Glioblastoma Multiforme

Updated: May 26, 2022
Author: Jeffrey N Bruce, MD; Chief Editor: Herbert H Engelhard, III, MD, PhD, FACS, FAANS 


Practice Essentials

Glioblastoma multiforme (GBM) is the most common and most malignant of the glial tumors.[1] See the image below.

Histopathologic slide demonstrating a glioblastoma 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:

  • Slowly progressive neurologic deficit, usually motor weakness
  • Headache
  • Generalized manifestations of increased intracranial pressure, including headaches, nausea and vomiting, and cognitive impairment
  • Seizures

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

  • General: Headaches, nausea and vomiting, personality changes, and slowing of cognitive function
  • Focal: Hemiparesis, sensory loss, visual loss, aphasia, and others

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

  • Genetic factors
  • Cell phone use (controversial)
  • Head injury, N-nitroso compounds, occupational hazards, electromagnetic field exposure (all inconclusive) [2]

See Presentation for more detail.


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:

  • Computed tomography
  • Magnetic resonance imaging, with and without contrast (study of choice)
  • Positron emission tomography
  • Magnetic resonance spectroscopy
  • Cerebral angiography is not necessary

Other diagnostic measures that may be considered include the following:

  • Electroencephalography: May show suggestive findings, but findings specific for GBM will not be observed
  • Lumbar puncture (generally contraindicated but occasionally necessary for ruling out lymphoma)
  • Cerebrospinal fluid studies do not significantly facilitate specific diagnosis of GBM

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.


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

  • Maximal safe surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide[3, 4]

  • Patients older than 70 years: Less aggressive therapy is sometimes considered, using radiation or temozolomide alone[5, 6, 7]

  • Supportive care for clinical manifestations (eg, headache, seizures, venous thromboembolism)[8, 9]

Surgical options include gross total resection (better survival), subtotal resection, and biopsy. Because GBM cannot be cured surgically, the surgical goals are as follows:

  • To establish a pathologic diagnosis
  • To relieve any mass effect
  • If possible, to achieve a gross total resection to facilitate adjuvant therapy [10]

In some cases, stereotactic biopsy is 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). The extent of surgery (biopsy vs resection) has been shown in a number of studies to affect length of survival.

Key points regarding radiotherapy for GBM include the following:[11, 12]

  • The addition of radiotherapy to surgery increases survival.[13, 14]

  • The responsiveness of GBM to radiotherapy varies.

  • Interstitial brachytherapy, in which radioactive seeds are placed intraoperatively, after tumor resection, allows immediate initiation of radiation therapy

  • Radiosensitizers, such as newer chemotherapeutic agents,[15] targeted molecular agents,[16, 17] and antiangiogenic agents[17] may increase the therapeutic effect of radiotherapy.[18]

  • Radiotherapy and/or radiosurgery for recurrent GBM is controversial.

The optimal chemotherapeutic regimen for GBM is not yet defined, but adjuvant chemotherapy appears to yield a significant survival benefit in more than 25% of patients.[19, 2, 20, 21, 22, 23]

Agents used include the following:

  • Temozolomide
  • Nitrosoureas (eg, lomustine, carmustine)
  • Bevacizumab (alone or with irinotecan) for recurrent cases
  • Tyrosine kinase inhibitors (eg, regorafenib, gefitinib, erlotinib)
  • Investigational therapies

See Treatment and Medication for more detail.

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


Glioblastoma multiforme (GBM) is by far the most common and most malignant of the glial tumors. Attention has been drawn to this form of brain cancer by the deaths of Senator Ted Kennedy and Senator John McCain from glioblastoma.

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.

A T1-weighted axial MRI without intravenous contra 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 contra 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.[24, 25, 26]


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), and patients 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:

  • 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.[27] 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.[28]

  • 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.[29] The p53 immunoreactivity also appears to be associated with tumors that arise in younger patients.

