the brain can serve as a nidus for cerebral edema after radiotherapy. The influence of surgical resection in malignant gliomas has been controversial. The aim of palliation of symp-toms was always clear, but the survival advantage was debated. However the evidence suggests that patients with more complete resections designed to minimize the volume of residual tumor

Table 21-3 MalignantGliomaRecursivePartitioningAnalysisClassification

Class Definition

I Age<50,anaplasticastrocytoma,andnormalmentalstatus

II Age≥50,KPS70-100,anaplasticastrocytoma,andatleast3monthsfromtimeoffirstsymptomstoinitiationtreatment

III —Age<50,anaplasticastrocytomaandabnormalmentalstatus

—Age<50,glioblastomamultiformeandKPS90-100

IV —Age<50,glioblastomamultiforme,KPS<90

—Age≥50,KPS70-100,anaplasticastrocytomaand3monthsorlessfromtimeoffirstsymptomstostartoftreatment

—Age>50,glioblastomamultiforme,surgicalresection,andgoodneurologicfunction

V —Age≥50,KPS70-100,glioblastomamultiforme,eithersurgicalresectionandneurologicfunctionthatinhibitstheabilitytoworkorbiopsyonlyfollowedbyatleast54.4GyofRT

—Age≥50,KPS<70,normalmentalstatus

VI —Age≥50,KPS<70,abnormalmentalstatus

—Age≥50,KPS70-100,glioblastomamultiforme,biopsyonly,receivinglessthan54.4GyofRT


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live longer and have an improved functional status compared with those who undergo a biopsy or partial resection only. An analysis of an RTOG database of 645 patients with malignant gliomas revealed a median survival of 11.3 months with total resection, 10.4 months with subtotal resection, and 6.6 months with biopsy alone.23 However, tumor size was not found to be a predictor of survival. Unfortunately, there are no well-conducted randomized clinical trials in high-grade gliomas that have tested the extent of surgical resection. A poorly done study on 30 elderly patients with radiologically obvious malignant glioma ran-domized to biopsy alone versus resection showed a borderline survival benefit with resection.24 Advances in neurosurgery, including diagnostic ultrasound, lasers, ultrasonic tissue aspira-tors, cortical mapping, functional imaging, and computer-assisted stereotactic laser techniques, have improved the ability of neurosurgeons to radically remove intracranial tumors.22

A closed-needle biopsy, using computed tomography (CT)- or MRI-coupled stereotactic techniques, may be indicated in many clinical settings. A biopsy is preferred for tumors located in func-tionally important or inaccessible areas of the brain. In addition, surgical resection is not practical for patients with significant tumor infiltration across the midline and around the ventricular system, or for those with diffuse, nonfocal lesions.22

Radiation TherapyRandomized trials conducted by the Brain Tumor Cooperative

Group (BTCG) and the Scandinavian Glioblastoma Study Group (SGSG) provided seminal evidence that external-beam irradia-tion favorably affects the outcome of malignant gliomas. BTCG trials 6901 and 7201 demonstrated a significant survival advan-tage for irradiated patients who received 50 to 60 Gy to the whole brain (in single daily fractions of 1.7-2.0 Gy, 5 days per week) either alone or with chemotherapy compared with those treated with either resection and supportive care only (P = 0.001) or with chemotherapy alone (P < 0.01).25,26 The median survival of patients receiving 60 Gy was 2.3 times longer than that observed for nonirradiated patients. Nearly 30% of irradiated patients in the SGSG trial maintained a full or partial working capacity, whereas the nonirradiated patients progressively deteriorated, and none regained their original performance level.27 Ran-domized trials of postoperative radiotherapy in gliomas is shown in Fig. 21-7. These studies were so convincing that virtually all patients with malignant gliomas receive adjuvant radiation therapy.

ChemotherapyUntil recently, the role of adjuvant chemotherapy in high-

grade gliomas remained controversial. Historically, the nitro-soureas, especially carmustine (bis-chloroethyl-nitrosourea [BCNU]), was the most active single agent and no other drug or drug combination had been found to be more effective with the exception of the procarbazine, lomustine (CCNU), and vincris-tine (PCV) regimen.28 However, a retrospective analysis of RTOG data and a phase III trial conducted at the Medical Research Council (MRC) showed no benefit in survival with the PCV regimen. Similarly, no benefit of chemotherapeutic agents like tirapazamine, topotecan, paclitaxel (Taxol), interferon-β, and thalidomide were noted when used with standard radiation in RTOG phase II trials.28

Introduction of temozolomide has redefined the role of che-motherapy in gliomas and represents the new standard of care. It is a derivative of dacarbazine and an inactive prodrug that undergoes hydrolysis to active metabolite monomethyl triazeno

imidazole carboximide when absorbed and results in methylation of guanine at the O6 and N7 positions at the deoxyribonucleic acid. It has several advantages over conventional chemotherapy agents. These include oral administration, rapid absorption, 100% bioavailability, ability to cross the blood-brain barrier, linear pharmacokinetics, and minimal delayed myelosuppres-sion. A large, multicenter phase II trial done in recurrent gliomas refractory to PCV chemotherapy treated with temozolomide showed a 35% response rate (RR) and a 6-month progression-free survival (PFS) rate of 46%, and was subsequently Food and Drug Administration–approved for relapsed AA.29 Based on these responses, the European Organisation for Research and Treat-ment of Cancer (EORTC) conducted a phase III trial of 60 Gy of radiation with or without temozolomide at 75 mg/m2/day fol-lowed by six cycles of adjuvant therapy with temozolomide at 200 mg/m2 for 5 days per month in 543 patients.30 With a median follow-up of 28 months, the median overall survival improved from 12.1 to 14.6 months and the 2-year overall survival improved from 10.4% to 26.5% with the addition of temozolomide therapy.

Current focus of clinical development involves targeted thera-pies in glioma. Several agents have shown confirmed activity and are currently being investigated for integration in the initial man-agement of malignant gliomas. These include antiangiogenic agents, tyrosine kinase blockers, inhibitors of Ras/MAPK path-ways, and histone deacetylase inhibitors.31

Techniques of RadiotherapyMost malignant gliomas are unifocal at the time of initial pres-

entation, and after treatment the majority recur at or within 1 to 2 cm of their original location.32 Thus, limited treatment portals are used for malignant gliomas. Intracranial metastases that appear after partial brain irradiation do not affect the ultimate outcome, because they are nearly always accompanied by relapse at the primary tumor site. Whole-brain radiation therapy (WBRT) is commonly recommended for patients with multifocal tumors, but even for these lesions, relapses occur most frequently in the sites of known disease.32

The conventional dose schedule is 59.4 to 60 Gy, given in single daily fractions of 1.8 to 2.0 Gy, 5 days per week. With this scheme, approximately 25% of patients with GBM and 50% of those with AA exhibit a significant radiographic response. Rapid fractiona-tion schemes (such as 30-40 Gy in 10-15 fractions of 2.67-3.0 Gy each) may be appropriate for some elderly or poor-performance-status patients with GBM who have relatively short survival expectancies.

The gross target volume (GTV) represents a three-dimensional (3-D) reconstruction of the location of the tumor, determined by merging data from contrast-enhanced CT scans and MRI studies. The integration of MRI into CT-based treatment planning pro-vides complementary information for accurately defining the GTV. Little agreement exists as to the definition of the clinical target volume (CTV) or the planning target volume (PTV). A shrinking field approach is used in RTOG trials. The initial PTV (PTV1) encompasses the enhancing lesion (GTV) and edema (CTV) with a 2-cm margin. After 46 Gy of a conventionally frac-tionated treatment course, the PTV (PTV2) is reduced to include only the enhancing lesion with a 2.5 cm margin. Using the extent of edema to define the CTV has some limitations. The identifica-tion of peritumoral edema is subjective, and its volume may vary with corticosteroid dosage. An analysis of the patterns of failure using the RTOG-defined PTVs demonstrated that nearly all relapses occurred within the reduced PTV2 at the site of the enhancing tumor.33 Based on these data, we define the CTV by


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Study Post-operativeradiotherapy

No post-operative

95% confidenceinterval

Shapiro, 1976 (62)

Andersen, 1978 (1)

Walker, 1978* (78)

Walker, 1980 (79)

Kristiansen, 1981 (36)

Sandberg-Wollheim,1991 (60)

TOTAL

*Only results for the evaluable patients were reported.

Deaths

12

44

52

74

51

34

267

Total

17

418

84

80

118

68

51

Deaths

10

57

30

82

35

50

264

Total

16

340

87

38

111

31

57

Risk ratio for 1-yearmortality

(random effects)

1.13

0.86

0.79

0.85

0.69

0.70

0.81

Low

0.69

0.74

0.51

0.57

0.71

0.68

0.77

High

1.84

0.88

0.97

0.84

1.01

0.92

0.97

Risk ratio 95% Cl0.01 0.02 0.05 0.1 0.2 0.5 1 2 5 10 20 50 100

z = –4.71 2P < 0.00001

Study Year #pts

1 Shapiro

2 Andersen

3 Walker

4 Walker

5 Kristiansen

6 Sandberg

Overall

1991

1981

1980

1978

1978

1976

758

171

118

33

108

99

229

Favors post-operative RT ≈ = Favors no post-operative RToverall risk ratio = 0.81 (95% Cl, 0.74 to 0.88; P < 0.00001)

FIGURE 21-7 • Pooledresultsofpostoperativeradiotherapyversusnoradiotherapyingliomas.

adding a margin of approximately 2.5 cm around the T1 contrast or a 1.5-cm margin around the FLAIR series. The PTV is deter-mined by adding an additional 0.3- to 0.5-cm margin to the CTV to account for treatment uncertainties.

Patients are fixed in a custom-designed immobilization device, and are simulated and treated in the supine or prone position, depending on tumor location. Field arrangements and beam energy are selected after consideration of the location of the tumor within the brain and the geometry of the PTV. Lateral opposed fields are used only when extensive bilateral tumor involvement is present. This technique is suboptimal for most lesions because a substantial volume of normal brain tissue will be irradiated to the same dose as the tumor. Three-dimensional conformal radiation therapy (3D-CRT) is ideally suited for the treatment of brain tumors. Three-dimensional treatment plans are designed directly from CT (and MRI) image data sets, and the target volume and surrounding normal tissues are displayed using the beam’s-eye view technique. The use of multiple 3-D–planned nonaxial coplanar and noncoplanar fields reduces the volume of normal brain tissue treated to high doses. This approach allows higher than traditional doses to be safely admin-istered to tumors located proximal to critical structures.

