Glioblastoma Multiforme - Uphill Battle

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eMedicine Specialties > Oncology > Carcinomas of the Central and Peripheral Nervous System

Glioblastoma Multiforme Jeffrey N Bruce, MD, Edgar M Housepian Professor of Neurological Surgery Research, Professor of Neurological Surgery, Director of Brain Tumor Tissue Bank, Director of Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Columbia University College of Physicians and Surgeons Benjamin Kennedy,, Columbia University College of Physicians and Surgeons

Updated: Nov 5, 2009

Introduction

Background

Glioblastoma multiforme (GBM) is by far the most common and most malignant of the glial tumors. Attention was recently drawn to this form of brain cancer when Senator Ted Kennedy was diagnosed with glioblastoma and ultimately died from it. Senator Kennedy's illness is described on Medscape.

Of the estimated 17,000 primary brain tumors diagnosed in the United States each year, approximately 60% are gliomas. Gliomas comprise a heterogeneous group of neoplasms that differ in location within the central nervous system, in age and sex distribution, in growth potential, in extent of invasiveness, in morphological features, in tendency for progression, and in response to treatments.

A T1-weighted axial MRI without intravenous contrast. This image demonstrates a hemorrhagic

multicentric tumor (glioblastoma multiforme [GBM]) in the right temporal lobe. Effacement of

the ventricular system is present on the right, and mild impingement of the right medial

temporal lobe can be observed on the midbrain.

Page 1 of 41Glioblastoma Multiforme: [Print] - eMedicine Oncology

21-12-2010http://emedicine.medscape.com/article/283252-print

A T1-weighted sagittal MRI with intravenous contrast in a patient with glioblastoma multiforme

(GBM).

Composed of a heterogenous mixture of poorly differentiated neoplastic astrocytes, glioblastomas primarily affect adults, and they are located preferentially in the cerebral hemispheres. Much less commonly, glioblastoma multiforme can affect the brainstem (especially in children) and the spinal cord. These tumors may develop from lower-grade astrocytomas (World Health Organization [WHO] grade II) or anaplastic astrocytomas (WHO grade III), but, more frequently, they manifest de novo, without any evidence of a less malignant precursor lesion. The treatment of glioblastomas is palliative and includes surgery, radiotherapy, and chemotherapy.[1,2,3 ]

Pathophysiology

Glioblastomas can be classified as primary or secondary. Primary glioblastoma multiforme accounts for the vast majority of cases (60%) in adults older than 50 years. These tumors manifest de novo (ie, without clinical or histopathologic evidence of a preexisting, less-malignant precursor lesion), presenting after a short clinical history, usually less than 3 months.

Secondary glioblastoma multiformes (40%) typically develop in younger patients (<45 y) through malignant progression from a low-grade astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time required for this progression varies considerably, ranging from less than 1 year to more than 10 years, with a mean interval of 4-5 years. Increasing evidence indicates that primary and secondary glioblastomas constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and differ in response to some of the present therapies. Of all the astrocytic neoplasms, glioblastomas contain the greatest number of genetic changes, which, in most cases, result from the accumulation of multiple mutations.

Over the past decade, the concept of different genetic pathways leading to the common phenotypic endpoint (ie, GBM) has gained general acceptance. Genetically, primary and secondary glioblastomas show little overlap and constitute different disease entities. Studies are beginning to assess the prognoses associated with different mutations.[4,5 ]Some of the more common genetic abnormalities are described as follows:

� Loss of heterozygosity (LOH): LOH on chromosome arm 10q is the most frequent gene alteration for both primary and secondary glioblastomas; it occurs in 60-90% of cases. This mutation appears to be specific for glioblastoma multiforme and is found rarely in other tumor grades. This mutation is associated with poor survival. LOH at 10q plus 1 or 2 of the additional gene mutations appear to be frequent alterations and are most likely major players in the development of glioblastomas.



� p53: Mutations in p53, a tumor suppressor gene, were among the first genetic alterations identified in astrocytic brain tumors. The p53 gene appears to be deleted or altered in approximately 25-40% of all glioblastoma multiformes, more commonly in secondary glioblastoma multiformes.[6 ]The p53 immunoreactivity also appears to be associated with tumors that arise in younger patients.[6,7,8,9,10 ]

� Epidermal growth factor receptor (EGFR) gene: The EGFR gene is involved in the control of cell proliferation. Multiple genetic mutations are apparent, including both overexpression of the receptor as well as rearrangements that result in truncated isoforms. However, all the clinically relevant mutations appear to contain the same phenotype leading to increased activity. These tumors typically show a simultaneous loss of chromosome 10 but rarely a concurrent p53 mutation. Overexpression or activation mutations in this gene are more common in primary glioblastoma, with mutations appearing in 40-50% of these tumors. One such common variant, EGFRvIII, has shown promise as a target for kinase inhibitors, immunotoxins, and peptide vaccines.[11,12,13,14,15,16,17 ]

� MDM2: Amplification or overexpression of MDM2 constitutes an alternative mechanism to escape from p53 -regulated control of cell growth by binding to p53 and blunting its activity. Overexpression of MDM2 is the second most common gene mutation in glioblastoma multiformes and is observed in 10-15% of patients. Some studies show that this mutation has been associated with a poor prognosis.[7 ]

� Platelet-derived growth factor–alpha (PDGF-alpha) gene: The PDGF gene acts as a major mitogen for glial cells by binding to the PDGF receptor (PDGFR). Amplification or overexpression of PDGFR is typical (60%) in the pathway leading to secondary glioblastomas.

� PTEN: PTEN (also known as MMAC and TEP1) encodes a tyrosine phosphatase located at band 10q23.3. The function of PTEN as a cellular phosphatase, turning off signaling pathways, is consistent with possible tumor-suppression action. When phosphatase activity is lost because of genetic mutation, signaling pathways can become activated constitutively, resulting in aberrant proliferation. PTEN mutations have been found in as many as 30% of glioblastomas, more commonly in primary glioblastoma multiformes.[14,18,19 ]

Less frequent but more malignant mutations include the following:

� MMAC1-E1 - A gene involved in the progression of gliomas to their most malignant form

� MAGE-E1 - A glioma-specific member of the MAGE family that is expressed at up to 15-fold higher levels in glioblastoma multiformes than in normal astrocytes

� NRP/B - A nuclear-restricted protein/brain, which is expressed in neurons but not in astrocytes (NRP/B mutants are found in glioblastoma cells.)

Additional genetic alterations in primary glioblastomas include p16 deletions (30-40%), p16INK4A, and retinoblastoma (RB) gene protein alterations. Progression of secondary glioblastomas often includes LOH at chromosome arm 19q (50%), RB protein alterations (25%), PTEN mutations (5%), deleted-in-colorectal-carcinoma gene (DCC) gene loss of expression (50%), and LOH at 10q.



Axial CT scan without intravenous contrast. This image reveals a large right temporal intraaxial

mass (glioblastoma multiforme [GBM]). Extensive surrounding edema is present, as

demonstrated by the peritumoral hypodensity, and a moderate right-to-left midline shift can be

noted. Images 2-8 are radiologic studies of the same patient.

Glioblastoma multiformes occur most often in the subcortical white matter of the cerebral hemispheres. In a series of 987 glioblastomas from University Hospital Zurich, the most frequently affected sites were the temporal (31%), parietal (24%), frontal (23%), and occipital (16%) lobes.[20 ]Combined frontotemporal location is particularly typical. Tumor infiltration often extends into the adjacent cortex or the basal ganglia. When a tumor in the frontal cortex spreads across the corpus callosum into the contralateral hemisphere, it creates the appearance of a bilateral symmetric lesion, hence the term butterfly glioma. Sites for glioblastomas that are much less common are the brainstem (which often is found in affected children), the cerebellum, and the spinal cord.

Frequency

United States

Overall incidence is very similar among countries (see International). Glioblastoma multiformes are slightly more common in the United States, Scandinavia, and Israel than in Asia. This may reflect differences in genetics, diagnosis and the healthcare system, and reporting practices.

International

Glioblastoma multiforme is the most frequent primary brain tumor, accounting for approximately 12-15% of all intracranial neoplasms and 50-60% of all astrocytic tumors. In most European and North American countries, incidence is approximately 2-3 new cases per 100,000 people per year.

Mortality/Morbidity

Only modest advancements in the treatment of glioblastoma have occurred in the past 25 years. Although current therapies remain palliative, they have been shown to prolong quality survival. Mean survival is inversely correlated with age, which may reflect exclusion of older patients from clinical trials. Without therapy, patients with glioblastoma multiformes uniformly die within 3 months. Patients treated with optimal therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of approximately 12 months, with fewer than 25% of patients surviving up to 2 years and fewer than 10% of patients surviving up to 5 years. Whether the prognosis of patients with secondary glioblastoma is better than or similar to the prognosis for those patients with primary glioblastoma remains controversial.