  • 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.[30] 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.[31]

  • 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.[32]

  • 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 20% of glioblastomas, more commonly in primary glioblastoma multiformes.[33]

In 2015, 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[34] :

  • Among patients with a histopathologic diagnosis of glioblastoma, those with both TERT and IDH mutations had poor overall survival
  • Isolated IDH mutations were significantly more frequent in younger patients (mean age at diagnosis, 37 years) and seemed to be associated with tumor evolution along a secondary glioblastoma pathway
  • Mean age at diagnosis was highest (59 years) in patients whose tumors harbored TERT mutations only
  • Patients whose tumors harbored TERT mutations suffered worse overall survival compared with the other molecular subgroups
  • Patients with triple-negative gliomas (IDH-, TERT -, 1p19q intact) had poorer overall survival than patients who had gliomas with TERT or  IDH, or who had triple-positive gliomas

The 2016 World Health Organization Classification of Tumors of the Central Nervous System includes two primary designations of glioblastoma: IDH wild type and IDH mutant.[35] IDH–wild type glioblastomas comprise 71% of all adult gliomas, while IDH–mutant glioblastomas comprise 7%. Patients with IDH-wild type glioblastoma are generally older (median age at diagnosis, 59 years) and have the worst prognosis (median overall survival 1.2 years), while patients with IDH-mutant glioblastoma tend to be younger (median age at diagnosis, 38 years) and have a better prognosis (median overall survival 3.6 years).[36]

Less frequent but more malignant mutations in glioblastomas 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.

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.[37] 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.

Glioblastoma cells have the ability to migrate and invade healthy brain tissue. Active migration of glioblastoma cells makes curative surgical resection impossible. Hypoxia promotes the migration of glioblastoma cells and increases tumor aggressivenes. Glioblastomas contain extensive hypoxic areas, which distinguishes this tumor from low-grade malignancies.[38]


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).[2]

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.[39, 3, 4, 5, 6, 7]  

Studies of association with head injury, N-nitroso compounds, occupational hazards, and electromagnetic field exposure have been inconclusive.[39]


Overall incidence is very similar among countries. 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. 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.

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

In a review of 1003 glioblastoma biopsies from the University Hospital Zurich,[40]  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.[40]  In a series reported by Dohrman (1976), only 8.8% of glioblastoma multiformes occurred in children.[41]


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. 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.

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.

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.[42]

Patient survival depends on a variety of clinical parameters. Younger age, higher Karnofsky performance scale (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.[43, 44, 45, 46] Tumors that are deemed unresectable due to location (eg, in the brainstem) also portend a poorer prognosis.[47]

A review by Perrini et al of 48 patients with recurrent glioblastoma found that preoperative performance status at recurrence and subtotal versus gross-total repeat resection were independent predictors of survival. These authors concluded that gross-total resection at repeat craniotomy is associated with longer overall survival and should be performed whenever possible in patients with recurrent glioblastoma who have good performance status.[48]

Survival has not been shown to correlate with p53, EGFR, or MDM2 mutations.[49]

Two separate reviews of outcomes in elderly patients have been published. One found that although elderly patients have a poor prognosis, gross-total resection confers a modest survival benefit and treatment with bevacizumab significantly increased overall survival. Older age and preoperative Karnofsky Performance Scale score also were significant prognostic factors.[50]

The results of the second study concurred that there is a survival advantage for those who undergo maximal safe resection. The review also found that radiotherapy extends survival in selected patients and temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation.[51]

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.[52]

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.[53]

Patient Education

For patient education information, see the Brain Cancer Health Center. In addition, information about glioblastoma (and other brain tumors) is available from the American Brain Tumor Association (ABTA) at Brain Tumor Information.




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:

  • 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 Examination

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:

  • 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.


Diagnostic Considerations

Other conditions to consider in the differential diagnosis of glioblastoma multiforme include the following:

  • Anaplastic astrocytoma

  • Cavernous malformation

  • Cerebral abscess

  • CNS lymphoma

  • Encephalitis

  • Intracranial hemorrhage

  • Metastasis

  • Oligodendroglioma

  • Radiation necrosis

  • Toxoplasmosis



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). For complete discussion, see Imaging in Glioblastoma Multiforme.

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

Magnetic resonance imaging (MRI) with and without contrast is the study of choice (see the images below). 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.[11]

A T1-weighted axial MRI without intravenous contra 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. 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 contras 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 contra A T1-weighted sagittal MRI with intravenous contrast in a patient with glioblastoma multiforme (GBM).
A T2-weighted axial MRI. The tumor (glioblastoma m 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) axia 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).

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 (see the image below).

Magnetic resonance (MR) spectroscopy is representa Magnetic resonance (MR) spectroscopy is representative of a glioblastoma multiforme (GBM), demonstrating a high peak ratio of choline (CHO) to creatine (CR), a decreased N-acetylaspartate (NAA) peak, and an increased lactate (LAC) peak.