Intensity-modulated radiation therapy (IMRT) is an advanced form of 3D-CRT that uses inverse planning and computer-con-trolled radiation dose deposition. The advantage of precision delivery of radiation enables dose escalation and sparing of normal tissues. The brain IMRT treatment planning consists of

immobilization using an Aquaplast face mask. A CT simulation with intravenous contrast is done with the acquisition of 1.5- to 3-mm thickness images. The previously obtained MRI data is superimposed on the CT images using the fusion program. GTV, CTV, and PTV are defined as in a 3D-CRT plan. All normal structures are outlined in three dimensions. User-defined con-straints, including maximum and minimum dose constraints both for the PTV and the normal structures, are prescribed. As in 3D-CRT, noncoplanar beams are used. The plan consists of an intensity profile that is created for each beam. This is translated to leaf motion of the dynamic multileaf collimator using the inverse planning algorithm (Fig. 21-8). We have seen that the use of IMRT decreases the dose to the critical structures like optic nerves and brainstem when compared with the 3-D conformal plan.34 There is evidence that use of IMRT decreases the dose to the cochlea in children with medulloblastoma when used for the posterior fossa boost.

Special Issues With Radiation Management

Volume of RadiationIn the BTCG 8001 trial, patients were randomized to receive

either 6000 cGy WBRT or 4300 cGy WBRT with 1720 cGy boost. No difference in survival or recurrence was noted.35 In a Japanese trial, patients were randomized to 4000 cGy WBRT with 1800 cGy boost or 5600 cGy local field radiation alone.36 Again, the 2-year survival rate was no different in this study (43% versus 39%),


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pared with radiation therapy alone. Difluoromethylornithine, an inhibitor of polyamine synthesis, has not shown any benefit in a phase III clinical trial.40 Efaproxiral (RSR13), a synthetic allosteric modifier of hemoglobin, showed a median survival of 12.3 months when used along with 60-Gy radiation therapy in a phase II study, and is being presently tested in a phase III trial.41

Two halogenated pyrimidine analogues, bromodeoxyuridine (BUdR) and iododeoxyuridine, have been tested and in ran-domized trials have failed to show any benefit. Northern Califor-nia Oncology Group data had shown a median survival of 252 weeks with BUdR with concomitant radiation and chemotherapy in AA compared with 82 weeks without BUdR.42 However, an RTOG trial of 60 Gy in 30 fractions combined with PCV chemo-therapy with or without BUdR in 189 patients of AA had to be prematurely closed because of lack of benefit (1-year survival 68% versus 82%) and higher toxicity.43

Altered FractionationAgain, multiple randomized trials conducted by RTOG,

EORTC, and others have failed to show any survival benefit with hyperfractionation when compared with conventional radiation therapy alone.44 Similarly, several trials using different accelerated fractionation regimens have been reported; none have shown a survival benefit over conventional irradiation. An EORTC trial involving 60 Gy given in either conventional fractionation or with three fractions of 2 Gy given in a single day, 4 hours apart, in 340 patients showed no difference in survival or any increased toxicity.45 Doses of 64 and 70.4 Gy in 1.6-Gy, twice-daily fractions with BCNU tested in an RTOG trial showed no benefit.46 Shortening the treatment time has again failed to show any improvement.47 A Johns Hopkins trial of 30 Gy in 10 frac-tions followed by 2 weeks rest and then another 21 Gy in 7 frac-tions to reduced fields in 219 patients showed a survival similar to RTOG recursive partitioning analysis (RPA) groups I through VI patients.48

BrachytherapyAn earlier BTSG trial that randomized malignant glioma

patients to 60 Gy radiation with or without iodine-125 (I-125) seed implant to 50 Gy showed a survival benefit with the addition of brachytherapy (median survival of 13 versus 16 months).49 Since the information was presented as an abstract only and never published, it remains difficult to establish that this approach clearly improves survival. However, a randomized trial done at

indicating that large-volume irradiation is unnecessary in high-grade gliomas.

Dose of RadiationRadiation dose is another important consideration. In an MRC

phase III trial, 444 patients were randomized to either 45 Gy in 20 fractions or 60 Gy in 30 fractions (1 : 2 randomization). A benefit of 60 Gy was seen in terms of 1-year survival (29% versus 39%) and the median survival (9 versus 11 months).37 In the RTOG phase III trial, patients received either 60 Gy WBRT or 60 Gy WBRT with a 10 Gy boost (Fig. 21-9). There was no benefit with the boost in terms of the median survival (9.3 versus 8.2 months).38 Researchers at the University of Michigan reported dose escalation to 80 Gy and 90 Gy with 3D-CRT and showed no difference in patterns of relapse or survival, indicating the absence of benefit with dose escalation beyond 60 Gy in malignant gliomas.39

Radiation SensitizersMultiple randomized trials conducted by the RTOG, the Brain

Tumor Study Group (BTSG), and others have failed to show any survival benefit with misonidazole or other agents when com-

FIGURE 21-8 • Intensity-modulatedradiationtherapytreatmentplanforapatientwithhigh-gradegliomaofrightparietalregion.

100

80

60

40

20

00 20 40 60 80 100

Survival post-treatment (weeks)

Per

cent

age

surv

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0 Gy50 Gy55 Gy60 Gy

FIGURE 21-9 • Overallsurvivalasafunctionofradiationdose.


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fatal necrosis. Rarely, therapeutic irradiation can cause an occlu-sive arterial cerebrovasculopathy or secondary neoplasia.

Approximately 3% to 9% of patients irradiated for brain tumors develop clinically detectable focal radiation necrosis.53 Radiation necrosis may appear as early as 3 months after treat-ment, but usually develops within 1 to 2 years after treatment is completed. The breakdown of white matter may induce marked edema and mass effect. The symptoms of focal necrosis frequently recapitulate those of the tumor, leading the clinician to suspect recurrence. MRI may show a contrast-enhancing mass with extensive white matter alterations on T2-weighted images. His-topathologic findings are generally limited to the white matter and include focal coagulation necrosis and demyelination. Endothelial cell atypia and a unique form of fibrinoid necrosis of small arterial vessels are characteristic features that suggest the underlying pathophysiology.

Radiation necrosis is uncommon at doses less than 60 Gy with conventionally fractionated irradiation. The probability of necro-sis increases with larger daily fraction sizes (2.2-2.5 Gy).37 For patients treated with hyperfractionated irradiation (twice-daily fractions of 1.2 Gy), the incidence of necrosis increased from 4.6% for 64.8 Gy to 19.2% for 81.6 Gy. Individual host factors, including the use of chemotherapy, may alter sensitivity and increase the risk of injury.

Because neither the symptoms nor the radiographic findings clearly distinguish tumor from necrosis, the clinical diagnosis of radiation necrosis may be difficult to confirm. 18Fluorodeoxyglu-cose–positron emission tomography (18FDG-PET), 201T1–single photon emission computed tomography (201Tl-SPECT), per-fusion imaging, and MRS studies may help to differentiate necro-sis from recurrent tumor. However, many patients have a mixture of necrosis and tumor. Thus, a biopsy may be required to confirm the diagnosis, especially when the injury occurs at or near the tumor site.

Corticosteroids may improve or stabilize the neurologic symp-toms associated with the effects of radiation injury. Surgical resection is frequently beneficial to patients with favorably situ-ated focal necrotic lesions who deteriorate neurologically and become steroid-dependent. There is no evidence that anticoagu-lation may lead to clinical improvement when surgery is not feasible. However, recent reports suggest a role for bevacizumab in the management of radiation-induced brain necrosis.54

Diffuse white matter injury develops in at least 40% of patients irradiated for intracranial neoplasms.52 The T2-weighted MRI images reveal hyperintensity of the periventricular white matter. Cerebral cortical atrophy occurs in 17% to 50% of patients treated for brain tumors. Enlarged cerebral sulci and ventricular dilatation are seen on neuroimaging studies. The abnormalities that accompany white matter change and cerebral atrophy are discernible within the first year after irradiation and persist or progress thereafter. They tend to be more severe with larger treat-ment volumes, higher doses, older age, longer intervals after irra-diation, and chemotherapy. Clinical features range from mild lassitude or personality change to incapacitating dementia. Some patients with cerebral atrophy may also develop gait abnormali-ties and urinary incontinence suggestive of the syndrome of normal pressure hydrocephalus. Many patients with radiographic changes have no symptoms, but in those who do, the degree of impairment correlates approximately with the severity of the MRI appearance.

Decreased levels of intellectual function have been observed in adults after cranial irradiation. Certain cognitive functions, such as memory, may be more susceptible to decline than others.52

Princess Margaret Hospital that randomized patients to 50-Gy external-beam radiation with or without temporary I-125 seed implant to 60 Gy did not show any survival benefit (median survival of 13.2 versus 13.8 months).50

Stereotactic RadiosurgerySeveral retrospective trials have indicated that there is a pos-

sible survival advantage with the addition of a stereotactic radio-surgery (SRS) boost to high-grade gliomas. The RTOG conducted a randomized trial of conventional radiotherapy to 60 Gy and BCNU alone or preceded by a radiosurgery boost to 15 to 24 Gy in patients with GBM measuring 4 cm or less.51 However, the results were disappointing. The median survival (14 versus 13.7 months), 2-year survival (22% versus 18%), and 3-year survival (16% versus 8%), were similar with or without the boost. There was no improvement in any RPA class. No increased toxicities were seen with the addition of the SRS boost. Failures were still predominantly local (>90%).

Normal Tissue ReactionsSeveral adverse neurologic reactions may be observed in

patients receiving cranial irradiation. They are classified into acute reactions, early-delayed reactions, and late-delayed injuries. With daily fractions of 1.8 to 2.0 Gy, the acute reaction most often presents as mild headache and nausea, beginning within a few hours after the first treatment and becoming progressively less severe with each succeeding fraction.52 The pathogenesis is thought to be increased cerebral edema caused by radiation-induced permeability changes in the blood-brain barrier. Corti-costeroids may prevent or relieve most symptoms. Thus, if symptoms of increased intracranial pressure are present, patients undergoing cranial irradiation should be pretreated with corti-costeroids (i.e., dexamethasone, 8-16 mg per 24 hours), admin-istered for at least 48 to 72 hours before beginning treatment.

The early-delayed reaction (also called radiation encephalopa-thy) is characterized by transient, self-limited neurologic deterio-ration, somnolence, or focal encephalopathy.52 Early-delayed encephalopathy occurs in 15% to 40% of patients with primary or metastatic brain tumors. This reaction, which begins within 1 to 12 weeks after the completion of radiation therapy, usually peaks by 8 weeks after treatment and resolves spontaneously within the subsequent 4 months. Patients complain of headache, lethargy, and an exacerbation of their neurologic symptoms. At times, corticosteroid therapy and intensive medical support may be required. Declines in long-term memory within 1 to 2 months after irradiation followed by recovery 4 to 8 months later have also been observed.

