Glioblastoma Multiforme

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Practice Essentials

Glioblastoma multiforme (GBM) is the most common and most malignant of the glial tumors. See the image below.



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Histopathologic slide demonstrating a glioblastoma multiforme (GBM).

See Brain Lesions: 9 Cases to Test Your Management Skills, a Critical Images slideshow, to review cases including meningiomas, glioblastomas and craniopharyngiomas, and to determine the best treatment options based on the case history and images.

Signs and symptoms

The clinical history of a patient with glioblastoma multiforme (GBM) is usually short (< 3 months in >50% of patients). Common presenting symptoms include the following:

Neurologic symptoms and signs can be either general or focal and reflect the location of the tumor, as follows:

The etiology of GBM is unknown in most cases. Suggested causes include the following:

See Clinical Presentation for more detail.

Diagnosis

No specific laboratory studies are helpful in diagnosing GBM. Tumor genetics are useful for predicting response to adjuvant therapy.

Imaging studies of the brain are essential for making the diagnosis, including the following:

Other diagnostic measures that may be considered include the following:

In most cases, complete staging is neither practical nor possible. These tumors do not have clearly defined margins; they tend to invade locally and spread along white matter pathways, creating the appearance of multiple GBMs or multicentric gliomas on imaging studies.

See Workup for more detail.

Management

No current treatment is curative. Standard treatment consists of the following:

Key points regarding radiotherapy for GBM include the following:[7, 8, 9]

The optimal chemotherapeutic regimen for glioblastoma is not yet defined, but adjuvant chemotherapy appears to yield a significant survival benefit in more than 25% of patients.[16, 1, 17, 18, 19, 20]

Agents used include the following:

Because GBM cannot be cured surgically, the surgical goals are as follows:

In some cases, stereotactic biopsy followed by radiation therapy (eg, for 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 who cannot undergo general anesthesia)

See Treatment and Medication for more detail.

Background

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

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.

See images below.



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A T1-weighted axial MRI without intravenous contrast. This image demonstrates a hemorrhagic multicentric tumor (glioblastoma multiforme [GBM]) in the ....



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A T1-weighted sagittal MRI with intravenous contrast in a patient with glioblastoma multiforme (GBM).

Composed of a heterogeneous 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.[28, 29, 30]

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, glioblastoma multiforme) 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. Some of the more common genetic abnormalities are described as follows:

Eckel-Passow and colleagues classified gliomas into groups on the basis of three tumor markers: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. Findings included the following[39] :

Less frequent but more malignant mutations in glioblastomas include the following:

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.

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.[40] 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-, Sex-, and Age-related Demographics

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

In a review of 1003 glioblastoma biopsies from the University Hospital Zurich,[41] males had a slight preponderance over females, with a male-to-female ratio of 3:2.

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.[41] In a series reported by Dohrman (1976), only 8.8% of glioblastoma multiformes occurred in children.[42]

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. Note the following:

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. Note the following:

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).[1]

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.[43, 2, 3, 4, 5, 6] 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,[7] 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.[43]

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 ....

MRI with and without contrast is the study of choice. These lesions typically have an enhancing ring observed on T1-weighted images and a broad surrounding zone of edema apparent on T2-weighted images. The central hypodense core represents necrosis, the contrast-enhancing ring is composed of highly dense neoplastic cells with abnormal vessels permeable to contrast agents, and the peripheral zone of nonenhancing low attenuation is vasogenic edema containing varying numbers of invasive tumor cells. Several pathological studies have clearly shown that the area of enhancement does not represent the outer tumor border because infiltrating glioma cells can be identified easily within, and occasionally beyond, a 2-cm margin.[8]



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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....



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A T1-weighted coronal MRI with intravenous contrast. This image demonstrates the lesion (glioblastoma multiforme [GBM]) within the medial temporal lob....



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A T1-weighted sagittal MRI with intravenous contrast in a patient with glioblastoma multiforme (GBM).



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A T2-weighted axial MRI. The tumor (glioblastoma multiforme [GBM]) and surrounding white matter within the right temporal lobe show increased signal i....



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A fluid-attenuated inversion recovery (FLAIR) axial MRI. This image is similar to the T2-weighted image and demonstrates extensive edema in a patient ....