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.[12]

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

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.


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.[13, 14, 15, 16, 17, 18, 19]

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.[54]

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 Histopathologic slide demonstrating a glioblastoma multiforme (GBM).


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.[20, 21, 22, 23, 55, 56]



Approach Considerations

The treatment of glioblastomas remains difficult in that no contemporary treatments are curative.[57]  While overall mortality rates remain high, improved 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 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.[58, 59, 8]  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. 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 neuro-oncologist and radiation oncologist, should be considered postoperatively.

For patients older than 70 years, less aggressive therapy is sometimes employed, using radiation or temozolomide alone.[60, 10, 24]  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.[25]

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 is enhanced in patients with MGMT promoter methylation.[26]  Data from a randomized phase III trial suggests that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter.[61]

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.[62]   

Median time to recurrence after standard therapy is 6.9 months.[63]  For recurrent glioblastoma multiforme, surgery is appropriate in selected patients, and various radiotherapeutic, chemotherapeutic, biologic, or investigational therapies are also employed.[64, 32]

Surgical Care

Because glioblastomas 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.[65] 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 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. Positron emission tomography (PET) scans and magnetic resonance (MR) spectroscopy have proven useful in discriminating between those 2 entities.

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.[66]

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%.[67]

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).[68]

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.[45] An analysis of 28 studies found a mean duration of survival advantage of total over subtotal resection for glioblastoma multiforme (14 vs 11 mo).[44, 69]

Li and colleagues compared the survival of patients having 100% removal of the contrast-enhancing tumor, with or without additional resection of the surrounding FLAIR abnormality region to that of patients undergoing 78% to < 100% extent of resection of the enhancing mass. The median survival time for patients acheiving complete resection (15.2 months) was significantly longer than that for patients undergoing less than complete resection (9.8 months; P < 0.001). The patients who underwent resection of ≥ 53.21% of the surrounding FLAIR abnormality beyond the 100% resection achieved significant prolongation of survival (median survival times 20.7).[70]

In a cohort study of 761 patients with newly diagnosed glioblastoma, Molinari et al reported longer overall survival with maximal resection of contrast-enhanced tumor plus, in younger patients, resection of non–contrast-enhanced tumor as well. Best overall survival was in two subgroups of temozolomide-treated patients: those with IDH-mutated tumors (n = 28) and those with IDH–wild-type tumors who were younger than 65 years and had a median of 100% of contrast-enhanced tumor resected and a median of 90% of non–contrast-enhanced tumor resected, resulting in no more than 5.4 mL of residual non–contrast-enhanced tumor. Overall survival in those subgroups was 37.3 months, compared with 16.5 months in comparable young patients who had more than 5.4 mL of residual non–contrast-enhanced tumor after resection.[71]

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.[72]

Oral aminolevulinic acid (ALA; Gleolan) was approved by the US Food and Drug Administration (FDA) in 2017 as an adjunct for visualization of malignant tissue during surgery in patients with malignant glioma (suspected WHO grades III or IV on preoperative imaging). During surgery, an operating microscope adapted with a blue-emitting light source and filters for excitation light of wavelength 375-440 nm, and observation at wavelengths of 620-710 nm is used to visualize PpIX (an ALA metabolite) accumulation in tumor cells that shows up as red fluorescence.[73]

Fluorescence-guided surgery (FGS), an emerging technology that combines detection devices with fluorescent contrast agents, may provide more complete and precise resection of gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate for FGS of glioma and other tumor types. In a phase 1 study, tozuleristide (BLZ-100) provided a viable fluorescence signal in both high- and low-grade glial tumors, but did not bind to normal tissues. Signal intensity in high-grade tumors was found to improve with increasing doses of tozuleristide, regardless of the time of dosing relative to surgery.[74, 75]

Medical Care

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[76] :

  • Temozolomide is recommended over procarbazine in patients who have a first relapse of glioblastoma after treatment with nitrosourea chemotherapy or who had no prior cytotoxic chemotherapy at the time of initial therapy (level II recommendation)

  • Carmustine (BCNU)-impregnated biodegradable polymer wafers are recommended for use as a surgical adjunct when cytoreductive surgery is indicated; the associated toxicities must be taken into account (level II recommendation)