The early-delayed reaction is thought to result from transient demyelination, resulting from damage to proliferating oli-godendrocytes, and temporary changes in the blood-brain barrier. CT and MRI studies during this period may show appar-ent tumor enlargement, increased tumor enhancement, and edema, and in some cases new enhancement may appear. These changes appear to relate to intralesional reactions, indicative of tumor response, or localized perilesional edema and demyelina-tion. It is important to recognize that the appearance of new findings during the early post-treatment interval does not always indicate that the tumor has recurred or that a change in therapy is warranted.

Late-delayed radiation injuries vary in their appearance and severity from asymptomatic white matter changes to cerebral atrophy, hemorrhagic vascular telangiectasia, neurobehavioral impairment, pituitary-hypothalamic dysfunction, and potentially


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common subtype, and protoplasmic astrocytomas have been referred to as “ordinary” astrocytomas and share a similar prog-nosis. Over time, at least 50% of these tumors transform into more anaplastic lesions. Gemistocytic astrocytomas are com-posed of large, plump astrocytes with abundant eosinophilic cytoplasm. Because gemistocytes commonly transform into highly anaplastic cells, they behave in an aggressive fashion and should be treated as anaplastic gliomas.

Pilocytic astrocytomas typically occur in the first two decades of life but also arise in adults. They are composed of fusiform cells with unusually long, wavy processes called Rosenthal fibers. Mitosis is rarely seen. Endothelial proliferation may be present, but does not signify malignancy.56 Pilocytic astrocytomas have a long natural history and rarely dedifferentiate into tumors with more malignant histologic appearances.

Although low-grade astrocytomas are often similar in their histologic appearance, their biologic behavior may vary consider-ably. In one study, a Ki-67 labeling index (LI) of more than 10% was associated with higher histologic grade and poorer survival, and this value was more significant than histologic grading.57 These data suggest that patients with a high LI may be considered for more aggressive treatment programs.

Clinical PresentationAbout two thirds of adult patients with low-grade astrocyto-

mas present with seizures but are otherwise neurologically intact.4 Others exhibit a slowly progressive neurologic syndrome consist-ing of headache, vomiting, motor deficit, visual or sensory loss, language disturbance, or personality change. Symptoms may be present for months or years before a diagnosis is made. Seizures are associated with a better survival, whereas the presence of functional deficits predicts a poorer outcome.

Impairment is most pronounced in those who have had chemo-therapy and WBRT. Intellectual decline is first discernible within 4 to 6 months after treatment and becomes more pronounced by 2 to 3 years of follow-up. Memory loss may prevent patients from returning to their premorbid occupation. However, an analysis55 found that 60% of long-term survivors irradiated for gliomas were employed at occupations comparable to those they had held before treatment. Patients treated with partial brain irradiation tended to have a higher KPS, superior memory function, and a better employment history compared with those who received WBRT.

Neuropsychologic testing of patients treated for a variety of brain tumors who failed to retain their premorbid social or occu-pational levels of function demonstrated that newly learned tasks requiring attention and immediate problem-solving ability were performed poorly. In contrast, tests that evaluated long-term memory and overlearned material were generally consistent with premorbid levels.53 IQ testing alone is a less sensitive indicator of changes in cognitive function in adults. Prompt neuropsycho-logic intervention when necessary and early return to work after treatment may lead to improvement in or recovery of cognitive function.

OutcomeThe median survival times using conventional radiation

therapy alone or with chemotherapy for patients with GBM is 10 to 14 months, whereas the 2-year survival rate is only 10% to 25%.30 The median survival for patients with AA is 36 months, and the 3-year survival rate is approximately 50%.

LOW-GRADE ASTROCYTOMA

IncidenceLow-grade astrocytomas make up 5% to 15% of adult primary

brain tumors and 67% of low-grade gliomas, the remainder of low-grade gliomas being mixed oligoastrocytomas (19%) and oligodendrogliomas (13%).4 Unlike the incidence of their malignant counterparts, the incidence of low-grade astro-cytomas decreases with increasing age. They are most common between the ages of 20 and 40 years and rarely occur after the age of 50.

AnatomyLow-grade astrocytomas in adults typically involve the cerebral

hemispheres. Among 995 cases of supratentorial astrocytomas culled from the literature, 42% were located in the frontal lobes, 37% in the temporal, 5% in the parietal, and 10% in more than one lobe, whereas 6% presented at other sites.4

Pathologic ConditionsAstrocytomas are well-differentiated tumors that display

increased cellularity compared with normal brain tissue and have mild to moderate nuclear pleomorphism (see Fig. 21-3). Micro-cysts are frequently present, a feature that distinguishes astrocy-tomas from reactive gliosis.54 The majority of low-grade astrocytomas are classified as grade II in the WHO classification. Juvenile pilocytic astrocytomas are classified as grade 1 in the WHO system (see Table 21-1).

The various astrocytoma subtypes, including the fibrillary, protoplastic, gemistocytic, and pilocytic forms, are distinguished by their intracytoplasmic fibrillary processes, demonstrated by staining for GFAP (Fig. 21-10). Fibrillary astrocytomas, the most

FIGURE 21-10 • Low-gradeastrocytomashowingmildlyincreasedcellularitywithuniformcellsandnuclei.(Hematoxylinandeosin;originalmagnification×250.)


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to 80% are amenable to total removal.60 Long-term survival approaches 100% after complete surgical resection. After partial resection, survival rates range from 80% to 90% at 5 years, 70% to 80% at 10 years, and 50% to 60% at 20 years. The 10- to 20-year survival after biopsy alone varies from 40% to 50%.

Resection of the more common diffuse astrocytomas is limited by the lack of clear demarcation between the infiltrating tumor and normal brain tissue. Newer surgical techniques make the attempted resection safer, more complete, and more likely to control seizures. Most series show an improvement in time to progression and survival with more extensive surgery.59 In one series, 80% of adult patients with completely resected tumors survived 5 years, compared with 50% for subtotal resection and 45% for biopsy. Other studies, however, have not shown a cor-relation between the extent of resection and prognosis.

The earlier diagnosis of patients with low-grade astrocytomas has raised questions regarding the timing of therapeutic interven-tion. There is general agreement that large symptomatic and progressive tumors should be treated at diagnosis, and a complete surgical resection should be attempted. A diagnostic biopsy should be performed on patients with deep or unresect-able symptomatic tumors. Patients with small, asymptomatic (other than medically controlled seizures), apparently indolent tumors may be considered for close observation. Surgical inter-vention is offered should the tumor change its radiographic appearance or cause new symptoms or medically uncontrollable seizures.59

Alternatively, more aggressive local treatment in the form of surgery alone or surgery and postoperative irradiation can be offered. Arguments for performing immediate surgery are to confirm the diagnosis and to identify patients with nonenhancing anaplastic tumors. Complete resection of smaller tumors may improve survival,60 obviate the need for irradiation, and decrease the risk of malignant transformation, the most common cause of death from low-grade astrocytomas.

Radiation TherapyPatient selection for and the timing and dose of postoperative

irradiation are controversial issues. Postoperative irradiation is not indicated for completely resected pilocytic astrocytomas.60 There is insufficient data relative to the role of radiation therapy for incompletely resected pilocytic tumors. Therefore, after sub-total resection or biopsy, close follow-up and deferring treatment is generally recommended until there is evidence of disease progression.

Opinions differ regarding the need for postoperative irradia-tion for completely resected ordinary astrocytomas. The 5-year recurrence-free survival rates of patients with supratentorial astrocytomas or mixed oligoastrocytomas who undergo total or radical subtotal tumor resection range from 52% to 95%.59 The outcome in adult patients after total resection has been found in some series to be similar to that of patients undergoing less exten-sive surgery. Thus, in adults, postoperative irradiation has been recommended after complete resection by some, whereas others suggest that radiotherapy be withheld until recurrence.

Most retrospective reviews suggest that postoperative irradia-tion is beneficial for incompletely resected nonpilocytic astrocy-tomas. A major question concerns whether radiotherapy should be given immediately after surgery or be delayed until recurrence or progression. Patients with intractable seizures or with large, progressive, symptomatic, unresectable, or incompletely resected tumors should be considered for radiotherapy. Immediate post-operative irradiation has been recommended for patients older

Routes of SpreadPilocytic astrocytomas are well circumscribed and grow by

expansion, whereas the nonpilocytic tumors diffusely infiltrate adjacent tissues in a pattern similar to that of malignant gliomas. One variant, called gliomatosis cerebri and found in the second and third decade of life, may involve considerable areas of the cerebral hemispheres, cerebellum, and brainstem. The wide-spread nature of this lesion has been regarded as evidence for multifocal astrocytic neoplastic transformation.

Diagnostic StudiesPilocytic astrocytomas appear on imaging as discrete, enhanc-

ing lesions. The classic appearance is a large cyst with an enhanc-ing mural nodule. Ordinary astrocytomas appear as diffuse, poorly defined, low-density, nonenhancing lesions.16 Approxi-mately 40% of ordinary astrocytomas enhance on imaging, and calcification is found in 10% of cases.12,16 MRI typically shows low signal intensity changes on T1-weighted images, high signal intensity on T2, and an absence of enhancement (Fig. 21-11).

Prognostic Factors and GroupingBauman and associates have proposed a grouping system for

predicting the survival for patients with low-grade gliomas using RPA based on a database of 401 patients.58 Age, KPS, and pres-ence or absence of contrast enhancement were used as prognostic indicators. Group I (KPS <70 and age >40) had the worst median survival, at 12 months. Group II (KPS >70, age >40 and contrast enhancement present) had a median survival of 46 months. Group III (KPS >70, age >40 and contrast enhancement absent or KPS <70 and age <40) had a median survival of 87 months. Group IV (KPS >70, age 18-40) had the best median survival of 128 months.


SurgeryThe goals of surgery are to establish a tissue diagnosis, to

remove as much tumor as possible without increasing the neu-rologic deficit, and to remove an epileptogenic focus if present.59 Pilocytic astrocytomas are relatively well circumscribed, and 60%

FIGURE 21-11 • Axialmagneticresonanceimageoflow-gradeastrocytomaofrighttemporalregionwithfluid-attenuationimagerecoverysequence.


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designed complex treatment plans with multiple fields are used whenever appropriate to limit the high-dose volume and to mini-mize the risk of long-term radiation sequelae. Doses of 50.4 to 54 Gy in daily fractions of 1.8 to 2.0 Gy, five fractions per week, are recommended.

OutcomeThe outcome of patients diagnosed and treated in the CT and

MRI era is notably better than that reported in the past, when the conditions of diagnosis were different than they are now. Median survival times in recent series range from 7 to 12 years as com-pared with 5 years or less in older series, raising concerns over the value of the older literature in making treatment decisions today.65 The improved outcome appears to be related to the early diagnosis of neurologically intact patients who exhibit only sei-zures at the time of diagnosis.