View Image

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.

A study by Piroth et al found that O-(2-[(18)F]fluoroethyl-l-tyrosine (FET) PET to measure tumor volume after surgery has a strong prognostic impact.[9]

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



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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.[10, 11, 12, 13, 14, 15, 16]

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.[44]

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.



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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.[17, 18, 19, 20, 21, 22]

Medical Care

The treatment of glioblastomas remains difficult in that no contemporary treatments are curative.[23] 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. See Brain Cancer Treatment Protocols for summarized information.

Upon initial diagnosis of glioblastoma multiforme (GBM), standard treatment consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide.[24, 25] For patients older than 70 years, less aggressive therapy is sometimes employed, using radiation or temozolomide alone.[26, 27, 28] A study by Scott et al found that elderly patients with glioblastoma who underwent radiotherapy had improved cancer-specific survival and overall survival compared with those who did not undergo radiotherapy treatment.[29]

Recent evidence suggests that in patients over 60 years old, treatment with temozolomide is associated with longer survival than treatment with standard radiotherapy, and for those over 70 years old, temozolomide or hypofractionated radiotherapy is associated with prolonged survival than treatment with standard fractionated radiotherapy. The improvement in survival with temozolomide isenhancedinpatientswithMGMTpromotermethylation.[30]

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.[45]

Median time to recurrence after standard therapy is 6.9 months.[46] For recurrent glioblastoma multiforme, surgery is appropriate in selected patients, and various radiotherapeutic, chemotherapeutic, biologic, or experimental therapies are also employed.[47, 37] A study by Wernicke et al report that prostate-specific membrane antigen is expressed in the vasculature of GBM vessels and represents a potential novel therapeutic vascular target. Future clinical trials are planned.[48]

Clinical practice guideline

In an evidence-based clinical practice guideline formulated to address the impact of cytotoxic chemotherapy on disease control and survival in adults with progressive glioblastoma, Olson et al make the following recommendations[49] :

Radiation therapy [50, 51, 35, 52]

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.[46, 53]

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.[54, 36]

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.[55]

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,[56] targeted molecular agents,[41, 42] and antiangiogenic agents[42] may increase the therapeutic effect of radiotherapy.[57]

Radiotherapy for recurrent glioblastoma multiforme is controversial, though some studies have suggested a benefit to stereotactic radiosurgery or fractionated stereotactic reirradiation.[58, 59, 60]  In adult patients with progressive glioblastoma, American Association of Neurological Surgeons/Congress of Neurological Surgeons (AANS/CNS) guidelines recommend that when the target tumor is amenable for additional radiation, re-irradiation should be performed to improve local tumor control. This re-irradiation may take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery.[61]

Chemotherapy – Antineoplastic agents [62, 63, 64, 65, 66, 67]

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.[68, 69]

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.[70, 71]

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.[72] Note the following:

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.[75, 76, 77]

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.[78, 79]

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.[80] When used with irinotecan, bevacizumab improved 6-month survival in recurrent glioma patients to 46% compared with 21% in patients treated with temozolomide.[81, 82] This bevacizumab and irinotecan combination for recurrent glioblastoma multiforme has been shown to improve survival over bevacizumab alone.[83] 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.[84, 85, 86] 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.[87, 88, 89, 90, 91, 92]

A population-based analysis of 5607 adult patients with glioblastoma in the SEER (Surveillance Epidemiology and End Results) database found that bevacizumab therapy may improve survival. In the study, glioblastoma patients who died in 2010 (after the FDA approved bevacizumab for this condition) survived significantly longer than those who died of the disease in 2008. Median survival was 8 months for patients who died in 2006, 7 months in 2008, and 9 months in 2010. This difference in survival was highly significant between 2008 (pre-bevacizumab) and 2010 (post-bevacizumab). This survival difference was unlikely due to improvements in supportive care during this time interval, because there was no significant difference between those who died in 2006 and patients who died 2 years later, in 2008.[93, 94]

Electric-field therapy

The Optune device uses low-intensity, intermediate-frequency, alternating electric fields (tumor- treating fields) to target dividing cells in glioblastoma multiforme while generally not harming normal cells. The tumor-treating fields are generated via electrodes placed directly on the scalp. To target the tumor, array placement is based on the individual patient's magnetic resonance imaging results.[95]

Optune, also known as the NovoTTF-100A System, was initially approved in 2011 for use in glioblastoma multiforme that had recurred or progressed after treatment. In October 2015, the FDA expanded approval to include use of the device in conjunction with temozolomide chemotherapy in the first-line setting. Approval was based on an open-label, randomized phase 3 trial in 700 patients, in which median overall survival was 19.4 months with use of the device plus temozolomide, versus 16.6 months with chemotherapy only.[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 the images below.