  • Various agents of uncertain benefit may be considered for use, depending on the treating clinician's clinical judgment; prior treatment exposure, systemic health, and tolerance must be taken into account; enrollment in clinical trials of these agents is encouraged (level III recommendation)

According to a consensus review by the Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO), standard-of-care therapy for newly diagnosed glioblastoma in adults begins with maximal safe surgical resection.[8] In patients age 18-70 with good functional status, regardless of MGMT promoter methylation, options for subsequent therapy are as follows:

  • Clinical trial participation
  • Radiotherapy for 6 weeks and concurrent temozolomide, followed by six cycles of temozolomide with or without tumor-treating fields
  • In addition to the above, patients with MGMT methylated tumors may receive 6 weeks of radiotherapy plus six cycles of lomustine and temozolomide, with or without tumor-treating fields.

For patients age 65-70, or those with poor functional status, options in those able to tolerate multimodality therapy are as follows:

  • Radiotherapy for 6 weeks plus concurrent temozolomide, followed by six cycles of temozolomide with or without tumor-treating fields
  • Hypofractionated (or 6 wks) radiotherapy plus concurrent temozolomide followed by six cycles of temozolomide with or without tumor-treating fields

For patients age 65-70, or those with poor functional status, who are unable to tolerate multimodality therapy, therapeutic options are as follows:

  • MGMT methylated tumor - Temozolomide monotherapy, with or without tumor-treating fields
  • MGMT unmethylated tumor - Hypofractionated (or 6 wks) radiotherapy
  • Hospice/best supportive care

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.

Radiation therapy

Radiation therapy in addition to surgery or surgery combined with chemotherapy has been shown to prolong survival in patients with glioblastoma multiformes compared with surgery alone.[77, 78] The addition of radiotherapy to surgery has been shown to increase survival from 3-4 months to 7-12 months.[63, 79]

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.[80]

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.[81, 82]

Jablonska et al reported that in patients with poor clinical factors other than advanced age, the combination of hypofractionated radiation therapy and temozolomide produced results comparable to those seen with standard fractionation. In the 17 patients in the study, poor clinical factors included postoperative neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Patients received 40, 45, and 50 Gy in 15 fractions to 95% of the planning target volume (PTV), clinical target volume (CTV), and gross tumor volume (GTV), respectively. Treatment was delivered using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT).[83]

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.[84, 85]

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.

Delivery of external beam radiation therapy typically requires a waiting period of 3–5 weeks after tumor resection, to allow for wound healing and recovery, and tumor regrowth may occur during that time. Interstitial brachytherapy, in which radioactive seeds are placed intraoperatively, after tumor resection, allows immediate initiation of radiation therapy.[86] GammaTile, a brachytherapy device comprising cesium 131 (131Cs)–emitting seeds embedded in a resorbable collagen-based carrier tile, received FDA approval in 2019 for treatment of recurrent brain tumors; in 2020, approval was extended to include newly diagnosed brain tumors. Tumor cells more than 5–8 mm distant from implantation site are unlikely to benefit from interstitial brachytherapy.[87]

Radiosensitizers, such as newer chemotherapeutic agents,[88] targeted molecular agents,[40, 41] and antiangiogenic agents[41] may increase the therapeutic effect of radiotherapy.[89]

Radiotherapy for recurrent glioblastoma multiforme is controversial, though some studies have suggested a benefit to stereotactic radiosurgery or fractionated stereotactic reirradiation.[90, 91, 92]  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.[58]

Fleischmann et al reported that in patients undergoing re-irradiation for recurrent glioblastoma, concomitant treatment with bevacizumab significantly reduced the rate of radiation toxicity, both in the short and the long term. Bevacizumab was given in a dose of 10 mg/kg on days 1 and 15 of re-irradiation therapy.[93]

Chemotherapy – Antineoplastic agents

Temozolomide is an orally active alkylating agent that is indicated for newly diagnosed glioblastoma multiforme and for maintenance therapy; is also used in recurrent glioblastoma. It was approved by the United States Food and Drug Administration (FDA) in 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%).

MGMT (O6-methylguanine-DNA methyltransferase) 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 MGMT gene, decreasing the tumor cell's capacity for DNA repair and increasing susceptibility to temozolomide.[94] Note the following:

  • In older patients, MGMT promoter methylation is a favorable prognostic factor and predicts response to temozolomide. 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.
  • MGMT promoter methylation status may help guide treatment decisions. In particular, elderly patients, who are at greater risk of toxicity from combined radiotherapy and chemotherapy, might be treated with radiation therapy alone if their tumors lack MGMT methylation (and hence are less likely to respond to temozolomide) or be treated with chemotherapy alone if MGMT promoter methylation is present.[36]

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.