The initial results of a prospective phase II randomized trial from RTOG (9802), which followed totally resected young patients and randomized unfavorable low-grade gliomas to radi-ation alone or with PCV chemotherapy showed that the 5-year PFS was poor in all the groups ranging from 39% to 61%. Only half of the favorable patients were disease free at 5 years.67 Addi-tion of PCV chemotherapy resulted in a statistically insignificant improvement in PFS with no overall survival benefit. A subse-quent RTOG trial (0424) that gave daily temozolomide with con-current radiotherapy (54 Gy/30 fractions/6 weeks) followed by temozolomide for 12 cycles in high-risk low-grade gliomas has met its accrual target.

OLIGODENDROGLIOMA

IncidenceOligodendrogliomas, which compose less than 5% of adult

primary brain tumors, occur most commonly between the ages of 25 and 49 years.4 Losses of genetic information from chromosomes 1p (75%) and 19q (81%) are commonly seen in oligodendroglioma specimens, whereas losses on 17p (19%) and p53 gene mutations are notably less frequent, suggesting that early events in their oncogenesis are distinct from those associ-ated with astrocytic tumors. The genetic pathway in the develop-ment of oligodendrogliomas is shown in Fig. 21-12. Anaplastic

than 40 years who appear to benefit most from this treatment approach.61,62 Postoperative irradiation is commonly deferred in patients with well-controlled seizures who present with otherwise asymptomatic tumors. Proponents of this approach argue that with CT and MRI, the disease is diagnosed earlier in its natural history than in the past and that it is unclear whether early irra-diation provides an outcome advantage over delayed irradiation, whether irradiation can delay or prevent tumor dedifferentiation, or whether it even alters the prognosis.

A randomized trial of early versus delayed radiotherapy in adult patients was conducted by the EORTC.63 In this trial, 311 patients with low-grade gliomas were randomized to no immedi-ate therapy or 54-Gy postoperative radiation. In this study, biopsy alone was the surgical procedure in 40% of the patients; the histologic examination revealed oligodendroglioma in 25% of the patients. With a median follow-up of 5 years, the 5-year disease-free survival was better with immediate postopera-tive radiation (37% versus 44%). However, the 5-year overall survival was the same (63% versus 66%), indicating that defer-ring the postoperative therapy is an option for a selected group of patients.

The optimal dose of radiation remains unclear. In a ran-domized trial conducted by the EORTC involving 379 patients, no survival difference was observed when 45 Gy was compared with 59.4 Gy. With a median follow-up of 6 years, the 5-year disease free survival (47% versus 50%) and the 5-year overall survival were the same (58% versus 59%).64 In another combined North Central Cancer Treatment Group, RTOG, and ECOG trial, patients were randomized to receive either 50.4 Gy in 28 fractions or 64.8 Gy in 36 fractions. With a median follow-up of 6.3 years, the 5-year disease-free survival (44% versus 40%) and the 5-year overall survival were again the same (72% versus 64%), indicat-ing that lower doses of radiation therapy are probably as effective as higher doses of radiation for low-grade gliomas.65

ChemotherapyThe role of chemotherapy is controversial in adult low-grade

astrocytomas. In a Southwest Oncology Group trial, patients with incompletely excised tumors were randomly assigned to receive radiotherapy alone or with CCNU. The median survival of all patients was 4.45 years, with no difference between the two treat-ment arms.62 There was an RTOG trial that randomized high-risk, low-grade glioma patients to postoperative radiation to 54 Gy with or without PCV chemotherapy for six cycles. In an initial report, although the 5-year PFS was improved with the addition of chemotherapy (39% versus 61%), the overall survival was unchanged.65 Recently, temozolomide has shown its effec-tiveness in the initial treatment of low-grade glioma. In the largest reported retrospective analysis of 149 patients, Kaloshi and col-leagues reported a 15% partial response (PR) and 37% stable disease with temozolomide as the initial therapy. The median PFS was 2.8 years and the 3-year overall survival was 70%.66 Based on this data, EORTC is conducting an ongoing trial in which patients are randomized to either radiotherapy or temozolomide at the time of initial diagnosis.

Techniques of RadiotherapyLimited radiation fields are used for the treatment of low-grade

astrocytomas. The PTV encompasses the T2-weighted, MRI-defined GTV with a 1.5- to 2-cm margin of normal brain. In general, contrast administration is not helpful because enhance-ment is either weak or absent altogether. Nearly all recurrences occur at the original primary tumor site. Three-dimensionally

Oligodendroglial progenitor cell

Oligodendroglioma WHO grade II

Anaplastic oligodendroglioma WHO grade III

Translocation t(1:19) q10; p101p and 19q lossP14ARF/CDKN2A/B/methylationMGMT methylation

EGFR over expressorPDGF/PDGFR overexpression

ARF/deletion/methylationCDKN2A/B/deletion/methylationCDKN2C mutation/deletionRB1 methylation10q loss/PTEN mutation (rare)TP53 mutation (rare)

VEGF over expressorAmplification (rare):CDK4EGFRPDGFRA

FIGURE 21-12 • Geneticpathwayforoligodendroglioma.


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patients who received neoadjuvant chemotherapy and in associa-tion with 1p/19q deletion. A subsequent tumor histopathologic review separated 115 tumors deemed to be classic for oligo-dendroglioma (CFO) from 132 lacking classic features of oli-godendroglioma (NCFO) and evaluated the relationship of histopathologic condition and 1p/19q status to treatment and outcome.69 This study showed that that overall survival of patients with CFO was significantly longer than for patients with NCFO and was not affected by necrosis. Also, the classic oli-godendroglial morphology was highly associated with 1p/19q deletion, present in 80% of CFO and in only 13% of NCFO. On multivariate analysis, both classic oligodendroglial morphology and 1p/19q deletion remained significantly associated with improved PFS and overall survival, suggesting that these features may in the future be predictive of therapeutic response and survival.69

Many oligodendrogliomas are admixed with astrocytoma or ependymoma components. The presence of up to 50% astroglial component is accepted to make the diagnosis of mixed oli-goastrocytoma in the new WHO classification.66 The median survival for patients with low-grade mixed oligoastrocytomas is 7 years and the 5- and 10-year survival rates are 63% and 33%, respectively.70 Most oligoastrocytomas and 50% to 75% of oli-godendrogliomas recur as AAs or GBM.

Clinical PresentationOligodendrogliomas present in a fashion similar to that of

hemispheral astrocytomas. However, two features distinguish them from astrocytomas: the antecedent history, averaging 7 to 8 years, tends to be longer, and seizures are more common, occurring in 70% to 90% of patients by the time of diagnosis.4 Headache, altered mental status, papilledema, and focal neuro-logic deficits are also common at presentation.

Patterns of SpreadOligodendrogliomas grow in a diffuse infiltrative pattern. They

may invade the cerebral cortex or expand centrally into the deep midline structures. Ventricular extension accounts for a 5% to 10% incidence of spread through the cerebrospinal fluid path-ways. Metastases may occur to the spinal cord and rarely to extracranial sites.4

Diagnostic StudiesA provisional diagnosis may be made by CT or MRI. Oligoden-

drogliomas are typically hypodense or isodense, poorly defined, and nonenhancing on CT. Calcification is present in 60% of cases, and peritumoral edema is minimal. They are of low signal intensity on T1-weighted MRI and hyperintense on T2-weighted studies except for regions of signal void that correspond to frag-ments of calcium (see Fig. 21-10).12 Some aggressive low-grade oligodendrogliomas enhance on CT and MRI.12 Anaplastic oli-godendrogliomas and mixed gliomas more often enhance and may contain hemorrhagic and necrotic areas. Although these tumors do rarely spread through the cerebrospinal fluid, cyto-logic and spinal MRI studies are not obtained unless clinically warranted.


SurgerySurgery is required for histologic confirmation. The principles

of surgical resection are similar to those for cerebral astrocyto-mas, with gross total removal being the goal when this is consist-

oligodendrogliomas show additional allelic losses involving chro-mosomes 9p and 10q and in some cases EGF-R gene amplifica-tion in a pattern similar to that of AAs, indicating a common progression pathway.68

AnatomyMore than 80% of oligodendrogliomas arise in the white

matter of the cerebral hemispheres, most commonly in the frontal, temporal, and parietal lobes.4 Approximately 15% are found in the third or lateral ventricles, and the remainder arise in the posterior fossa.

Pathologic ConditionsOligodendrogliomas are composed of small, uniform cells with

round central nuclei and distinct cytoplasmic borders. Formalin fixation causes a perinuclear halo that produces a “fried egg” or “honeycomb” appearance. The cells lack fibrillary cytoplasmic processes. A rich, vascular network, called “chicken-wire” vessels, divides the tumor into discrete lobules (Fig. 21-13). Anaplastic oligodendrogliomas, which represent only 3% to 5% of malig-nant gliomas,4 may evolve from low-grade oligodendrogliomas or arise de novo. They have recognizable oligodendroglial com-ponents, but also exhibit features of anaplasia, including nuclear pleomorphism, vascular endothelial proliferation, mitoses, and necrosis.68

A two-tiered system, low-grade and anaplastic, is used to grade oligodendrogliomas. In the new WHO classification (see Table 21-1), low-grade lesions are labeled grade II and anaplastic lesions are labeled as grade III.68 Patients with grade II tumors have a median survival of 9.8 years and 5- and 10-year survival rates of 73% and 49%, respectively, whereas those with grade III tumors have a median survival of 4.6 years and 5- and 10-year survival rates of 45% and 26%.65

An important additional diagnostic assessment that should be performed on all oligodendroglial tumors is for the presence of deletions of chromosomes 1p and 19q. If these deletions are present, tumors tend to behave more indolently and are more responsive to therapy (especially chemotherapy). Although the reason why these deletions are associated with a favorable prog-nosis remain unclear, most studies indicate that only the absence of both fully portends a good prognosis.

The RTOG 9402 trial confirmed the prognostic significance of 1p/19q deletion and showed that only PFS was prolonged in

FIGURE 21-13 • Low-gradeoligodendrogliomashowinguniformcellswithclearcytoplasmandfragmentsofcalcification.(Hematoxylinandeosin;originalmagnification×250.)


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60 Gy in daily fractions of 1.8 to 2.0 Gy using an approach similar to that used for malignant gliomas.

OutcomeFive-year survival rates for oligodendrogliomas range from

36% to 83% and 10-year rates vary from 8% to 56%. For incom-pletely resected oligodendrogliomas, several studies suggest a benefit for postoperative irradiation during the first 5 years after treatment, but this effect diminishes over time.