Race

Within the United States, glioblastoma multiforme is slightly more common in whites.

Sex

In a review of 1003 glioblastoma biopsies from the University Hospital Zurich,[20 ]males had a slight preponderance over females, with a male-to-female ratio of 3:2.

Age

Glioblastoma multiforme may manifest in persons of any age, but it affects adults preferentially, with a peak incidence at 45-70 years. In the series from University Hospital Zurich (a review of 1003 glioblastoma biopsies), 70% of patients were in this age group, with a mean age of 53 years.[20 ]In a series reported by Dohrman (1976), only 8.8% of glioblastoma multiformes occurred in children.[21 ]

Clinical

History

The clinical history of patients with glioblastoma multiformes (GBMs) usually is short, spanning less than 3 months in more than 50% of patients, unless the neoplasm developed from a lower-grade astrocytoma.

� The most common presentation of patients with glioblastomas is a slowly progressive neurologic deficit, usually motor weakness. However, the most common symptom experienced by patients is headache.

� Alternatively, patients may present with generalized symptoms of increased intracranial pressure (ICP), including headaches, nausea and vomiting, and cognitive impairment.

� Seizures are another common presenting symptom.

Physical

Neurologic symptoms and signs affecting patients with glioblastomas can be either general or focal and reflect the location of the tumor.

� General symptoms include headaches, nausea and vomiting, personality changes, and slowing of cognitive function.

� Headaches can vary in intensity and quality, and they frequently are more severe in the early morning or upon first awakening.

� Changes in personality, mood, mental capacity, and concentration can be early indicators or may be the only abnormalities observed.

� Focal signs include hemiparesis, sensory loss, visual loss, aphasia, and others.

� Seizures are a presenting symptom in approximately 20% of patients with supratentorial brain tumors.

Causes

The etiology of glioblastoma remains unknown in most cases. Familial gliomas account for approximately 5% of malignant gliomas, and less than 1% of gliomas are associated with a known genetic syndrome (eg, neurofibromatosis, Turcot syndrome, or Li-Fraumeni syndrome).[22 ]

Although concerns have been raised regarding cell phone use as a potential risk factor for development of gliomas, study results have been inconsistent, and this possibility remains controversial. The largest studies have not supported cell phone use as a cancer risk factor.[23,24,25,26,27,28 ]However, a recently released multinational report concluded that studies that are independent of the telecom industry show that cell phone use may pose a



significant risk for brain tumors,[29 ]and some European countries have taken steps to limit cell phone use by children. Studies of association with head injury, N-nitroso compounds, occupational hazards, and electromagnetic field exposure have been inconclusive.[23 ]

Differential Diagnoses

Other Problems to Be Considered

Anaplastic astrocytoma Cavernous malformation Cerebral abscess CNS lymphoma Encephalitis Intracranial hemorrhage Metastasis Oligodendroglioma Radiation necrosis Toxoplasmosis

Workup

Laboratory Studies

� Currently, no specific laboratory studies are helpful in making a diagnosis of glioblastoma.

� Response to adjuvant therapy may be predicted based on the tumor's genetics.

Imaging Studies

� Imaging studies of the brain are essential to make the diagnosis of glioblastoma multiforme (GBM).

� On CT scans, glioblastomas usually appear as irregularly shaped hypodense lesions with a peripheral ringlike zone of contrast enhancement and a penumbra of cerebral edema.

�



A T1-weighted axial MRI without intravenous contrast. This image demonstrates a

hemorrhagic multicentric tumor (glioblastoma multiforme [GBM]) in the right temporal

lobe. Effacement of the ventricular system is present on the right, and mild impingement

of the right medial temporal lobe can be observed on the midbrain.

� MRI with and without contrast is the study of choice. These lesions typically have an enhancing ring observed on T1-weighted images and a broad surrounding zone of edema apparent on T2-weighted images. The central hypodense core represents necrosis, the contrast-enhancing ring is composed of highly dense neoplastic cells with abnormal vessels permeable to contrast agents, and the peripheral zone of nonenhancing low attenuation is vasogenic edema containing varying numbers of invasive tumor cells. Several pathological studies have clearly shown that the area of enhancement does not represent the outer tumor border because infiltrating glioma cells can be identified easily within, and occasionally beyond, a 2-cm margin.[30 ]

�



A T1-weighted axial MRI with intravenous contrast. Heterogenous enhancement of the

lesion is present within the right temporal lobe. The hypointensity circumscribed within

the enhancement is suggestive of necrosis. This radiologic appearance is typical of a

multicentric glioblastoma multiforme (GBM).

�

A T1-weighted coronal MRI with intravenous contrast. This image demonstrates the

lesion (glioblastoma multiforme [GBM]) within the medial temporal lobe and the

stereotypical pattern of contrast enhancement.

�



A T1-weighted sagittal MRI with intravenous contrast in a patient with glioblastoma

multiforme (GBM).

�

A T2-weighted axial MRI. The tumor (glioblastoma multiforme [GBM]) and surrounding

white matter within the right temporal lobe show increased signal intensity compared to

a healthy brain, suggesting extensive tumorigenic edema.

�



A fluid-attenuated inversion recovery (FLAIR) axial MRI. This image is similar to the T2-

weighted image and demonstrates extensive edema in a patient with glioblastoma

multiforme (GBM).

�

Histopathologic slide demonstrating a glioblastoma multiforme (GBM).

� Positron emission tomography (PET) scans and magnetic resonance (MR) spectroscopy can be helpful to identify glioblastomas in difficult cases, such as those associated with radiation necrosis or hemorrhage. On PET scans, increased regional glucose metabolism closely correlates with cellularity and reduced survival. MR spectroscopy demonstrates an increase in the choline-to-creatine peak ratio, an increased lactate peak,



and decreased N- acetylaspartate (NAA) peak in areas with glioblastomas.

� Cerebral angiograms are not necessary for the diagnosis or clinical management of glioblastomas.

�

Magnetic resonance (MR) spectroscopy is representative of a glioblastoma multiforme

(GBM).

Other Tests

� Electroencephalography (EEG) performed on a patient with glioblastoma multiforme may show generalized diffuse slowing and/or epileptogenic spikes over the area of the tumor. However, findings specific for glioblastoma cannot be observed on EEG.

Procedures

� Lumbar puncture is generally contraindicated in the setting of a brain tumor because of the possibility of transtentorial herniation with increased intracranial pressure. However, if ruling out lymphoma, it may be necessary.

� CSF studies do not aid significantly in the specific diagnosis of glioblastoma multiforme.

Histologic Findings

As its name suggests, the histopathology of glioblastoma multiforme is extremely variable. Glioblastoma multiformes are composed of poorly differentiated, often pleomorphic astrocytic cells with marked nuclear atypia and brisk mitotic activity. Necrosis is an essential diagnostic feature, and prominent microvascular proliferation is common. Macroscopically, glioblastomas are poorly delineated, with peripheral grayish tumor cells, central



yellowish necrosis from myelin breakdown, and multiple areas of old and recent hemorrhages. Most glioblastomas of the cerebral hemispheres are clearly intraparenchymal with an epicenter in the white matter, but some extend superficially and contact the leptomeninges and dura.[31,32,33,34,35,36,37 ]

Despite the short duration of symptoms, these tumors are often surprisingly large at the time of presentation, occupying much of a cerebral lobe. Undoubtedly, glial fibrillary acidic protein (GFAP) remains the most valuable marker for neoplastic astrocytes. Although immunostaining is variable and tends to decrease with progressive dedifferentiation, many cells remain immunopositive for GFAP even in the most aggressive glioblastomas. Vimentin and fibronectin expression are common but less specific.[38 ]

The regional heterogeneity of glioblastomas is remarkable and makes histopathological diagnosis a serious challenge when it is based solely on stereotactic needle biopsies. Tumor heterogeneity is also likely to play a significant role in explaining the meager success of all treatment modalities, including radiation, chemotherapy, and immunotherapy.


Staging

Completely staging most glioblastomas is neither practical nor possible because these tumors do not have clearly defined margins. Rather, they exhibit well-known tendencies to invade locally and spread along compact white matter pathways, such as the corpus callosum, internal capsule, optic radiation, anterior commissure, fornix, and subependymal regions. Such spread may create the appearance of multiple glioblastomas or multicentric gliomas on imaging studies.

