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.

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 (see Image 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.

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 (see Image 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.

• MRI with and without contrast is the study of choice. These lesions typically have an enhancing ring observed on T1-weighted images (see Images 3-6) and a broad surrounding zone of edema apparent on T2-weighted images (see Images 7-8). 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.

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

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

• 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 agents⁶¹ 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 (see Images 1-8).

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).

Histopathologic slide demonstrating a glioblastoma multiforme (GBM).

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

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

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

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 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

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 (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

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)

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 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.

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.

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).

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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
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 at Tucson; 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; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

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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