Although some authors have noted worse outcomes in mixed anaplastic tumors compared with pure anaplastic oligodendro-gliomas, others have noted similar outcomes. Winger and col-leagues74 reported median survival times of 1.1 years for mixed anaplastic oligoastrocytomas and 5.3 years for anaplastic oli-godendrogliomas treated with radiotherapy and chemotherapy. In contrast, Shaw and associates75 found that patients with high-grade mixed oligoastrocytomas and high-grade oligodendroglio-mas had similar outcomes with median survival times and 5- and 10-year survival rates of 4.3 years (45% and 23%, respectively) for high-grade oligoastrocytomas and 4.6 years (45% and 26%) for high-grade oligodendrogliomas.

PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

Epidemiologic StatisticsUntil the 1980s, primary CNS lymphomas (PCNSLs) repre-

sented less than 2% of intracranial neoplasms. However, during the decade from 1985 through 1994, there was nearly a fivefold increase in incidence.2 Although this partly reflected the higher prevalence of acquired immunodeficiency syndrome (AIDS) during that time, the incidence was also noted within the appar-ently immunocompetent general population. However, a sharp decrease in incidence is now noted (with the peak in 1995) that mirrors the decrease in the AIDS rate and the introduction of more effective antiretroviral therapy.2 The peak incidence in human immunodeficiency virus (HIV)-negative patients is in the fifth to seventh decades of life with a 3 : 2 to 2 : 1 male/ female ratio. In contrast, immunocompromised patients are fre-quently diagnosed in the third and fourth decades, and nearly all are male.76 The molecular genetics and pathogenesis of PCNSL have not been elucidated. Epstein-Barr virus (EBV) genome-protein expression is present in two thirds of HIV-related PCNSL, but in only 15% of immunocompetent patients, suggesting that EBV does not play an essential role in the pathogenesis of PCNSL in immunocompetent patients and that HIV-related and HIV-negative PCNSL may represent pathogenetically distinct entities.76

Anatomy and Routes of SpreadCNS lymphomas most frequently arise in the supratentorial

paraventricular region of the brain, but they also occur in the cerebellum and brainstem. Rarely, they present only in the lep-tomeninges or spinal cord.77 Multifocal tumors are present at diagnosis in 25% to 50% of immunocompetent patients and in 60% to 80% of AIDS patients. CNS lymphomas tend to infiltrate extensively along the corpus callosum and other deep white matter tracts. They frequently traverse the ependyma to involve the ventricular surface or spread peripherally into the overlying leptomeninges. Cytologic examination of cerebrospinal fluid reveals malignant or suspicious cells in up to two thirds of immu-nocompetent patients and in nearly all AIDS patients. Ocular

ent with good neurologic outcome. The margins of oligodendrogliomas appear to be more distinct than those of astrocytomas, but generally they are infiltrative, and surgical cure is unlikely. The extent of resection and postoperative tumor volume59 have been shown to affect survival in some series, but not in others. As in the case of low-grade astrocytomas, some small tumors that are asymptomatic except for controlled sei-zures can be observed, delaying surgical intervention until there is disease progression. However, if feasible, large, symptomatic, or progressive tumors should be resected.

Radiation TherapyConclusions regarding the value of radiotherapy are contradic-

tory, and the lack of randomized trials precludes the statement of firm recommendations. The infrequent occurrence of oli-godendrogliomas and their variable and often long natural history make it difficult to evaluate the effect of radiotherapy on these tumors. Certain histologic features affect the prognosis,71 and it is likely that many retrospective studies contain patients with both differentiated and anaplastic oligodendrogliomas.

Patients with completely resected low-grade oligodendroglio-mas can be observed, deferring radiotherapy until the time of recurrence. Large, symptomatic, unresectable, or incompletely resected tumors should receive postoperative irradiation.61 On the other hand, certain small tumors that are asymptomatic except for controlled seizures may be observed after subtotal resection, delaying radiotherapeutic intervention until there is tumor progression. Patients with pure or mixed anaplastic oligodendrogliomas should routinely receive postoperative irradiation.

ChemotherapyChemotherapy is generally withheld in low-grade oligoden-

drogliomas until the time of disease progression. Anaplastic oli-godendrogliomas are chemosensitive tumors. PCV regimen has produced RRs of 75% or more in newly diagnosed anaplastic oligodendrogliomas.72

To test the efficacy of chemotherapy in newly diagnosed pure and mixed anaplastic oligodendrogliomas, the RTOG conducted a trial comparing radiotherapy alone with neoadjuvant intensive PCV chemotherapy (four 6-week cycles) followed by radiother-apy. The median survival times were similar (4.9 years after PCV plus radiotherapy versus 4.7 years after radiotherapy alone). However, PFS time favored PCV plus radiotherapy (2.6 years versus 1.7 years for radiotherapy alone). Of these patients, 65% experienced grade 3 or 4 toxicity, and one patient died.72 In an EORTC trial, 368 patients were randomly assigned to either 59.4 Gy of radiotherapy in 33 fractions only or to the same radio-therapy followed by six cycles of standard PCV chemotherapy. Adjuvant PCV chemotherapy did not prolong overall survival (31 versus 40 months), but did increase PFS (23 versus 13.2 months).73 RTOG also has conducted another phase II trial of pre–radiation therapy with temozolomide chemotherapy for six cycles to delay radiation therapy (59.4 Gy) in partial responders or to even with-hold it in complete responders in pure or mixed anaplastic oli-godendroglioma patients. The study has met the accrual and results are awaited.

Radiation Therapy TechniquesThe PTV for radiotherapy for low-grade oligodendrogliomas

encompasses the MRI-defined GTV with a 1.5- to 2-cm margin. A dose of 54 Gy in daily 1.8-Gy fractions is used. Patients with pure and mixed anaplastic oligodendrogliomas receive 59.4 to


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SurgeryThe role of surgery is to establish a tissue diagnosis, and this is

best obtained by stereotactic biopsy. Because of the multifocal nature of this tumor, extensive resections produce little survival benefit and increase the risk of postoperative deficits.77 Large single hemispheric lesions may be surgically reduced when intracranial pressure cannot be medically controlled.

CorticosteroidsPCNSLs respond dramatically to corticosteroid therapy. At

least 90% of patients improve clinically, whereas 40% of lesions shrink considerably and 10% disappear on CT and MRI. Tumor biopsy after corticosteroid therapy may be problematic, due to the disappearance of a target for biopsy, and may yield nondiag-nostic tissue. Thus, when the diagnosis of PCNSL is suspected, corticosteroids should be withheld, if possible, until a tissue diag-nosis has been obtained.77

Radiation TherapyHistorically, WBRT with corticosteroids had remained the

standard treatment for PCNSL. Focal radiation is not indicated for PCNSL because of the multicentric and infiltrating nature of the disease, but WBRT has never been compared with focal radiotherapy in a randomized controlled study. Shibamoto and colleagues have reported a retrospective analysis of patients who underwent focal radiotherapy with margins smaller than 4 cm or larger than 4 cm. In their study, patients with smaller margins had an out-of-field recurrence rate of 83% compared with 22% in the group with wider margins.79 Also, the median survival was longer in the group that received larger margins (28.5 months versus 15 months).

The RTOG examined the efficacy of high-dose radiotherapy in a prospective study (trial 8315).78 Patients with non-AIDS PCNSL were treated with WBRT to 40 Gy plus an additional 20 Gy boost to the tumor. The median survival from the start of radiotherapy was only 11.6 months, and the 1- and 2-year survival rates were 48% and 28%, respectively. Recurrence of disease in the brain occurred in 61% of patients, and most relapses occurred within the region that received 60 Gy, suggesting that there is no clear

lymphoma is found in association with PCNSL in approximately 20% of patients at diagnosis.77 Lymphoma can also begin within the globe. Of patients presenting with ocular lymphoma, 50% to 80% will subsequently develop CNS lymphoma within a median of 9 months.

Pathologic ConditionsHistologic examination shows perivascular cuffs and sheets of

lymphoid tumor cells infiltrating brain tissue with expansion of the Virchow-Robin spaces. The neoplastic cells are similar to those of non-Hodgkin lymphoma arising in extranodal sites. They are predominantly of B-cell origin, the majority being high-grade large cell or small noncleaved cell lymphomas, with large cell immunoblastic the most common subtype. Intermediate-grade lymphomas are less common, and low-grade subtypes and T-cell lymphomas are rare.78

Clinical PresentationPresenting symptoms include focal neurologic deficits, sei-

zures, neuropsychiatric disturbance, headache, lethargy, and con-fusion.4,76 Neck or back pain and symptoms or signs of myelopathy may indicate parenchymal spinal cord involvement, whereas blurred vision or floaters suggests ocular lymphoma.

Diagnostic StudiesThe diagnostic evaluation begins with a cranial MRI. Single or

multiple densely and uniformly contrast-enhancing lesions in the paraventricular regions, basal ganglia, thalamus, or corpus cal-losum are characteristic findings (Fig. 21-14). Irregular ring enhancement may be present on imaging studies in AIDS-related PCNSL, making it difficult to distinguish lymphoma from toxo-plasmosis and other opportunistic infections.12

Cerebrospinal fluid cytologic examination and an ophthalmo-logic evaluation that includes a slit-lamp examination are also performed. A spinal MRI is obtained only if parenchymal spinal cord involvement is suspected.77 Because systemic involvement at the time of diagnosis (or relapse) is extremely rare, extensive testing for occult systemic lymphoma is not warranted. However, CNS metastases are common in AIDS patients with systemic non-Hodgkin lymphoma. Thus, a systemic staging evaluation is recommended for AIDS patients with a suspected PCNSL.

FIGURE 21-14 • Magneticresonanceimagingscanofprimarycentralnervoussystemlymphomabefore(A)andafter(B)sixcyclesofmethotrexate-basedchemotherapyandwhole-brainradiationtherapy.


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median survival was 14 months, but this still compared favorably with a median survival of only 7 months after WBRT alone for older patients.82 Delayed neurotoxicity was reported in 12% of patients, indicating that aggressive chemotherapy itself could induce the late changes.

OutcomeHistorically, survival times from the onset of symptoms to

death with no treatment or with surgical resection alone ranged from 0.9 to 4.6 months. The median survival for WBRT alone varies from 12 to 18 months, and only 3% to 4% of patients survive for 5 years. Median survival times for treatment programs that include high-dose MTX–based chemotherapy range from 33 to 42 months. Age younger than 60 and good performance status are favorable prognostic indicators. Molecular markers are being studied as a prognostic factor for PCNSL.76

UNCOMMON ADULT PRIMARY BRAIN TUMORS

Brainstem GliomaBrainstem gliomas account for less than 2% of brain tumors

in adults.4 In series of brainstem gliomas that include patients of all ages, adults constitute approximately one third of those reported. Radiation therapy alone by conventional fractionation to 54 Gy in symptomatic or large brainstem lesions remains the current standard of care. Overall, radiotherapy induces neuro-logic improvement, allows reduction or discontinuation of ster-oids, and is associated with radiologic response.83 The clinical response (85%) seems to be higher than the radiologic response (approximately 50%). No correlation has been shown between clinical and radiologic response. A survival benefit for radiologic responders has not been shown.