Careful histological analyses have indicated that only 2-7% of glioblastomas are truly multiple independent tumors rather than distant spread from a primary site. Despite its rapid infiltrative growth, the glioblastoma tends not to invade the subarachnoid space and, consequently, rarely metastasizes via cerebrospinal fluid (CSF). Hematogenous spread to extraneural tissues is very rare in patients who have not had previous surgical intervention, and penetration of the dura, venous sinuses, and bone is exceptional.[39,40,41,42,43,44 ]

Treatment



Medical Care

The treatment of glioblastomas remains difficult in that no contemporary treatments are curative. While overall mortality rates remain high, recent work leading to an understanding of the molecular mechanisms and gene mutations combined with clinical trials are leading to more promising and tailored therapeutic approaches. Multiple challenges remain, including tumor heterogeneity, tumor location in a region where it is beyond the reach of local control, and rapid, aggressive tumor relapse. Therefore, the treatment of patients with malignant gliomas still remains palliative and encompasses surgery, radiotherapy, and chemotherapy.

Upon initial diagnosis of glioblastoma multiforme (GBM), standard treatment consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide.[12,14 ]For patients older than 70 years, less aggressive therapy is sometimes employed, using radiation or temozolomide alone.[45,46,47 ]

Stupp et al reported the final results of the randomized phase III trial for patients with glioblastoma who were treated with adjuvant temozolomide and radiation with a median follow-up of more than 5 years. Stupp et al previously reported improved median and 2-year survival when temozolomide was added to radiation therapy in glioblastoma. Survival in the combined therapy group (ie, temozolomide and radiation) continued to exceed that of radiation alone throughout the 5-year follow-up (p<0.0001). Survival of patients who received adjuvant temozolomide with radiotherapy for glioblastoma is superior to radiotherapy alone across all clinical prognostic subgroups.[48 ]

Median time to recurrence after standard therapy is 6.9 months.[49 ] For recurrent glioblastoma multiforme, surgery is appropriate in selected patients, and various radiotherapeutic, chemotherapeutic, biologic, or experimental therapies are also employed.[50,51 ]

� Radiation therapy[52,53,54,55 ]

� Radiation therapy in addition to surgery or surgery combined with chemotherapy has been shown to prolong survival in patients with glioblastoma multiformes compared to surgery alone. The addition of radiotherapy to surgery has been shown to increase survival from 3-4 months to 7-12 months.[49,56 ]

� Dose response relationships for glioblastomas demonstrate that a radiation dose of less than 4500 cGy results in a median survival of 13 weeks compared with a median survival of 42 weeks with a dose of 6000 cGy. This is usually administered 5 days per week in doses of 1.8-2.0 Gy.

� The responsiveness of glioblastoma multiformes to radiotherapy varies. In many instances, radiotherapy can induce a phase of remission, often marked with stability or regression of neurologic deficits as well as diminution in the size of the contrast-enhancing mass. Unfortunately, any period of response is short-lived because the tumor typically recurs within 1 year, resulting in further clinical deterioration and the appearance of an expansile region of contrast enhancement.[57,58 ]

� Two studies investigated tumor recurrence after whole-brain radiation therapy and found that the tumor recurred within 2 cm of the original site in 90% and 78% of patients, supporting the use of focal radiation therapy. Multifocal recurrence occurred in 6% of patients in one study and in 5% of patients in a second trial.

� Interstitial brachytherapy is of limited use and is rarely used. By implantation of radioactive seeds, a large dose of radiation is delivered to the tumor volume, with rapid fall-off of radiation in surrounding tissue. The tumor must be unilateral and smaller than 5 cm in diameter. In one study, patients treated with interstitial brachytherapy had a significantly better median survival (2 mo) compared with the conventional focal external beam radiation therapy. Following interstitial brachytherapy, up to 40% of patients require another surgery for removal of tissue damaged by radiation necrosis.

� Experimental studies are underway in which focal radiation is delivered directly to tumors through an implanted balloon containing interstitial radiation. MRI and MR spectroscopy can be used to monitor therapy. Clinical outcomes from these studies are not yet available.

� Radiosensitizers, such as newer chemotherapeutic agents,[59 ]targeted molecular agents,[60,61 ]and antiangiogenic agents[61 ]may increase the therapeutic effect of radiotherapy.[62 ]



� Radiotherapy for recurrent glioblastoma multiforme is controversial, though some studies have suggested a benefit to stereotactic radiosurgery or fractionated stereotactic reirradiation.[63,64,65 ]

� Chemotherapy – Antineoplastic agents[66,67,68,69,70,71 ]

� Although the optimal chemotherapeutic regimen for glioblastoma is not defined at present, several studies have suggested that more than 25% of patients obtain a significant survival benefit from adjuvant chemotherapy. Meta-analyses have suggested that adjuvant chemotherapy results in a 6-10% increase in 1-year survival rate.[72,73 ]

� Temozolomide is an orally active alkylating agent that is used for persons newly diagnosed with glioblastoma multiforme. It was approved by the United States Food and Drug Administration (FDA) in March 2005. Studies have shown that the drug was well tolerated and provided a survival benefit. Adjuvant and concomitant temozolomide with radiation was associated with significant improvements in median progression-free survival over radiation alone (6.9 vs 5 mo), overall survival (14.6 vs 12.1 mo), and the likelihood of being alive in 2 years (26% vs 10%).

� Nitrosoureas: BCNU (carmustine)-polymer wafers (Gliadel) were approved by the FDA in 2002. Though Gliadel wafers are used by some for initial treatment, they have shown only a modest increase in median survival over placebo (13.8 vs. 11.6 months) in the largest such phase III trial, and are associated with increased rates of CSF leak and increased intracranial pressure secondary to edema and mass effect.[74 ]

� MGMT is a DNA repair enzyme that contributes to temozolomide resistance. Methylation of the MGMT promoter, found in approximately 45% of glioblastoma multiformes, results in an epigenetic silencing of the gene, decreasing the tumor cell's capacity for DNA repair and increasing susceptibility to temozolomide.[75 ]

� When patients with and without MGMT promoter methylation were treated with temozolomide, the groups had median survivals of 21.7 versus 12.7 months, and 2-year survival rates of 46% versus 13.8%, respectively.

� Though temozolomide is currently a first-line agent in the treatment of glioblastoma multiforme, unfavorable MGMT methylation status could help select patients appropriate for future therapeutic investigations.[76 ]

� O6-benzylguanine and other inhibitors of MGMT as well as RNA interference-mediated silencing of MGMT offer promising avenues to increase the effectiveness of temozolomide and other alkylating antineoplastics, and such agents are under active study.[76,77 ]

� Carmustine (BCNU) and cis -platinum (cisplatin) have been the primary chemotherapeutic agents used against malignant gliomas. All agents in use have no greater than a 30-40% response rate, and most fall into the range of 10-20%.

� Data from the University of California at San Francisco indicate that, for the treatment of glioblastomas, surgery followed by radiation therapy leads to 1-, 3-, and 5-year survival rates of 44%, 6%, and 0%, respectively. By comparison, surgery followed by radiation and chemotherapy using nitrosourea-based regimens resulted in 1-, 3-, and 5-year survival rates of 46%, 18%, and 18%, respectively.

� A major hindrance to the use of chemotherapeutic agents for brain tumors is the fact that the blood-brain barrier (BBB) effectively excludes many agents from the CNS. For this reason, novel methods of intracranial drug delivery are being developed to deliver higher concentrations of chemotherapeutic agents to the tumor cells while avoiding the adverse systemic effects of these medications.

� Pressure-driven infusion of chemotherapeutic agents through an intracranial catheter, also known as convection-enhanced delivery (CED), has the advantage of delivering drugs along a pressure gradient rather than by simple diffusion. CED has shown promising results in animal models with agents including BCNU and topotecan.[78,79,80 ]

� Initial attempts investigated the delivery of chemotherapeutic agents via an intraarterial route rather than intravenously. Unfortunately, no survival advantage was observed.



� Chemotherapy for recurrent glioblastoma multiforme provides modest, if any, benefit, and several classes of agents are used. Carmustine wafers increased 6-month survival from 36% to 56% over placebo in one randomized study of 222 patients, though there was a significant association between the treatment group and serious intracranial infections.[81,82 ]

� Genotyping of brain tumors may have applications in stratifying patients for clinical trials of various novel therapies.

� The anti-angiogenic agent bevacizumab was approved by the U.S. Food and Drug Administration for recurrent glioblastoma in May 2009.[83 ]When used with irinotecan, bevacizumab improved 6-month survival in recurrent glioma patients to 46% compared with 21% in patients treated with temozolomide.[84,85 ]This bevacizumab and irinotecan combination for recurrent glioblastoma multiforme has been shown to improve survival over bevacizumab alone.[86 ]Anti-angiogenic agents also decrease peritumoral edema, potentially reducing the necessary corticosteroid dose.