Chemotherapy for recurrent glioblastoma multiforme provides modest benefit at best. Agents from several classes are used. According to the National Comprehensive Cancer Network, preferred agents include the following[59] :

  • Bevacizumab
  • Temozolomide
  • Lomustine or carmustine
  • PCV (procarbazine, lomustine [CCNU], vincristine)
  • Regorafenib


Carmustine-polymer wafers (Gliadel) were approved by the FDA in 2002. Gliadel wafers are placed on the surface of the resected tumor bed. 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 cerebrospinal fluid leak and increased intracranial pressure secondary to edema and mass effect.[95, 96] 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.[97, 98]


The anti-angiogenic agent bevacizumab was approved by the FDA for recurrent glioblastoma in 2009.[99] When used with irinotecan, bevacizumab improved 6-month survival in recurrent glioma patients to 46%, compared with 21% in patients treated with temozolomide.[100, 101]  The anti-angiogenic effect of bevacizumab also decreases peritumoral edema, potentially reducing the necessary corticosteroid dose. The bevacizumab-irinotecan combination for recurrent glioblastoma multiforme has been shown to improve survival over bevacizumab alone.[102]

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.[103, 104]

Electric-field therapy

Tumor-treating fields (also known as alternating electric field therapy) is a noninvasive modality that involves the transcutaneous delivery of low-intensity, intermediate-frequency alternating electric fields that exert biophysical force on charged and polarizable molecules known as dipoles. This modality targets dividing cells in glioblastoma multiforme in several ways, including interference with the mitotic apparatus, DNA repair, and cell permeability. Normal cells are generally not harmed.[105] 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.[106]

The Optune tumor-treating field device, 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 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.[106]

In a randomized, open-label trial in 695 patients with glioblastoma, the addition of  tumor-treating fields to treatment with temozolomide improved median progression-free survival from 4.0 months to 6.7 months (hazard ratio [HR], 0.63; 95% confidence index [CI], 0.52-0.76; P < 0.001). Median overall survival improved from 16.0 months to 20.9 months (HR, 0.63; 95% CI, 0.53-0.76; P <  0.001).[107, 108]

Supportive Care

Common complications of glioblastoma that may require supportive care include the following:

  • Vasogenic brain edema
  • Seizures
  • Venous thromboembolism (VTE)

Vasogenic edema

Brain edema can cause focal neurologic deficits and, by increasing intracranial pressure (ICP), produce headache, nausea, and vomiting. Corticosteroids are used to treat patients with symptoms from peritumoral vasogenic edema. Dexamethasone is the steroid of choice for these patients, because of its potency, long half-life, and high brain penetrance. There is no standard regimen for steroid use in this setting, so dosing must be individualized. Most patients respond to low doses of dexamethasone (eg, 4-16 mg/day, given in 1–2 doses).[8, 9, 109]

Because of the many adverse effects of steroids, which worsen with increased dose and duration of treatment, dexamethasone should generally be used at the lowest effective dose and for the shortest period of time. Patients on high-dose steroids should receive concomitant gastric protection (eg, with an H2 antagonist) and those on long-term treatment (≥20 mg prednisone equivalents daily for ≥1 month) should be considered for prophylaxis against osteoporosis and Pneumocystis jirovecii pneumonia.[8]

A number of studies have reported that in addition to reducing brain edema, dexamethasone may exert an antitumoral effect, inhibiting proliferation and migration of glioblastoma cells. In contrast, other studies have reported that dexamethasone may enhance the aggressiveness of glioblastomas. These contradictory results may reflect the different actions of dexamethasone on glioblastomas with different gene expression profiles. In future, precision medicine may address this by combining glucocorticoids with agents that inhibit the unwanted signalling pathways activated by glucocorticoids.[38, 110]

In patients at risk of herniation, ICP can be reduced emergently with mannitol and hypertonic saline, diuretics, and fluid restriction, together with elevation of the head of the bed and hyperventilation. For long-term control of brain edema and treatment of steroid-refractory cases, use of antiangiogenic agents such as bevacizumab has been proposed.[9]