There are no prospective trials that have specifically addressed adult brainstem gliomas alone. As a result, the prognostic covari-ates identified in children may not necessarily be significant in the adult population. Shrieve and associates84 have reported 41 pediatric and 19 adult patients who received 66 to 78 Gy with a hyperfractionation schedule of 1.0 Gy twice daily. The median survival time and 1- and 2-year survival rates for children were 16 months and 63% and 32%, respectively, compared with 44 months and 68% and 53% for adults. The 2-year survival for patients with thalamic and midbrain tumors (40%) was similar to that of patients with tumors arising in the pons or medulla (57%, P = NS). Furthermore, the 2-year survival (54%) of patients with diffuse tumors was the same as that of patients with focal tumors (50%). In an update of that series, the median sur-vival of 42 adult patients was 16 months, and the median time to progression was 11.4 months.85

So far no adjuvant treatment has shown any benefit over con-ventional radiation therapy alone for brainstem gliomas. The use of chemotherapy either before or after radiation has not shown any survival advantage.83 Concomitant chemotherapy and radio-therapy has been investigated in multiple pediatric trials and did not seem to confer a survival benefit.

EpendymomaEpendymomas account for 2% of all intracranial tumors in

adults.86 Although they are most common in children, approxi-mately one third occur in adults. The incidence peaks at 5 years and again at 34 years of age. Between 30% and 40% of ependy-momas arise in the supratentorial brain, and 40% to 60% of tumors in this location occur in adults. The remaining 60% to

dose response over 40 Gy. For patients with primary leptomenin-geal lymphoma, the craniospinal axis is generally treated to 36 Gy, and areas of grossly identifiable tumor are given an addi-tional 9 to 14.4 Gy.

When ocular lymphoma is present at the time of diagnosis of cerebral lymphoma, the eyes are treated to 36 Gy concurrently with the brain. A similar dose is used if an ocular recurrence develops in a patient who has had previous cranial irradiation.77 Radiation therapy improves visual acuity in up to 75% of patients with symptomatic ocular lymphoma, unless extensive retinal damage has already occurred.77 The treatment of isolated ocular lymphoma is controversial. Although some advocate treatment with ocular radiotherapy and WBRT, most prefer administering only ocular radiotherapy because of the potential toxicity of WBRT.

Additional data regarding the dose of radiotherapy came from recent studies that have combined chemotherapy with WBRT. In two sequential studies, Bessell and colleagues80 studied the effect of a reduced dose of radiotherapy in patients with PCNSL after achieving a complete response (CR) with chemotherapy. After chemotherapy, patients from their initial study received 45 Gy WBRT. In the second study, the radiotherapy dose was reduced to 30.6 Gy in 26 patients who had a CR after chemotherapy. Among 25 patients younger than 60 years who achieved a CR after chemotherapy, the 3-year relapse risk was higher in the group that received the lower dose of radiotherapy (25% versus 83%). In addition, RT dose was also the only predictor of overall survival in this group (92% versus 60%). The RTOG study 93-10 was modified midway during the trial (because of the risk of neurotoxicity) so that patients who achieved CR after chemo-therapy would receive 36 Gy hyperfractionated RT instead of 45 Gy standard WBRT. There was no difference in PFS, overall survival, or late neurotoxicity between the two groups.81

ChemotherapySeveral reports have documented improved survival when

chemotherapy is added to radiation therapy.74,75,79 Lipophilic agents, such as methotrexate (MTX) and cytarabine, are used most frequently. High-dose, MTX-based regimens followed by WBRT has been shown in multiple phase II trials to increase survival (medians from 32-60 mo) compared with radiotherapy alone.74 Although high-dose MTX is an established chemother-apy agent for PCNSL, the optimal dose and the best combination regimen remain unclear. The RTOG 9310 protocol consisted of high-dose MTX (2.5 g/m2), PCV, procarbazine, and intrathecal (IT) MTX followed by 45 Gy WBRT and high-dose cytarabine. Of these patients, 58% achieved a CR and 36% had a PR after preirradiation chemotherapy. PFS was 24 months and overall survival was 37 months.80

Of concern in the PCNSL trials was the observation of demen-tia and ataxia among 27% of patients older than age 50 who achieved a CR. These findings were not seen in younger patients.77 In the RTOG 9310 study, there was no prospective neuropsycho-logic testing, and the 15% incidence of neurotoxicity reported was a minimum. This has led to the policy of deferring radio-therapy in selected older patients who respond to chemotherapy until the time of disease progression. Others are exploring regi-mens in which radiotherapy is withheld until recurrence to avoid radiation-induced neurotoxicity. EORTC reported a multicenter phase II study in patients older than 60 years treated with chemo-therapy alone as initial treatment. The protocol consisted of high-dose MTX (1 g/m2), CCNU, procarbazine, methylprednisolone, IT MTX, and IT cytarabine. Only 42% achieved a CR. Overall


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MedulloblastomaApproximately 30% of patients with medulloblastoma are 16

years of age or older (median 22-28 years) when first diagnosed.89 In adults, medulloblastomas more frequently arise laterally in the cerebellar hemispheres or cerebellopontine angle (38%-67%) than in children (7%-9%). Thus, adults commonly present with lateral cerebellar dysfunction. The desmoplastic histopathologic variant of medulloblastoma is more common in adults (25%-47%) than in children (13%-18%). On microscopic examination, thick bundles of collagen are found to divide the tumor into fol-licular nests of anaplastic cells. These changes have been thought to result from extension of the tumor to the leptomeninges, which incites a proliferation of fibrous connective tissue. However, the finding of loss of heterozygosity at chromosome 9q with this histologic subtype suggests that desmoplastic medul-loblastomas may be pathogenetically distinct from their classic counterparts.90 Approximately 30% of adults have disease outside the primary site,89 similar to the rates reported in the pediatric literature.

Radiation therapy to the entire craniospinal axis is essential. The dose to the craniospinal axis is 36 Gy in daily fractions of 1.8 Gy. A boost of 18 Gy is given to the posterior fossa to bring the total to 54 Gy. A 3D-CRT or IMRT approach can be used to deliver the boost to the primary site.

The role of chemotherapy in adult medulloblastomas is not well defined. Spreafico and colleagues retrospectively studied 26 consecutive adults treated for medulloblastoma using intensive chemotherapy pediatric protocols.91 With a median follow-up of 46 months, 5-year disease-free and overall survival rates were 65% and 73%, respectively. However, 87% of the patients devel-oped grade IV hematologic toxicity. Prados and colleagues have found an improvement in survival and time to progression with adjuvant chemotherapy, and they recommend that chemother-apy be given to poor-risk patients.89

The prognostic factors for adult medulloblastomas include M stage, functional status at the time of radiotherapy, and extent of surgical resection.90 The T stage has less prognostic value in adults than in children,92 and tumor location and desmoplastic histo-logic appearance do not affect the prognosis. A recent histologic analysis of a large series of 181 medulloblastoma patients revealed a lower labeling index and higher apoptotic index in adults, indi-cating a biologic difference between the two age groups, thus potentially raising the question of less aggressive therapy for adult medulloblastoma.93

A retrospective review of literature suggests a 5-year survival rate range from 46% to 81%; 10-year rates vary from 38% to 55%, comparable to the rates reported in children.89,90 Brandes and colleagues have reported the results a multicentric phase II trial on 26 patients to study the value of prognostic factors and the outcome of medulloblastoma in adults. In low-risk patients, treatment consisted of 36 Gy to the craniospinal axis, supple-mented by a local tumor dose of 18.8 Gy. In high-risk patients, two cycles of up-front chemotherapy were delivered before the same radiation therapy, followed by maintenance chemotherapy if metastatic disease was present. Over a 12-year period, 36 evalu-able patients were enrolled. PFS at 5 years was higher in low-risk patients compared with the high-risk group: 76% versus 61%. Patients with M-negative disease showed a significantly better outcome than M-positive patients, with 75% showing PFS at 5 years versus 45%. They concluded that the overall PFS observed was comparable to that obtained in the pediatric series and sug-gested that a more effective therapy must be developed for high-risk patients.94

70% of ependymomas arise in the infratentorial brain, and 25% of these occur in adults.

Although the correlation between survival and histopathologic grade is controversial, histopathologic grade is a useful predictor of outcome.87 Ependymomas are separated into low-grade and high-grade lesions (grades II and III in the new WHO classifica-tion). The 5-year survival for low-grade tumors ranges from 60% to 80%, whereas it varies from 10% to 47% for high-grade tumors. Supratentorial ependymomas generally have a poorer prognosis than their infratentorial counterparts because of a greater proportion of lesions that are high-grade87 and the ten-dency for larger volumes of residual disease to be present after surgical resection.

Many ependymomas cannot be completely excised because of their location and growth characteristics.87 Postoperative irradia-tion improves local tumor control and survival and is an accepted part of the standard treatment for these tumors. Although most ependymomas are slow-growing, circumscribed tumors that seldom spread, others are more aggressive and may disseminate throughout the cerebrospinal fluid pathways. The frequency of tumor seeding, the identification of patients who are at high risk for dissemination, and the volume of the CNS to treat have been controversial topics in the past. A literature review found that local relapse had the greatest effect on the development of spinal seeding, regardless of tumor grade or site.87 The incidence of spinal dissemination was 3.3% in locally controlled patients and 9.5% in those with uncontrolled primary tumors. The risk of seeding was not affected by prophylactic spinal irradiation.

The outcome with partial-brain irradiation appears to be com-parable to that of WBRT or craniospinal axis irradiation. As a result, low-grade ependymomas are treated using a PTV of 2 cm beyond the MRI-defined lesion to a dose of 54 Gy. The dose is modified if there is extension below the foramen magnum. The craniospinal axis is treated to 36 Gy when the spinal fluid con-tains malignant cells or when there is radiographic evidence of seeding.