� A small proportion of glioblastomas responds to gefitinib or erlotinib (tyrosine kinase inhibitors). The simultaneous presence in glioblastoma cells of mutant EGFR (EGFRviii) and PTEN was associated with responsiveness to tyrosine kinase inhibitors, whereas increased p-akt predicts a decreased effect.[87,88,89 ]Other targets include PDGFR, VEGFR, mTOR, farnesyltransferase, and PI3K.

� Other therapy modalities under investigation include gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.[90,91,92,93,94,95 ]

Surgical Care

The extent of surgery (biopsy vs resection) has been shown in a number of studies to affect length of survival. In a study by Ammirati and colleagues (1987), patients with high-grade gliomas who had a gross total resection had a 2-year survival rate of 19%, while those with a subtotal resection had a 2-year survival rate of 0%.[96 ]

In another study of 416 patients, gross total resection, defined as >98% on MRI, conferred a survival advantage over subtotal resection (13 vs 8.8 mo).[97 ]

In another study of 92 patients, a total tumor resection without any residual disease resulted in a median survival of 93 weeks, whereas the smallest percent of resection (<25%) and greatest volume of residual tumor (>20 cm3) gradually shortened the survival to 31 weeks and 50 weeks, respectively.[98 ]

An analysis of 28 studies found a mean duration of survival advantage of total over subtotal resection for glioblastoma multiforme (14 vs 11 mo).[99,100 ]

Because these tumors cannot be cured with surgery, the surgical goals are to establish a pathological diagnosis, relieve mass effect, and, if possible, achieve a gross total resection to facilitate adjuvant therapy.[101 ]Most glioblastomas recur in and around the original tumor bed, but contralateral and distant recurrences are not uncommon, especially with lesions near the corpus callosum. The indications for reoperation of malignant astrocytomas after initial treatment with surgery, radiation therapy, and chemotherapy are not firmly established. Reoperation is generally considered in the face of a life-threatening recurrent mass, particularly if radionecrosis rather than recurrent tumor is suspected as the cause of clinical and radiographic deterioration. PET scans and MR spectroscopy have proven useful in discriminating between these 2 entities.



Axial CT scan without intravenous contrast. This image reveals a large right temporal intraaxial

mass (glioblastoma multiforme [GBM]). Extensive surrounding edema is present, as

demonstrated by the peritumoral hypodensity, and a moderate right-to-left midline shift can be

noted. Images 2-8 are radiologic studies of the same patient.

A T1-weighted axial MRI without intravenous contrast. This image demonstrates a hemorrhagic

multicentric tumor (glioblastoma multiforme [GBM]) in the right temporal lobe. Effacement of

the ventricular system is present on the right, and mild impingement of the right medial

temporal lobe can be observed on the midbrain.



A T1-weighted axial MRI with intravenous contrast. Heterogenous enhancement of the lesion is

present within the right temporal lobe. The hypointensity circumscribed within the

enhancement is suggestive of necrosis. This radiologic appearance is typical of a multicentric

glioblastoma multiforme (GBM).

A T1-weighted coronal MRI with intravenous contrast. This image demonstrates the lesion

(glioblastoma multiforme [GBM]) within the medial temporal lobe and the stereotypical pattern

of contrast enhancement.



A T1-weighted sagittal MRI with intravenous contrast in a patient with glioblastoma multiforme

(GBM).

A T2-weighted axial MRI. The tumor (glioblastoma multiforme [GBM]) and surrounding white

matter within the right temporal lobe show increased signal intensity compared to a healthy

brain, suggesting extensive tumorigenic edema.



A fluid-attenuated inversion recovery (FLAIR) axial MRI. This image is similar to the T2-

weighted image and demonstrates extensive edema in a patient with glioblastoma multiforme

(GBM).


Although no formal studies have been performed, observations indicate that variables, such as young age, prolonged interval between operations, and extent of the second surgical resection, have prognostic significance.[102 ]

Stereotactic biopsy followed by radiation therapy may be considered in certain circumstances. These include



patients with a tumor located in an eloquent area of the brain, patients whose tumors have minimal mass effect, and patients in poor medical condition, precluding general anesthesia. Median survival after stereotactic biopsy and radiation therapy is reported to be from 27-47 weeks.[103 ]

Consultations

Patients with glioblastomas should be evaluated by a team of specialists, including a neurologist, neurosurgeon, neurooncologist, and radiation oncologist, in order to develop a coordinated treatment strategy.

Diet

No dietary restrictions are necessary.

Activity

No universal restrictions on activity are necessary for patients with glioblastomas. The patient's activity depends on his or her overall neurologic status. The presence of seizures may prevent the patient from driving. In many circumstances, physical therapy and/or rehabilitation are extremely beneficial. Activity is encouraged to reduce the risk of deep venous thrombosis.

Medication

No specific medications exist to treat glioblastomas. However, certain conditions require medical treatment. For seizures, the patient usually is started on levetiracetam (Keppra), phenytoin (Dilantin), or carbamazepine (Tegretol). Levetiracetam is often used because it lacks the effects on the P450 system seen with phenytoin and carbamazepine, which can interfere with antineoplastic therapy. Vasogenic cerebral edema is typically managed with corticosteroids (eg, dexamethasone), usually in combination with some form of antiulcer agent (eg, famotidine, ranitidine). The American Academy of Neurology's practice parameters state that prophylactic antiepileptic drugs (AEDs) should not be administered routinely to patients with newly diagnosed brain tumors (standard) and should be discontinued in the first postoperative week in patients who have not experienced a seizure.[104 ]

Antineoplastic agents

Although the optimal chemotherapeutic regimen for glioblastoma is not yet defined, several studies have suggested significant survival benefit from adjuvant chemotherapy.

Temozolomide (Temodar)

Oral alkylating agent converted to MTIC at physiologic pH; 100% bioavailable; approximately 35% crosses the blood-brain barrier. Indicated for glioblastoma multiforme combined with radiotherapy. Significant overall survival improvement was demonstrated in patients treated with temozolomide and radiation compared with radiotherapy alone.

Dosing

Adult

Adjust dose according to nadir neutrophil and platelet counts from previous cycle and at time of initiating next cycle Concomitant phase: 75 mg/m2/d PO for 42-49 d with concomitant radiotherapy

Maintenance cycle 1: 150 mg/m2/d PO for 5 d followed by 23 d without treatment; initiated 4 wk following concomitant phase completion Maintenance cycles 2-6: 200 mg/m2/d PO for 5 d; escalate dose from phase 1 only if blood count stable

Pediatric

Not established

Interactions



None reported

Contraindications

Documented hypersensitivity to temozolomide or DTIC, since each drug is metabolized to MTIC

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Causes bone marrow suppression resulting in thrombocytopenia, anemia, and leukopenia (check blood counts weekly during concomitant phase, then at day 1 and 21 of each cycle); common adverse effects include nausea, vomiting, and alopecia; not known if the drug is excreted in breast milk and because of potential serious adverse effects in infants, breastfeeding should be discontinued; PCP prophylaxis required during concomitant phase, continue if lymphocytopenia develops

Carmustine (BiCNU)

Alkylates and cross-links DNA strands, inhibiting cell proliferation.

Dosing

Adult

100-200 mg/m2 intra-arterially

200 mg/m2 IV; not to exceed cumulative dose of 1500 mg

8 BCNU-loaded biodegradable wafers in the resection cavity

Pediatric

200-250 mg/m2 IV q4-6wk

Interactions

Coadministration with cimetidine may increase toxicity; coadministration with etoposide may cause severe hepatic dysfunction (hyperbilirubinemia, ascites, and thrombocytopenia)

Contraindications

Documented hypersensitivity; myelosuppression from previous chemotherapy

Precautions

Pregnancy


Precautions

Caution in patients with depressed platelet, leukocyte, or erythrocyte counts or hepatic or renal impairment; perform baseline pulmonary function tests

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix.

Dosing



Adult

Currently, cisplatin is not administered routinely in adults with GBM because of poor penetration into CNS

Pediatric

60 mg/m2 IV for 2 consecutive d q3-4wk

Interactions

Increases toxicity of bleomycin and ethacrynic acid

Contraindications

Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment

Precautions

Pregnancy


Precautions

Administer adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, and nausea and vomiting may occur

Erlotinib (Tarceva)

Pharmacologically classified as a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells. Indicated for locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.