View Image

Axial CT scan without intravenous contrast. This image reveals a large right temporal intraaxial mass (glioblastoma multiforme [GBM]). Extensive surro....



View Image

A T1-weighted axial MRI without intravenous contrast. This image demonstrates a hemorrhagic multicentric tumor (glioblastoma multiforme [GBM]) in the ....



View Image

A T1-weighted axial MRI with intravenous contrast. Heterogenous enhancement of the lesion is present within the right temporal lobe. The hypointensity....



View Image

A T1-weighted coronal MRI with intravenous contrast. This image demonstrates the lesion (glioblastoma multiforme [GBM]) within the medial temporal lob....



View Image

A T1-weighted sagittal MRI with intravenous contrast in a patient with glioblastoma multiforme (GBM).



View Image

A T2-weighted axial MRI. The tumor (glioblastoma multiforme [GBM]) and surrounding white matter within the right temporal lobe show increased signal i....



View Image

A fluid-attenuated inversion recovery (FLAIR) axial MRI. This image is similar to the T2-weighted image and demonstrates extensive edema in a patient ....



View Image

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]

A study by El Hindy et al found that a common regulatory single-nucleotide polymorphism (-938C>A) is a survival prognosticator and a marker for high-risk in patients with glioblastoma multiforme who undergo gross total resection.[103]

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.[104]

A study by Jakola et al found that surgical procedures may not significantly alter the quality of life (QOL) in the average patient, however, the use of intraoperative ultrasonography may be associated with a preservation of QOL in that it helps avoid introducing new deficits.[105]

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 Summary

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.[106]

Temozolomide (Temodar)

Clinical Context:  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.

Carmustine (BiCNU)

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

Cisplatin (Platinol)

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

Erlotinib (Tarceva)

Clinical Context:  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.

Gefitinib (Iressa)

Clinical Context:  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.

Class Summary

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

Levetiracetam (Keppra)

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

Phenytoin (Dilantin)

Clinical Context:  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.

Carbamazepine (Tegretol)

Clinical Context:  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.

Class Summary

These agents are used to treat and prevent seizures.

Dexamethasone (Decadron)

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

Class Summary

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

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.[107]

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.[108, 99, 98, 97, 109] Tumors that are deemed unresectable due to location (eg, in the brainstem) also portend a poorer prognosis.[110]

A study by Li et al used an updated Radiation Therapy Oncology Group (RTOG) GBM database to produce a simplified original recursive partitioning analysis (RPA) model combining classes V and VI. This resulted in 3 distinct prognostic groups defined by performance status, age, neurologic function, and extent of resection. This classification will be used in future RTOG GBM trials.[111]

Survival has not been shown to correlate with p53, EGFR, or MDM2 mutations.[112]

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.

A study by Kaur et al determined that the presence of a large cyst in patients with GBM does not affect overall survival compared with those who do not have a cyst.[113]

Patient Education

For patient education resources, see the Cancer Center as well as the patient education article Brain Cancer.

Author

Jeffrey N Bruce, MD, Edgar M Housepian Professor of Neurological Surgery Research, Vice-Chairman and 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

Disclosure: Received grant/research funds from NIH for other.

Coauthor(s)

Benjamin Kennedy, MD, Columbia University College of Physicians and Surgeons

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Jules E Harris, MD, FACP, FRCPC, Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Disclosure: Nothing to disclose.

Additional Contributors

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

Disclosure: Nothing to disclose.

Acknowledgements

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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Histopathologic slide demonstrating a glioblastoma multiforme (GBM).

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).

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).

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

Histopathologic slide demonstrating a glioblastoma multiforme (GBM).

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. All of the radiologic studies in this article are 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).

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. All of the radiologic studies in this article are 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).

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