Almost half of patients with glioblastomas experience seizures over the course of the disease. Seizures often respond to treatment of the tumor (ie, surgical resection, radiotherapy, chemotherapy). When antiepileptic drugs (AEDs) are used, newer agents such as levetiracetam are usually selected.[8, 9]

Prolonged primary AED prophylaxis (ie, in patients who have never had a seizure) is generally not recommended. Similarly, little evidence supports the use of AEDs to prevent postoperative seizures in glioblastoma patients who have never had a seizure; however, if AEDs are used in that setting, they should be tapered 1–2 weeks postoperatively.[8, 9]

In patients who remain seizure-free while on AED therapy, deciding when to discontinue the drug can present a clinical challenge. At minimum, a period of 1 year without seizures and with clinical and radiological disease stability could be appropriate before considering withdrawal of AED treatment.[9]

Venous thromboembolism

Approximately 20% of glioblastoma patients experience VTE in the year following surgical resection.[8] Prevention and treatment of VTE in these patients is complicated by their increased risk for intracranial hemorrhage (ICH). Therapeutic anticoagulation may increase risk of ICH in patients with primary brain tumors, but lack of long-term anticoagulation has been associated with an increased risk of recurrent VTE in patients with glioblastoma.American Society of Clinical Oncology (ASCO) guidelines recommend anticoagulation for patients with primary brain malignancies and an established VTE, although because of limited data on this population, uncertainties remain about the choice of anticoagulant and selection of patients most likely to benefit.[111]

For cancer patients generally, ASCO guidelines recommend that those undergoing major surgery receive VTE prophylaxis with either unfractionated heparin or low molecular weight heparin (LMWH), unless contraindicated (eg, because of active bleeding or high bleeding risk).[111] In patients with systemic cancer, prophylaxis is started preoperatively; because of the risk of ICH, however, prophylaxis in glioblastoma patients is started within 24 hours after surgery.[9] Prophylaxis is continued for at least 7 to 10 days postoperatively.[111]

ASCO guidelines include direct oral anticoagulants (DOACs) as an option for VTE prophylaxis and treatment, but note an increased risk of major bleeding.[111] However, a retrospective study by Carney et al found that in patients with primary brain tumors, the incidence of major hemorrhage was significantly lower with use of DOACs compared with LMWH. These authors concluded that DOACs are a reasonable option for treatment of VTE in this population.[112]


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.

Investigational Approaches

The limited efficacy of current therapeutic options for glioblastoma multiforme (GBM) has prompted research into alternative approaches. Therapy modalities under investigation include the following[8] :

  • Targeted molecular therapies
  • Immunotherapy (eg, vaccines, checkpoint inhibitors, oncolytic viruses) [113]
  • Nanomedicines that can cross the blood-brain barrier [114]
  • Stem cells [115]
  • Cannabinoids [116]
  • Ketogenic diet [117]

Genotyping of brain tumors may have applications in stratifying patients for clinical trials of various novel therapies. In about 50% of patients with glionas, circulating tumor DNA can be sequenced from cerebrospinal fluid, allowing genotyping of the tumor without the need for brain re-biopsy.[118]

Vaccine therapy

Vaccines being studied for treatment of glioblastoma include modified polio vaccine and cytomegalovirus (CMV) vaccine.

Modified polio vaccine therapy

The poliovirus receptor CD155 is broadly upregulated on the surface of malignant solid tumors, and a preliminary study of intratumoral infusion of a modified poliovirus vaccine has demonstrated benefit in some cases of recurrent  malignant glioma. In a dose-finding and toxicity study, 61 patients with recurrent supratentorial WHO grade IV malignant glioma received seven doses of a live attenuated poliovirus type 1 vaccine with its cognate internal ribosome entry site replaced with that of human rhinovirus type 2. The recombinant nonpathogenic polio–rhinovirus chimera was infused into the glioma via an implanted catheter.[119]

In contrast to overall survival rates in a historical control group, which declined steadily to 14% at 24 months and 4% at 36 months, overall survival in the study patients stabilized at 21% at 24 months, remaining at that rate through 36 months. Adverse events that affected more than 20% of the study patients in the dose-expansion phase included headache (52%), hemiparesis (50%), seizure (45%), dysphasia (28%), and cognitive disturbance (25%).[119]

Cytomegalovirus vaccine

Approximately 90% of glioblastomas express CMV proteins, and Batich et al have reported benefit with a dendritic cell vaccine targeting CMV antigen pp65, using CMV as a proxy for glioblastoma.[120] Patients are first treated with dose-intensified temozolomide, as the temozolomide induces lymphopenia, which provides an opportunity to retrain the immune system.