Dosing

Adult

150 mg PO qd administered at least 1 h before or 2 h after food; continue treatment until disease progression or unacceptable toxicity occurs

Pediatric

Not established

Interactions

Predominantly metabolized by CYP3A4; potent CYP3A4 inhibitors may decrease clearance (eg, ketoconazole increased AUC by two-thirds), caution with other strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin [TAO], voriconazole); CYP3A4 inducers may decrease AUC (ie, rifampin decreased AUC by two-thirds)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy


Precautions



Caution with hepatic impairment; may cause interstitial lung disease (including fatalities), elevated INR and bleeding; instruct patient to immediately seek medical attention for severe or persistent diarrhea, nausea, anorexia, vomiting, onset or worsening of unexplained shortness of breath or cough, or eye irritation; commonly causes rash and diarrhea (diarrhea unresponsive to loperamide may require dose reduction or temporary therapy interruption)

Gefitinib (Iressa)

An anilinoquinazoline. Indicated as monotherapy to treat locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. The mechanism is not fully understood. Inhibits tyrosine kinases intracellular phosphorylation associated with transmembrane cell surface receptors.

Dosing

Adult

250 mg PO qd

Pediatric

Not established

Interactions

CYP3A4 inducers (eg, rifampin, phenytoin) may increase clearance (increase dose to 500 mg PO qd); CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin) may increase gefitinib plasma levels (monitor for toxicity); coadministration with warfarin may increase INR or bleeding; coadministration with drugs causing sustained gastric pH elevation (eg, H2 inhibitors) may decrease plasma concentrations

Contraindications


Precautions

Pregnancy


Precautions

Frequently causes poorly tolerated diarrhea or adverse skin reactions (interrupt treatment briefly for up to 14 d, then reinstate therapy); discontinue for acute onset or worsening pulmonary symptoms (investigate for interstitial lung disease) or new eye symptoms (ie, pain, corneal erosion); may cause acne, dry skin, rash, pruritus, nausea, vomiting, anorexia; asthenia, or weight loss

Anticonvulsants

These agents are used to treat and prevent seizures.

Levetiracetam (Keppra)

Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for primary generalized tonic-clonic seizures. Mechanism of action is unknown.

Dosing

Adult

1000 mg/d PO divided bid (500 mg bid); may increase by 1000 mg/d increments q2wk; not to exceed 3000 mg/d; long-term experience at doses >3000 mg/d is relatively minimal, and there is no evidence that doses >3000 mg/d



offer additional benefit

Pediatric

Partial onset seizures: <4 years: Not established 4-15 years: 20 mg/kg/d PO divided bid; may increase by 20 mg/kg/d increments q2wk; not to exceed 60 mg/kg/d; use oral solution if weight ≤ 20 kg ≥ 15 years: Administer as in adults Myoclonic seizures: <12 years: Not established ≥ 12 years: Administer as in adults Tonic-clonic seizures: <6 years: Not established 6-15 years: 10 mg/kg PO bid; may increase daily dose by 20-mg/kg increments q2wk, not to exceed 30 mg/kg bid ≥ 15 years: Administer as in adults

Interactions

None reported; does not inhibit CYP450 isoenzymes, epoxide hydrolase, or UDP-glucuronidation; probenecid inhibits renal clearance of ucb L057 (inactive levetiracetam metabolite)

Contraindications


Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal impairment (reduce dose); major side effects include somnolence, asthenia, incoordination, mild leukopenia (3%) and behavioral changes such as anxiety, hostility, emotional lability, depression and psychosis (1-2%), and depersonalization; seizure frequency may increase following discontinuing drug (discontinue gradually); statistically significant decreases in RBCs and WBCs have been observed

Phenytoin (Dilantin)

Acts to block sodium channels and prevent repetitive firing of action potentials. As such, it is a very effective anticonvulsant. First-line agent in patients with partial and generalized tonic-clonic seizures.

Dosing

Adult

Loading dose: 15 mg/kg or 1000 mg IV over 4 h divided into 2 or 3 doses Maintenance dose: 5 mg/kg/d or 300 mg PO/IV qd or divided tid; adjust dose based on serum levels

Pediatric

Administer as in adults

Interactions

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimide, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity; effects may decrease when taken concurrently with



barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid

Contraindications

Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome

Precautions

Pregnancy


Precautions

Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if skin rash appears, and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in patients with acute intermittent porphyria and diabetes (may elevate blood sugars); discontinue use if hepatic dysfunction occurs; signs of toxicity include nystagmus, ataxia, and diplopia (necessitate lowering dose)

Carbamazepine (Tegretol)

Like phenytoin, acts by interacting with sodium channels and blocking repetitive neuronal firing. First-line agent in patients with partial and tonic-clonic seizures. Serum levels should be checked and should be approximately 4-8 mcg/mL.

Dosing

Adult

200-600 mg PO tid/qid (bid with ER)

Pediatric

15-25 mg/kg/d PO divided tid/qid (bid with ER)

Interactions

Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (coadministration may increase carbamazepine levels)

Contraindications

Documented hypersensitivity; history of bone marrow depression; administration of MAOIs within last 14 d

Precautions

Pregnancy


Precautions

Caution with increased IOP; obtain CBCs and serum-iron baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; caution while driving or performing other tasks requiring alertness; signs of toxicity include diplopia, ataxia, GI distress, and drowsiness (serum levels should be checked)



Corticosteroids

These agents reduce edema around the tumor, frequently leading to symptomatic and objective improvement.

Dexamethasone (Decadron)

Postulated mechanisms of action in brain tumors include reduction in vascular permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased CSF production.

Dosing

Adult

16 mg/d PO/IV divided q6h, continue until patient shows improvement, taper as symptoms resolve

Pediatric

0.5 mg/kg/d PO/IV divided q6h

Interactions

Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; decreases effect of salicylates and vaccines used for immunization

Contraindications

Documented hypersensitivity; active bacterial or fungal infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of multiple complications, including severe infections; monitor for adrenal insufficiency when tapering drug because abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Follow-up

Further Inpatient Care

� Patients with glioblastomas who undergo surgical resection typically spend the night after surgery in an intensive care unit, followed by an inpatient stay of 3-5 days. The final length of stay depends on each patient's neurological condition.

� Postoperative antibiotics usually are continued for 24 hours, and deep vein thrombosis prophylaxis is continued until patients are ambulatory.

� Anticonvulsants are maintained at therapeutic levels throughout the inpatient stay, while steroids are reduced gradually, tailored to each patient's clinical status.

� Many patients benefit from occupational therapy and physical therapy or rehabilitation.

� While patients are in the hospital, they should receive postoperative imaging to determine the extent of surgical resection. Surgical resection is evaluated best within 3 days of surgery by using contrast-enhanced MRI. Contrast enhancement during this period accurately reflects residual tumor.



� If not performed preoperatively, complete evaluations by consulting physicians, including a neurooncologist and radiation oncologist, should be considered postoperatively.

Inpatient & Outpatient Medications

� Anticonvulsant medications are usually maintained, and levels are checked intermittently.

� Steroids are tapered to lower doses for radiation therapy and then tapered further if possible. While taking steroids, patients should be maintained on an antiulcer agent.

Transfer

� At some institutions, transferring the patient to another facility may be necessary if the proper consultations cannot be obtained.

� In most cases, surgical resection can be performed on an urgent, but not emergent, basis.

Complications

� Brain tumor resection has an overall mortality rate of 1-2%.

� Approximately 40% of patients have no or minimal deficits after surgery, 30% manifest no postoperative change relative to preoperative deficits, and 25% sustain an increased postoperative deficit that usually improves.

Prognosis

� Despite extensive clinical trials, individual prediction of clinical outcome has remained an elusive goal. Glioblastomas are among the most malignant human neoplasms, with a median survival despite optimal treatment of less than 1 year. In a series of 279 patients receiving aggressive radiation and chemotherapy, only 5 of 279 patients (1.8%) survived longer than 3 years.[105 ]

� Patient survival depends on a variety of clinical parameters. Younger age, higher Karnofsky performance (a standard measure of the ability of patients with cancer to perform daily tasks) score at presentation, radiotherapy, and chemotherapy all correlate with improved outcome. Clinical evidence also suggests that a greater extent of resection favors longer survival.[106,99,98,97 ] Tumors that are deemed unresectable due to location (eg, in the brainstem) also portend a poorer prognosis.[107 ]

� Survival has not been shown to correlate with p53, EGFR, or MDM2 mutations.

� Long-term survivors, defined as those who survive longer than 2 years, are rare.

� Clearly, new approaches for the management of glioblastomas are necessary. Enrollment of patients into clinical trials will generate new information regarding investigational therapies. Novel approaches, such as the use of gene therapy and immunotherapy, as well as improved methods for the delivery of antiproliferative, antiangiogenic, and noninvasive therapies, provide hope for the future.

Patient Education

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.