The treatment of anaplastic ependymomas has remained con-troversial. Despite the apparent superiority of craniospinal irra-diation in some series, the finding that spinal seeding is uncommon in the absence of local relapse, and the identification of similar patterns of failure in patients treated with local fields or to the craniospinal axis have led most investigators to question the routine use of craniospinal irradiation, WBRT, or even entire posterior fossa irradiation.87 Currently, at New York University we treat high-grade ependymomas with local fields using a PTV of 2 to 3 cm beyond the MRI-defined lesion to a dose of 59.4 Gy. The value of chemotherapy in adults with ependymomas and anaplastic ependymomas is not well defined.4

There are no prospective trials that have specifically addressed adult ependymoma. Metellus and colleagues have reported the results of the largest multi-institutional analysis of intracranial ependymomas in 152 adult patients diagnosed in 24 French neu-rosurgical university hospital centers from 1990 through 2004. The 5- and 10-year overall survival rates were 84.8% and 76.5%, respectively. The 5- and 10-year PFS rates were 63.5% and 52.8%, respectively. On multivariate analysis, overall survival rates were associated with histologic grade, extent of surgery, patient age, and KPS. The multivariate analysis also revealed that the risk of recurrence was associated with high histologic grade, incomplete resection and a KPS score of 80 or less. The effect of radiotherapy was found to be beneficial for incompletely resected low-grade ependymomas, and to a lesser extent for completely removed high-grade tumors.88


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Although the clinical history combined with the results of MRI establish the diagnosis of brain metastasis with reasonable cer-tainty, a definitive diagnosis of metastatic brain tumor cannot be made on scan results alone. Even a typical radiographically defined lesion may prove to be a primary tumor, an abscess, or another lesion.98 A known systemic cancer increases the likeli-hood of brain metastases, and multiple lesions make the diagno-sis even more likely. However, if doubt exists, a biopsy is required to establish the correct diagnosis.

GroupingAlthough no generally accepted grouping system exists for

brain metastases, one was proposed by investigators from the RTOG based on a RPA of prognostic factors.99 Three groups were defined by KPS (<70 versus ≥70), age (<65 versus ≥65), status of the primary tumor (controlled versus uncontrolled), and extent of metastases (brain only versus brain and other sites). The defi-nitions and corresponding survival rates for each group are shown in Table 21-4. The application of this scheme is important to ensure that new treatment techniques for brain metastases are tested in homogeneous patient groups.

Standard Treatment ApproachesBecause the majority of patients with metastatic brain lesions

have or will soon develop widely disseminated disease, treatment is dictated by the need to achieve immediate short-term palliation and the desire for durable, symptom-free remission. With early diagnosis and vigorous treatment, many of the symptoms associ-ated with brain metastases can be reversed, often returning the patients to a useful life, at least temporarily. The median survival of patients with symptomatic brain metastases is approximately 1 month without treatment and 2 months with corticosteroid administration. Survival is longer and the quality of life better if brain metastases are treated.95

CorticosteroidsCorticosteroids rapidly ameliorate many symptoms of brain

metastasis and should be used at the onset for all symptomatic

BRAIN METASTASES

Epidemiologic StatisticsMetastases to the brain occur in as many as 30% of patients

with systemic cancer and outnumber primary brain tumors by 8 : 1. In the United states, approximately 170,000 cancer patients are expected to develop brain metastases every year.95 Brain metastases exert a profound effect on the quality and length of survival, and despite the best current management, they repre-sent the direct cause of death in one third to one half of affected patients.96 Although brain metastases can arise from any primary cancer, certain tumors such as melanoma and carcinomas of the lung (especially small cell and adenocarcinoma), breast, and kidney have a propensity to metastasize to the brain.95 Approxi-mately one half of patients present with only a single lesion, and an additional 20% have only two. Most brain metastases, particu-larly those that arise from primary sites other than the lung, occur at a late stage when metastatic dissemination is present elsewhere in the body.

AnatomyBrain metastases arise from hematogenous spread to the white

matter of the watershed area of the brain at the junction of the gray and white matter. Most metastatic tumors distribute them-selves between the supratentorial and infratentorial compart-ments in proportion to the relative weight and blood supply of these structures; that is, 85% in the cerebral hemispheres, 10% to 15% in the cerebellum, and 1% to 3% in the brainstem.97 Certain metastatic tumors, particularly small cell lung cancer and tumors arising in the prostate, uterus, or gastrointestinal tract, have a predilection to the cerebellum.

Most brain metastases grow as spherical, well-demarcated, solid masses that displace rather than destroy adjacent tissue. They may be surrounded by minimal to extensive edema. Some rapidly growing metastases undergo central necrosis or cystic change, and others, especially those from melanoma, choriocar-cinoma, and testicular carcinoma, may be hemorrhagic. Carcino-matous meningitis is a clinical syndrome caused by widespread invasion of the cerebral cortex by small or microscopic foci of tumor that may or may not be seen on imaging studies.95

Pathologic ConditionsThe microscopic appearance of a brain metastasis resembles

the primary tumor from which it arises. Thus, in patients with an unknown primary cancer, extirpation of the metastasis with microscopic examination often provides an important clue as to the original site of the primary tumor.96

Clinical PresentationThe most common presenting signs and symptoms are sum-

marized in Table 21-2. They usually begin insidiously and evolve over a period of days or a few weeks. The spread of edema through the white matter frequently determines the speed of onset and progression of signs and symptoms.95 Hemorrhage into a tumor may cause a more sudden onset or acute worsening of symptoms.

Diagnostic StudiesGadolinium-enhanced MRI is the best diagnostic test for brain

metastases.98 MRI can detect small lesions not seen on CT, par-ticularly in the cerebellum and brainstem. The T2-weighted image reveals an area or areas of hyperintensity in the white matter, encompassing both the tumor and surrounding edema.

Table 21-4 StagingSystemforBrainMetastasesBasedonRecursivePartitioningAnalysisofPrognosticFactors

StageCharacteristics MedianSurvival

I KPS≥70,primarycontrolled,age<65y,metastasistobrainonly

7.1

II KPS≥70,primaryuncontrolled 4.2

KPS≥70,primaryuncontrolled,age≥65y

KPS≥70,primaryuncontrolled,age<65y

KPS≥70,primaryuncontrolled,age<65y,metastasistoBrainandothersites

III KPS<70 2.3

KPS,Kamofskyperformancestatus.

DatafromGasperL,ScottC,RotmanM,etal:Recursivepartitioninganalysis(RPA)ofprognosticfactorsinthreeRadiationTherapyOncol-ogyGroup(RTOG)brainmetastasistrials,IntJRadiatOncolBiolPhys37:745,1997.


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The standard approach is to treat the whole brain to 30 to 37.5 Gy in 10 to 15 daily fractions of 2.5 to 3 Gy each over 2 weeks.103 The advantages of WBRT include simple clinical set-up, its ease of delivery on an outpatient basis, its low cost, its minimal disrup-tion of quality of life, and its good palliation as a single modality. Depending on the symptom, the RR varies from 70% to 90%. Overall, neurologic function is improved in 50% of patients. Functional improvement depends on the degree of neurologic impairment at the time of treatment. Approximately two thirds of patients with severe neurologic dysfunction improve, whereas one third of those with moderate dysfunction improve to normal or near normal. The median time to improvement is 1 to 2 weeks in patients with severe dysfunction and 3 weeks for those with moderate impairment. The durability of response is problematic, as the median time to progression is only 2 to 3 months. Overall, 75% to 80% of remaining life is spent in an improved or stable neurologic state.103

RTOG has tried five schedules of fractionation varying from 2000 cGy in a week to 4000 cGy in 4 weeks in three randomized trials. All the regimens were similar in improvement in neurologic function (50%), duration of improvement (9-12 wk), time to progression (10 wk), survival (15-18 wk), or the quality of palliation.103 RTOG trials using accelerated fractionation (54.4 Gy in twice-daily 1.6-Gy fractions) or radiosensitizers (misonidazole/BrdU) did not improve the outcome (XX). Rapid dose schedules such as 10 Gy in one fraction or 15 Gy in two fractions have yielded a shorter duration of improvement, a lower RR, and earlier relapse. In addition, high-dose fractions often lead to severe acute side effects and in some cases cerebral hernia-tion and death. A minority of patients, perhaps only 10% to 20%, who have been treated with 30 Gy in 10 fractions to the whole brain and who survive for longer than 1 year develop radiation-induced dementia. In a series by DeAngelis and colleagues,104 12 patients treated with WBRT to a dose of 25 to 39 Gy in 3 to 6 Gy per fraction, with or without surgery, developed late toxicity. All these patients had no evidence of disease by CT or at the time of surgery. All these patients had severe dementia, ataxia, and incon-tinence 5 to 36 months (median 14 months) after therapy. CT scan revealed evidence of cortical atrophy, ventricular dilatation, and hypodensity of white matter. Thus, for patients who have favorable characteristics and are expected to have a good prog-nosis (such as RTOG class I), either delaying WBRT by pursuing alternative options or using a smaller dose per fraction is recommended.

Most series report no survival differences by tumor type except for melanoma. Studies indicate that patients harboring metas-tases from breast and lung carcinoma are likely to respond to radiotherapy both clinically and by scan, and those who respond are unlikely to die of their metastatic brain tumor. Patients with melanoma and colon cancer are less likely to have a radiographic response even when there is a clinical response, and they are more likely to die of their metastatic brain tumor than of systemic disease.105 However, occasional responses by these patients to irradiation, documented by CT or MRI, make treatment of all patients desirable.

The outcome of three randomized trials comparing surgery and radiotherapy to WBRT alone is summarized in Fig. 21-15.106-110 In the study by Patchell and associates,100 the recurrence rate was 20% in the surgery group and 52% in the radiation-only group (P < 0.02), and the median time to recur-rence was more than 59 weeks for combined treatment and 21 weeks for radiation alone (P < 0.0001). The median duration of functional independence, defined as KPS of 70 or more, was 38

patients. Symptomatic but stable patients can begin with approx-imately 16 mg of dexamethasone (or equivalent) daily in two to four divided doses. Patients who are receiving WBRT should receive steroids for at least 48 hours before treatment. Steroid tapering may begin during week 2 of radiotherapy. For patients receiving 16 mg of dexamethasone, the drug should be tapered by 2 to 4 mg every fifth day. If the patient develops symptoms of either brain tumor or steroid withdrawal, the dosage is increased to the next level for 4 to 8 days before the taper is started again. If symptoms return after drug withdrawal, the full dexametha-sone regimen is restarted.95 An alternative approach is to begin at 16 mg per day for 4 days followed by 8 mg for 4 days and 4 mg per day until the completion of treatment.

SurgerySurgery is used to establish the diagnosis of metastatic brain

disease when it is uncertain and as a treatment for single metas-tases. When the brain metastasis is resectable with a minimal risk of neurologic injury, surgical extirpation may provide local tumor control and immediate relief of neurologic signs and symptoms caused by a mass effect. Patients with a single acces-sible lesion, controlled or absent extracranial disease, a KPS of at least 70, age younger than 60, and a life expectancy of at least 2 months are most likely to benefit from surgery.100 Such patients live longer, have fewer recurrences of cancer in the brain, and enjoy a better quality of life compared with those treated by radiotherapy alone. After tumor removal, steroids can usually be discontinued, whereas it is more difficult to discontinue steroids after radiotherapy because residual tumor often remains as a nidus for continuing brain edema. However, only approximately 10% of patients in general are ideal candidates for surgical extir-pation. Rates of complete resection vary from 70% to 79%, whereas the operative mortality is 1% to 2%, and 5% to 10% of patients develop worsening of neurologic deficits.100 The outcome after surgery varies with the primary tumor type. Renal cell, lung, and breast carcinomas carry a better prognosis (median survival 11-12 months), whereas melanoma and colorectal cancers have a worse outcome (6.5-8 months).

