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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.
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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.
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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.
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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.
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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
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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.
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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 2cm margin.[30 ]
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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.
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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.
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A fluid-attenuated inversion recovery (FLAIR) axial MRI. This image is similar to the T2weighted 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,
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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
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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.
Histopathologic slide demonstrating a glioblastoma multiforme (GBM).
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
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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 ]
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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 610% 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 bloodbrain 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.
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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.
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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.
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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.
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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.
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A fluid-attenuated inversion recovery (FLAIR) axial MRI. This image is similar to the T2weighted image and demonstrates extensive edema in a patient with glioblastoma multiforme
(GBM).
Histopathologic slide demonstrating a 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
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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
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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
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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
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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
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
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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
Documented hypersensitivity
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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 tonicclonic 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
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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
Documented hypersensitivity
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 (12%), 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
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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; AdamsStokes syndrome
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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)
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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.
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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
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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.
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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
glioblastoma multiforme (GBM).
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.
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Media file 5: A T1-weighted sagittal MRI with intravenous contrast in a patient with
glioblastoma multiforme (GBM).
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.
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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).
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Media file 9: Magnetic resonance (MR) spectroscopy is representative of a glioblastoma
multiforme (GBM).
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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
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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.
Further Reading
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