Miscellaneous



Medicolegal Pitfalls

Because glioblastoma can be a devastating disease, meaningful communication between the physician and the patient and family is of paramount importance. To avoid medical legal pitfalls, including the patient's family in discussions regarding clinical management is essential. This often prevents family members from developing unrealistic expectations. Furthermore, communication among all the team members, including the neurosurgeon, neurologist, neurooncologist, and radiation oncologist, is important to ensure that the patient and family receive a unified treatment plan.

Multimedia

Media file 1: Axial CT scan without intravenous contrast. This image reveals a large right

temporal intraaxial mass (glioblastoma multiforme [GBM]). Extensive surrounding edema is

present, as demonstrated by the peritumoral hypodensity, and a moderate right-to-left midline

shift can be noted. Images 2-8 are radiologic studies of the same patient.



Media file 2: A T1-weighted axial MRI without intravenous contrast. This image demonstrates a

hemorrhagic multicentric tumor (glioblastoma multiforme [GBM]) in the right temporal lobe.

Effacement of the ventricular system is present on the right, and mild impingement of the right

medial temporal lobe can be observed on the midbrain.

Media file 3: A T1-weighted axial MRI with intravenous contrast. Heterogenous enhancement of

the lesion is present within the right temporal lobe. The hypointensity circumscribed within the

enhancement is suggestive of necrosis. This radiologic appearance is typical of a multicentric


Media file 4: A T1-weighted coronal MRI with intravenous contrast. This image demonstrates

the lesion (glioblastoma multiforme [GBM]) within the medial temporal lobe and the

stereotypical pattern of contrast enhancement.



Media file 5: A T1-weighted sagittal MRI with intravenous contrast in a patient with


Media file 6: A T2-weighted axial MRI. The tumor (glioblastoma multiforme [GBM]) and

surrounding white matter within the right temporal lobe show increased signal intensity

compared to a healthy brain, suggesting extensive tumorigenic edema.



Media file 7: A fluid-attenuated inversion recovery (FLAIR) axial MRI. This image is similar to

the T2-weighted image and demonstrates extensive edema in a patient with glioblastoma

multiforme (GBM).

Media file 8: Histopathologic slide demonstrating a glioblastoma multiforme (GBM).



Media file 9: Magnetic resonance (MR) spectroscopy is representative of a glioblastoma

multiforme (GBM).

References

1. Winger MJ, Macdonald DR, Cairncross JG. Supratentorial anaplastic gliomas in adults. The prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg. Oct 1989;71(4):487-93. [Medline].

2. Black PM. Brain tumor. Part 2. N Engl J Med. May 30 1991;324(22):1555-64. [Medline].

3. Black PM. Brain tumors. Part 1. N Engl J Med. May 23 1991;324(21):1471-6. [Medline].

4. Rich JN, Hans C, Jones B, et al. Gene expression profiling and genetic markers in glioblastoma survival. Cancer Res. May 15 2005;65(10):4051-8. [Medline]. [Full Text].

5. Kleihues P, Burger PC, Cavenee WK. Glioblastoma. In: WHO Classification: Pathology and genetics of tumors of the nervous system. ed. Lyon, France: International Agency for Research on Cancers; 1997:16-24.

6. Watanabe K, Sato K, Biernat W, et al. Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. Clin Cancer Res. Apr 1997;3(4):523-30. [Medline].

7. Korkolopoulou P, Christodoulou P, Kouzelis K, Hadjiyannakis M, Priftis A, Stamoulis G, et al. MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor. Br J Cancer. 1997;75(9):1269-78. [Medline]. [Full Text].

8. Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. Dec 7 1989;342(6250):705-8. [Medline].

9. Watanabe K, Tachibana O, Sata K, et al. Overexpression of the EGF receptor and p53 mutations are



mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. Jul 1996;6(3):217-23; discussion 23-4. [Medline].

10. Zauberman A, Flusberg D, Haupt Y, Barak Y, Oren M. A functional p53-responsive intronic promoter is contained within the human mdm2 gene. Nucleic Acids Res. Jul 25 1995;23(14):2584-92. [Medline]. [Full Text].

11. Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc Natl Acad Sci U S A. May 15 1992;89(10):4309-13. [Medline]. [Full Text].

12. Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN. Molecularly targeted therapy for malignant glioma. Cancer. Jul 1 2007;110(1):13-24. [Medline].

13. Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. Jun 1 2007;25(16):2288-94. [Medline]. [Full Text].

14. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. Nov 1 2007;21(21):2683-710. [Medline]. [Full Text].

15. Libermann TA, Nusbaum HR, Razon N, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. Jan 10-18 1985;313(5998):144-7. [Medline].

16. von Deimling A, Louis DN, von Ammon K, et al. Association of epidermal growth factor receptor gene amplification with loss of chromosome 10 in human glioblastoma multiforme. J Neurosurg. Aug 1992;77(2):295-301. [Medline].

17. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. Apr 1 1992;89(7):2965-9. [Medline]. [Full Text].

18. Duerr EM, Rollbrocker B, Hayashi Y, et al. PTEN mutations in gliomas and glioneuronal tumors. Oncogene. Apr 30 1998;16(17):2259-64. [Medline].

19. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. May 2007;170(5):1445-53. [Medline]. [Full Text].

20. Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. Jun 2005;64(6):479-89. [Medline].

21. Dohrmann GJ, Farwell JR, Flannery JT. Glioblastoma multiforme in children. J Neurosurg. Apr 1976;44(4):442-8. [Medline].

22. Farrell CJ, Plotkin SR. Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin. Nov 2007;25(4):925-46, viii. [Medline].

23. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of brain tumors. Neurol Clin. Nov 2007;25(4):867-90, vii. [Medline].

24. Hardell L, Carlberg M, Söderqvist F, Mild KH, Morgan LL. Long-term use of cellular phones and brain tumours: increased risk associated with use for > or =10 years. Occup Environ Med. Sep 2007;64(9):626-32. [Medline].

25. Lahkola A, Auvinen A, Raitanen J, Schoemaker MJ, Christensen HC, Feychting M, et al. Mobile phone use and risk of glioma in 5 North European countries. Int J Cancer. Apr 15 2007;120(8):1769-75. [Medline].



26. Inskip PD, Tarone RE, Hatch EE, Wilcosky TC, Shapiro WR, Selker RG, et al. Cellular-telephone use and brain tumors. N Engl J Med. Jan 11 2001;344(2):79-86. [Medline].

27. Weintraub MI. Glioblastoma multiforme and the cellular telephone scare. J Neurosurg. Jan 1994;80(1):169-70. [Medline].

28. Kan P, Simonsen SE, Lyon JL, Kestle JR. Cellular phone use and brain tumor: a meta-analysis. J Neurooncol. Jan 2008;86(1):71-8. [Medline].

29. International Electromagnetic Field (EMF) Collaborative. Cellphones and Brain Tumors: 15 Reasons for Concern. Science, Spin and the Truth Behind Interphone. Available at http://www.radiationresearch.org/pdfs/reasons_us.pdf. Accessed October 19, 2009.

30. Mukundan S, Holder C, Olson JJ. Neuroradiological assessment of newly diagnosed glioblastoma. J Neurooncol. Sep 2008;89(3):259-69. [Medline].

31. Russell DS, Rubinstein LJ. Pathology of tumors of the nervous system. 6th ed. London, England: Edward Arnold; 1998:426-52.

32. Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P. Grading of astrocytomas. A simple and reproducible method. Cancer. Nov 15 1988;62(10):2152-65. [Medline].

33. Kim TS, Halliday AL, Hedley-Whyte ET, Convery K. Correlates of survival and the Daumas-Duport grading system for astrocytomas. J Neurosurg. Jan 1991;74(1):27-37. [Medline].

34. Pedersen PH, Rucklidge GJ, Mork SJ, et al. Leptomeningeal tissue: a barrier against brain tumor cell invasion. J Natl Cancer Inst. Nov 2 1994;86(21):1593-9. [Medline].

35. Nagashima G, Suzuki R, Hokaku H, et al. Graphic analysis of microscopic tumor cell infiltration, proliferative potential, and vascular endothelial growth factor expression in an autopsy brain with glioblastoma. Surg Neurol. Mar 1999;51(3):292-9. [Medline].

36. Pompili A, Calvosa F, Caroli F, et al. The transdural extension of gliomas. J Neurooncol. Jan 1993;15(1):67-74. [Medline].

37. Brat DJ, Prayson RA, Ryken TC, Olson JJ. Diagnosis of malignant glioma: role of neuropathology. J Neurooncol. Sep 2008;89(3):287-311. [Medline].

38. Caccamo DV, Rubenstein LJ. Tumors: Applications of immunohistochemical methods. In: Neuropathology: The diagnostic approach. St Louis, Mo: Mosby-Year Book; 1997:193-218.