Although surgery is usually not the approach of choice for patients with multiple metastases, the presence of multiple brain metastases does not always constitute a contraindication to surgery. A patient with two accessible lesions that cannot be controlled by radiotherapy or chemotherapy (not lymphoma and leukemia, small cell lung cancer, or germ cell tumor) may be treated surgically.101 Furthermore, patients with a large metastatic lesion causing uncontrollable neurologic symptoms may be can-didates for resection, even if multiple brain metastases are present, before irradiation of the smaller lesions.

Approximately 5% to 20% of patients with brain metastases present with an unknown primary tumor.102 Most metastases arise from lung or renal cell carcinoma and melanoma. When a patient without known cancer presents with brain metastases, a search for the primary tumor should ensue before treatment of the metastatic brain disease is begun. If no other lesion is found and if the brain lesion is single and surgically accessible, extirpa-tion is indicated to establish the diagnosis and for therapy. If multiple lesions are present or if a single lesion is surgically inac-cessible, a stereotactic needle biopsy is warranted.

Whole-Brain Radiation TherapyRadiotherapy is the appropriate treatment for most patients

with brain metastases, including those with multiple lesions and those with single metastases who are not candidates for surgery.


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makes it an ideal target; the site at the junction of gray and white matter, which is a relatively noneloquent location permitting the delivery of single large doses; increased use of MRI, in which most lesions are detected while still relatively small (<3 cm); the pseu-docapsule of the lesions, which allows tight margins; and the hypothesis that better local control may improve the survival in these patients.

Several reports support the use of radiosurgery in the initial treatment of patients with one or two favorable brain metastases or in those who relapse after WBRT. Local control to complete radiologic response is noted in 80% to 90% of the cases, with a median survival of 9 months.112 These survival results are com-parable to those observed for surgical resection. There has never been a randomized trial comparing SRS with surgical resection. A multi-institutional retrospective data of SRS for solitary metas-tasis that comes closest to addressing this issue was reported by Auchter and colleagues.113 A total of 122 patients with solitary brain metastasis were treated to a 37.5-Gy median dose WBRT with SRS boost to 15 to 24 Gy. With a 123-week follow-up, the local control was 86%. The infield recurrence rate was 14% and the intracranial recurrence outside SRS volume was 22%. The median overall and functionally independent survival rates were 56 and 44 weeks respectively, indicating that the SRS is at least equivalent if not superior to surgical resection.

There have been many randomized trials that have tried to address the benefit of SRS when given in addition to WBRT. Kondziolka and colleagues108 reported a small randomized trial of 27 patients with two to four metastases to WBRT with or without SRS. The median time to local failure was 6 versus 36 months, and the median survival was significantly better with the addition of SRS boost (7.5 versus 11 months).112 The local failure decreased from 100% to 8% at 1 year with SRS. Chougle and colleagues did not report survival benefit in any of the three arms treated with SRS, WBRT, and WBRT and SRS. However, this study is difficult to interpret because the arms were not bal-anced.109 In the RTOG 9508 trial, 333 patients with 1 to 3 metas-tases were randomized to 37.5-Gy WBRT with or without SRS boost.103 A survival benefit was noted in RPA class I, solitary

weeks for combined treatment and 8 weeks for radiation alone (P < 0.005). Noordijk and colleagues found that the median survival of patients with inactive extracranial disease was 12 months for combined treatment and 7 months for radiotherapy alone (P = 0.02).111 In contrast, there was no benefit from com-bined treatment in patients with active extracranial disease or in those older than 60 years (median survival 5 months in both groups). However, Mintz and colleagues did not report a benefit in either survival or the quality of life with the addition of surgery in patients who received WBRT.110

WBRT is generally recommended after surgical resection of metastatic tumors. There is good evidence that suggests that post-operative irradiation decreases relapse both at the site of surgical removal and elsewhere in the brain.100 Patchell and colleagues randomized 95 patients with solitary metastasis to surgery with or without 50.4 Gy WBRT. They noted a benefit of WBRT in terms of decreased recurrence at the site of original disease (10% versus 46%), recurrence at other sites in brain (14% versus 37%), recurrence anywhere in the brain (18% versus 70%), and death resulting from neurologic causes (14% versus 44%). However, the overall survival (48 weeks) and functionally independent sur-vival (36 weeks) were the same in both the arms.100 Hence, a protracted radiotherapy course could be considered in favorable-prognosis patients because shorter treatment courses do not appear to prevent recurrence and may increase toxicity.

Patients who initially respond to irradiation and subsequently relapse may be candidates for reirradiation. A dose of 19.8 to 25.2 Gy in 1.8-Gy fractions is used. Although the RR (40%) is lower than after initial irradiation, some patients do benefit from another course of treatment. Patients who have had a good clini-cal and radiographic response to radiotherapy and who survive 6 months after the initial treatment are the best candidates for reirradiation.

Stereotactic RadiosurgerySRS is an excellent alternative to surgery for patients with

limited brain metastases. The rationale for SRS in brain metas-tases includes the pseudospherical shape of the lesion, which

StudyNo. of brainmetastases Treatment

No. ofpatients

Mediansurvival

Functionalindependence

SurgeryPatchell et al., 1990101

Vecht et al., 1993107

Mintz et al., 1996111

SRSKondziolka et al., 1999109

Chougule et al., 2000110

Andrews et al., 2004104

1

1

1

2-4

≤3

1-3

2523

3231

4143

1314

363731

333

Surgery + WBRT 36 Gy vWBRT 36 Gy



SRS + WBRT 30 Gy vWBRT 30 Gy

GK 30 Gy vGK 20 Gy + WBRT 30 Gy vWBRT 30 GySRS + WBRT 37.5 Gy vWBRT 37.5 Gy

40 weeks15 weeksP < .01

7 months5 months9 months6.5 months5.7 monthsP = .13‡

Not reported

Not reported

Not reported

38 weeks*8 weeksP < .0057.5 months†

3.5 monthsP = .06No effect*P = .98

5.6 months6.3 monthsP = .24

10 months6 months P = .04

11 months7.5 monthsP = .22

FIGURE 21-15 • Randomizedstudiesofsurgery/stereotacticradiosurgeryversuswhole-brainradiationtherapy.


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ence in neurologic response or overall survival was noted in the two arms. Use of experimental radiosensitizing agents like motex-afin gadolinium or efaproxiral in phase III trials has not shown a benefit in overall survival.118 Inhibitors of the EGFR-associated tyrosine kinase like gefitinib (ZD1839) have shown responses in patients who had received previous WBRT, and is being explored in ongoing clinical trials.95

CONCLUSION

During the preceding decade, there have been significant strides made in the imaging, neurosurgical techniques, radiation delivery systems, and systemic therapy in the management of adult brain tumors. The treatment results have started improv-ing, even in tumors like glioblastoma. It is clear that the results of conventional treatment alone with surgery, radiation, and chemotherapy will not dramatically alter the outcome. A better understanding of molecular events in the development of brain tumors has resulted in the use of targeted biologic agents in clini-cal trials presently under way. Quality-of-life issues in the man-agement of brain tumors are being recognized. Therapy is being customized because selective patients do benefit from aggressive treatment. Therefore, participation in properly conducted clini-cal studies remains the most optimal approach for the treatment of patients with brain tumors.

AcknowledgmentsThe authors gratefully acknowledge the assistance of Dr.

David Zagzag of the New York University Medical Center for contributing the pathology photomicrographs used in this chapter Saroj Kunakkat and Dr. Shahzad Raza for their careful review and editing of this work.

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metastasis, and non-small cell lung cancer patients. Local control at 1 year was 71% with WBRT compared with 82% with the addition of SRS boost. Improved KPS was also noted with the addition of SRS boost (27% versus 43%) at 6 months.

There is suggestion that treatment outcome may not be com-promised by omitting immediate WBRT in patients treated with SRS for limited brain metastasis. A retrospective data by Sneed on 105 patients, of which 62 were treated with SRS alone, showed an overall survival of 11-month and 1-year PFS of 75%.114 Although the brain PFS was lower (28% versus 69%) with the omission of upfront WBRT, with salvage it was the same (62% versus 73%), indicating that it could be an option for patients with one to two metastases. A word of caution comes from Regine and colleagues, who note that 70% of patients were symp-tomatic at the time of recurrence and 60% had neurologic defi-cits, and recommend that adjuvant WBRT should be considered a mainstay of treatment in brain metastases.115

There are two randomized trials that have looked at stereotac-tic radiosurgery plus WBRT versus SRS alone for treatment of brain metastases. Aoyami and colleagues116 have reported the results of a Japanese randomized trial in 132 patients with one to four brain metastases. The primary end-point of this study was overall survival. The median survival time was similar in both arms (7.5 and 8.0 months). The 1-year brain tumor recurrence rate was 46.8% in the WBRT-with-SRS group, and 76.4% for the SRS-alone group. Salvage brain treatment was less frequently required in the WBRT-with-SRS group than with SRS alone. Death was attributed to neurologic causes in 22.8% of patients in the WBRT-with-SRS group and in 19.3% of those treated with SRS alone. However, there were no significant differences in sys-temic and neurologic functional preservation and toxic effects of radiation between the arms. The American College of Surgery Oncology Group is conducting a randomized phase III trial of radiosurgery with or without WBRT.

Based on such data, we recommend SRS only for one to two metastases, with WBRT reserved for tumor recurrence or for new brain tumors when the patients have poor performance status and progressive systemic disease. We recommend repeating SRS for good-performance-status patients. For those with three to four metastases, we recommend WBRT along with planned SRS boost. WBRT alone is recommended for patients with progres-sive systemic disease, poor performance status, and for four or more lesions.

ChemotherapyThe role of chemotherapy has traditionally been minimal in

the treatment of brain metastases. This has been the result of short survival and poor performance status associated with symptomatic brain metastases as well as the assumption that an intact blood-brain barrier would limit the delivery of large and hydrophilic drugs to the site of brain lesions. However, during the last few years, several phase II studies have illustrated the activity of chemotherapy in the treatment of brain metastases. Temozolomide has shown the maximum activity among the agents that have been studied. In a large phase II trial reported by Antonadou,117 patients were assigned to receive temozolomide (75 mg/m2) plus WBRT (10 fractions of 3 Gy each) or WBRT alone. In addition, patients in the combined-therapy group con-tinued to receive temozolomide (200 mg/m2 days 1 through 5 every 4 weeks for six cycles) beginning 1 month after completing WBRT. The group receiving WBRT plus temozolomide experi-enced a significant improvement in RR compared with those receiving WBRT alone (53% versus 33%). However, no differ-


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