39. Lampl Y, Eshel Y, Gilad R, Sarova-Pinchas I. Glioblastoma multiforme with bone metastase and cauda equina syndrome. J Neurooncol. Apr 1990;8(2):167-72. [Medline].

40. Hulbanni S, Goodman PA. Glioblastoma multiforme with extraneural metastases in the absence of previous surgery. Cancer. Mar 1976;37(3):1577-83. [Medline].

41. Hoffman HJ, Duffner PK. Extraneural metastases of central nervous system tumors. Cancer. Oct 1 1985;56(7 Suppl):1778-82. [Medline].

42. Barnard RO, Geddes JF. The incidence of multifocal cerebral gliomas. A histologic study of large hemisphere sections. Cancer. Oct 1 1987;60(7):1519-31. [Medline].

43. Batzdorf U, Malamud N. The Problem of Multicentric Gliomas. J Neurosurg. Feb 1963;20:122-36. [Medline].

44. Pasquier B, Pasquier D, N'Golet A, Panh MH, Couderc P. Extraneural metastases of astrocytomas and glioblastomas: clinicopathological study of two cases and review of literature. Cancer. Jan 1 1980;45



(1):112-25. [Medline].

45. Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. Apr 12 2007;356(15):1527-35. [Medline]. [Full Text].

46. Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. May 1 2004;22(9):1583-8. [Medline]. [Full Text].

47. Glantz M, Chamberlain M, Liu Q, Litofsky NS, Recht LD. Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas. Cancer. May 1 2003;97(9):2262-6. [Medline].

48. [Best Evidence] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. May 2009;10(5):459-66. [Medline].

49. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. Mar 10 2005;352(10):987-96. [Medline]. [Full Text].

50. Chamberlain MC, Kormanik PA. Practical guidelines for the treatment of malignant gliomas. West J Med. Feb 1998;168(2):114-20. [Medline]. [Full Text].

51. Shapiro WR, Green SB, Burger PC, et al. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg. Jul 1989;71(1):1-9. [Medline].

52. Barker FG, Prados MD, Chang SM, et al. Radiation response and survival time in patients with glioblastoma multiforme. J Neurosurg. Mar 1996;84(3):442-8. [Medline].

53. Leibel SA, Scott CB, Loeffler JS. Contemporary approaches to the treatment of malignant gliomas with radiation therapy. Semin Oncol. Apr 1994;21(2):198-219. [Medline].

54. Liang BC, Thornton AF Jr, Sandler HM, Greenberg HS. Malignant astrocytomas: focal tumor recurrence after focal external beam radiation therapy. J Neurosurg. Oct 1991;75(4):559-63. [Medline].

55. Buatti J, Ryken TC, Smith MC, Sneed P, Suh JH, Mehta M, et al. Radiation therapy of pathologically confirmed newly diagnosed glioblastoma in adults. J Neurooncol. Sep 2008;89(3):313-37. [Medline].

56. Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. Sep 1978;49(3):333-43. [Medline].

57. Halperin EC, Bruger PC. Conventional external beam radiotherapy for central nervous system malignancies. In: Frank BD, ed. Symposium on Neuro-Oncology. Vol 3. 4th ed. New York, NY: Neurologic Clinics; 1985:867-82.

58. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. Sep 1980;30(9):907-11. [Medline].

59. Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol. Sep 10 2007;25(26):4127-36. [Medline].

60. Chi AS, Wen PY. Inhibiting kinases in malignant gliomas. Expert Opin Ther Targets. Apr 2007;11(4):473-96. [Medline].



61. Duda DG, Jain RK, Willett CG. Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J Clin Oncol. Sep 10 2007;25(26):4033-42. [Medline]. [Full Text].

62. Rodrigus P. Motexafin gadolinium: a possible new radiosensitiser. Expert Opin Investig Drugs. Jul 2003;12(7):1205-10. [Medline].

63. Butowski NA, Sneed PK, Chang SM. Diagnosis and treatment of recurrent high-grade astrocytoma. J Clin Oncol. Mar 10 2006;24(8):1273-80. [Medline].

64. Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol. Dec 1 2005;23(34):8863-9. [Medline].

65. Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys. Sep 1 2005;63(1):47-55. [Medline].

66. Kornblith PL. The role of cytotoxic chemotherapy in the treatment of malignant brain tumors. Surg Neurol. Dec 1995;44(6):551-2. [Medline].

67. Kornblith PL, Walker M. Chemotherapy for malignant gliomas [published erratum appears in J Neurosurg 1988 Oct;69(4):645]. J Neurosurg. Jan 1988;68(1):1-17. [Medline].

68. Lesser GJ, Grossman S. The chemotherapy of high-grade astrocytomas. Semin Oncol. Apr 1994;21(2):220-35. [Medline].

69. Levin VA. Chemotherapy of primary brain tumors. In: Frank BD, ed. Symposium on Neuro-Oncology. Vol 3. 4th ed. New York, NY: Neurologic Clinics; 1985:855-66.

70. Levin VA, Silver P, Hannigan J, et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. Feb 1990;18(2):321-4. [Medline].

71. Fadul CE, Wen PY, Kim L, Olson JJ. Cytotoxic chemotherapeutic management of newly diagnosed glioblastoma multiforme. J Neurooncol. Sep 2008;89(3):339-57. [Medline].

72. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer. Apr 15 1993;71(8):2585-97. [Medline].

73. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet. Mar 23 2002;359(9311):1011-8. [Medline].

74. Westphal M, Ram Z, Riddle V, Hilt D, Bortey E. Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien). Mar 2006;148(3):269-75; discussion 275. [Medline].

75. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. Mar 10 2005;352(10):997-1003. [Medline]. [Full Text].

76. Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol. Sep 1 2008;26(25):4189-99. [Medline].

77. Broniscer A, Gururangan S, MacDonald TJ, Goldman S, Packer RJ, Stewart CF, et al. Phase I trial of single-dose temozolomide and continuous administration of o6-benzylguanine in children with brain tumors:



a pediatric brain tumor consortium report. Clin Cancer Res. Nov 15 2007;13(22 Pt 1):6712-8. [Medline]. [Full Text].

78. Kaiser MG, Parsa AT, Fine RL, Hall JS, Chakrabarti I, Bruce JN. Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model. Neurosurgery. Dec 2000;47(6):1391-8; discussion 1398-9. [Medline].

79. Bruce JN, Falavigna A, Johnson JP, et al. Intracerebral clysis in a rat glioma model. Neurosurgery. Mar 2000;46(3):683-91. [Medline].

80. Lopez KA, Waziri AE, Canoll PD, Bruce JN. Convection-enhanced delivery in the treatment of malignant glioma. Neurol Res. Jul 2006;28(5):542-8. [Medline].

81. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet. Apr 22 1995;345(8956):1008-12. [Medline].

82. Bota DA, Desjardins A, Quinn JA, Affronti ML, Friedman HS. Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas. Ther Clin Risk Manag. Oct 2007;3(5):707-15. [Medline]. [Full Text].

83. FDA. Avastin Approval History. U.S. Food and Drug Administration. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf. Accessed 5/7/09.

84. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. Feb 15 2007;13(4):1253-9. [Medline]. [Full Text].

85. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. Oct 20 2007;25(30):4722-9. [Medline].

86. Cloughesy TF, Prados MD, Wen PY. A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combinationwith irinotecan (CPT) on 6-month progressionfree survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol. 2008;26:Suppl:91s.

87. Rich JN, Rasheed BK, Yan H. EGFR mutations and sensitivity to gefitinib. N Engl J Med. Sep 16 2004;351(12):1260-1; author reply 1260-1. [Medline].

88. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. Jan 1 2004;22(1):133-42. [Medline]. [Full Text].

89. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. Nov 10 2005;353(19):2012-24. [Medline]. [Full Text].

90. Fulci G, Chiocca EA. The status of gene therapy for brain tumors. Expert Opin Biol Ther. Feb 2007;7(2):197-208. [Medline]. [Full Text].

91. Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon JE 2nd, et al. Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results. J Clin Oncol. Jan 1 2006;24(1):115-22. [Medline].

92. Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB, Fiveash JB, et al. Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol. Aug 1 2006;24(22):3644-50. [Medline].



93. Ferguson S, Lesniak MS. Convection enhanced drug delivery of novel therapeutic agents to malignant brain tumors. Curr Drug Deliv. Apr 2007;4(2):169-80. [Medline].

94. Quang TS, Brady LW. Radioimmunotherapy as a novel treatment regimen: (125)I-labeled monoclonal antibody 425 in the treatment of high-grade brain gliomas. Int J Radiat Oncol Biol Phys. Mar 1 2004;58(3):972-5. [Medline].

95. Rich JN, Bigner DD. Development of novel targeted therapies in the treatment of malignant glioma. Nat Rev Drug Discov. May 2004;3(5):430-46. [Medline]. [Full Text].

96. Ammirati M, Vick N, Liao YL, et al. Effect of the extent of surgical resection on survival and quality of life in patients with supratentorial glioblastomas and anaplastic astrocytomas. Neurosurgery. Aug 1987;21(2):201-6. [Medline].

97. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. Aug 2001;95(2):190-8. [Medline].

98. Keles GE, Anderson B, Berger MS. The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surg Neurol. Oct 1999;52(4):371-9. [Medline].

99. Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. Apr 2008;62(4):753-64; discussion 264-6. [Medline].

100. Fadul C, Wood J, Thaler H, et al. Morbidity and mortality of craniotomy for excision of supratentorial gliomas. Neurology. Sep 1988;38(9):1374-9. [Medline].

101. Ryken TC, Frankel B, Julien T, Olson JJ. Surgical management of newly diagnosed glioblastoma in adults: role of cytoreductive surgery. J Neurooncol. Sep 2008;89(3):271-86. [Medline].

102. Ciric I, Rovin R, Cozzens JW. Role of surgery in the treatment of malignant cerebral gliomas. In: Malignant Cerebral Glioma. Park Ridge, Ill: American Association of Neurological Surgeons; 1990:141-53.

103. Coffey RJ, Lunsford LD, Taylor FH. Survival after stereotactic biopsy of malignant gliomas. Neurosurgery. Mar 1988;22(3):465-73. [Medline].

104. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. May 23 2000;54(10):1886-93. [Medline]. [Full Text].

105. Scott JN, Rewcastle NB, Brasher PM, et al. Long-term glioblastoma multiforme survivors: a population-based study. Can J Neurol Sci. Aug 1998;25(3):197-201. [Medline].

106. Sneed PK, Prados MD, McDermott MW, et al. Large effect of age on the survival of patients with glioblastoma treated with radiotherapy and brachytherapy boost. Neurosurgery. May 1995;36(5):898-903; discussion 903-4. [Medline].

107. Salmon I, Dewitte O, Pasteels JL, et al. Prognostic scoring in adult astrocytic tumors using patient age, histopathological grade, and DNA histogram type. J Neurosurg. May 1994;80(5):877-83. [Medline].

108. Bouvier-Labit C, Chinot O, Ochi C, Gambarelli D, Dufour H, Figarella-Branger D. Prognostic significance of Ki67, p53 and epidermal growth factor receptor immunostaining in human glioblastomas. Neuropathol Appl Neurobiol. Oct 1998;24(5):381-8. [Medline].

109. Bullard DE, Bigner DD. Applications of monoclonal antibodies in the diagnosis and treatment of primary



brain tumors. J Neurosurg. Jul 1985;63(1):2-16. [Medline].

110. Burger PC, Green SB. Patient age, histologic features, and length of survival in patients with glioblastoma multiforme. Cancer. May 1 1987;59(9):1617-25. [Medline].

111. Burger PC, Heinz ER, Shibata T, Kleihues P. Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg. May 1988;68(5):698-704. [Medline].

112. Burger PC, Scheithauer BW. Tumors of the central nervous system. In: Atlas of tumor pathology. Washington, DC: Armed Forces Institute of Pathology; 1994.

113. Burger PC, Vogel FS, Green SB, Strike TA. Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer. Sep 1 1985;56(5):1106-11. [Medline].

114. Devaux BC, O'Fallon JR, Kelly PJ. Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome. J Neurosurg. May 1993;78(5):767-75. [Medline].

115. Dropcho EJ, Soong SJ. The prognostic impact of prior low grade histology in patients with anaplastic gliomas: a case-control study. Neurology. Sep 1996;47(3):684-90. [Medline].

116. Giordana MT, Bradac GB, Pagni CA, et al. Primary diffuse leptomeningeal gliomatosis with anaplastic features. Acta Neurochir (Wien). 1995;132(1-3):154-9. [Medline].

117. Glantz MJ, Hoffman JM, Coleman RE, et al. Identification of early recurrence of primary central nervous system tumors by [18F]fluorodeoxyglucose positron emission tomography. Ann Neurol. Apr 1991;29(4):347-55. [Medline].

118. Greenberg MS. Tumor: Primary brain tumors. In: Handbook of Neurosurgery. 4th ed. Lakeland, Fla: Greenberg Graphics; 1997:244-311.

119. Herholz K, Pietrzyk U, Voges J, et al. Correlation of glucose consumption and tumor cell density in astrocytomas. A stereotactic PET study. J Neurosurg. Dec 1993;79(6):853-8. [Medline].

120. Lang FF, Miller DC, Koslow M, Newcomb EW. Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors. J Neurosurg. Sep 1994;81(3):427-36. [Medline].

121. Lantos PL, VandenBerg SR, Kleihues P. Tumors of the nervous system. In: Graham DI, Lantos PL, eds. Greenfield's Neuropathology. 6th ed. London, England: Edward Arnold; 1998:583-879.

122. Macdonald DR, Cascino TL, Schold SC, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. Jul 1990;8(7):1277-80. [Medline].

123. Mahaley MS, Mettlin C, Natarajan N, et al. National survey of patterns of care for brain-tumor patients. J Neurosurg. Dec 1989;71(6):826-36. [Medline].

124. Newcomb EW, Cohen H, Lee SR, et al. Survival of patients with glioblastoma multiforme is not influenced by altered expression of p16, p53, EGFR, MDM2 or Bcl-2 genes. Brain Pathol. Oct 1998;8(4):655-67. [Medline].

125. Ohgaki H, Watanabe K, Peraud A, et al. A case history of glioma progression. Acta Neuropathol (Berl). May 1999;97(5):525-32. [Medline].

126. Patronas NJ, Di Chiro G, Kufta C, et al. Prediction of survival in glioma patients by means of positron emission tomography. J Neurosurg. Jun 1985;62(6):816-22. [Medline].

127. Shiras A, Bhosale A, Shepal V, Shukla R, Baburao VS, Prabhakara K, et al. A unique model system for



tumor progression in GBM comprising two developed human neuro-epithelial cell lines with differential transforming potential and coexpressing neuronal and glial markers. Neoplasia. Nov-Dec 2003;5(6):520-32. [Medline]. [Full Text].

128. van den Bent MJ, Hegi ME, Stupp R. Recent developments in the use of chemotherapy in brain tumours. Eur J Cancer. Mar 2006;42(5):582-8. [Medline].

129. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. Jul 31 2008;359(5):492-507. [Medline]. [Full Text].

130. Wood JR, Green SB, Shapiro WR. The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group. J Clin Oncol. Feb 1988;6(2):338-43. [Medline].

131. Zulch KJ. Brain Tumors: their biology and pathology. 3rd ed. Berlin, Germany: Springer-Verlag; 1986.

Keywords

glioblastoma multiforme, GBM, brain cancer, brain malignancy, glioblastoma, WHO grade IV glioma, Kernohan grade IV astrocytoma, St. Anne/Mayo astrocytoma grade 4, p53, EGFR, MDM2, PDGF, PTEN, brain tumors, primary brain tumors, glial tumors, lower-grade astrocytomas, anaplastic astrocytomas, primary GBMs, secondary GBMs, astrocytic brain tumors, butterfly glioma, intracranial neoplasms, progressive neurologic deficit, motor weakness, seizures, supratentorial brain tumors, neurofibromatosis

Contributor Information and Disclosures

Author

Jeffrey N Bruce, MD, Edgar M Housepian Professor of Neurological Surgery Research, Professor of Neurological Surgery, Director of Brain Tumor Tissue Bank, Director of Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Columbia University College of Physicians and Surgeons Jeffrey N Bruce, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Neurological Surgeons, Congress of Neurological Surgeons, New York Academy of Sciences, North American Skull Base Society, Society for Neuro-Oncology, and Southwest Oncology Group Disclosure: NIH Grant/research funds Other

Coauthor(s)

Benjamin Kennedy,, Columbia University College of Physicians and Surgeons Disclosure: Nothing to disclose.

Medical Editor

Robert C Shepard, MD, FACP, Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine



Disclosure: eMedicine Salary Employment

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine; Consulting Staff, Arizona Cancer Center Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research Disclosure: GlobeImmune Salary Consulting

Acknowledgments

We would like to acknowledge previous contributions to this chapter from Katharine Cronk, MD,PhD; Richard C Anderson, MD; Chris E Mandigo, MD; Andrew T Parsa MD, PhD; Patrick B Senatus, MD, PhD; and Allen Waziri, MD.

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