In a study of 11 patients with newly diagnosed glioblastoma received temozolomide, 100 mg/m2/d × 21 days per cycle, and at least three pp65-directed vaccines admixed with granulocyte-macrophage colony-stimulating factor on day 23 ± 1 of each cycle. Despite increased proportions of regulatory T cells (Tregs), median progression-free survival was 25.3 months and overall survival was 41.1 months; three patients remained progression-free more than 7 years after diagnosis.[120]

Tyrosine kinase inhibitors

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.[121, 122, 123] Other targets include PDGFR, VEGFR, mTOR, farnesyltransferase, and PI3K.

Checkpoint inhibitor therapy

In preclinical studies, inhibitors of programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) have shown some potential for treatment of glioblastoma. In clinical studies, however, anti-PD-1/PD-L1 monotherapy has shown few satisfactory results. Efficacy may be better in certain patient subgroups (eg, those with higher tumor mutation burden, higher microsatellite instability, mismatch repair system deficiency,  germline POLE mutation). Neoadjuvant checkpoint inhibitor therapy has shown promise.[124]

CheckMate 143, a phase 3 randomized clinical trial, compared overall survival (OS) in 369 patients with recurrent glioblastoma treated with either bevacizumab or the  (PD-L1) inhibitor nivolumab. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab than with nivolumab (23.1% versus 7.8%, respectively). The rates of grade 3/4 treatment-related adverse events were similar in the two groups.[125]

Drug delivery systems

A major hindrance to the use of chemotherapeutic agents for brain tumors is that the blood-brain barrier effectively excludes many agents from the central nervous system. This has inspired the development of novel methods of intracranial drug delivery to deliver higher concentrations of chemotherapeutic agents to the tumor cells while avoiding the adverse systemic effects of these medications.

Pressure-driven infusion of therapeutic 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 been used to deliver both conventional chemotherapy drugs (eg, paclitaxel, topotecan) and investigational agents (eg, interleukin-4–Pseudomonas exotoxin fusion protein). Although preclinical and clinical studies involving CED has shown that it is safe, it has proved only somewhat effective, and has technical shortcomings that need to be addressed.[126]


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.



Guidelines Summary

The National Comprehensive Cancer Network (NCCN) has released guidelines on central nervous system (CNS) cancers that include recommendations for the diagnosis and treatment of glioblastomas (grade 4 gliomas). The goals of surgery are to obtain a diagnosis, alleviate symptoms of increased intracranial pressure or compression, increase survival, and decrease the need for corticosteroids. Adjuvant treatment options depend on the patient performance status (PS), age, and MGMT promoter methylation status.[59]  

Category 1 recommendations for first-line treatment are as follows[59] :

  • In patients 70 years or younger with good PS, regardless of the tumor's MGMT methylation status - Fractionated standard brain radiation therapy (RT) plus concurrent and adjuvant temozolomide (TMZ) with or without alternating electric field therapy.
  • In patients older than 70 years with good PS and MGMT promoter–methylated tumors - Hypofractionated brain RT plus concurrent and adjuvant TMZ or standard brain RT plus concurrent and adjuvant TMZ and alternating electric field therapy.
  • In patients older than 70 years with good PS and MGMT unmethylated or indeterminant tumors - Standard brain RT plus concurrent and adjuvant TMZ and alternating electric field therapy.

Progressive glioblastoma

Congress of Neurological Surgeons guidelines for the management of progressive glioblastoma include the following recommendations[127] :

  • Gadolinium contrast-enhanced magnetic resonance imaging (MRI) is recommended for diagnosis of progressive glioblastoma multiforme (pGBM). Diffusion-weighted imaging should be considered as part of the standard MRI sequences used.
  • 18-Fluorodeoxyglucose (FDG) is not recommended for routine diagnosis. Techniques using newer radiotracers may assist in the diagnosis.
  • Cytoreductive surgery is recommended for patients with symptomatic pGBM. It is also recommended to improve overall survival in pGBM patients.
  • Repeat assessment of 06-methylguanine-DNA methyltransferase (MGMT) methylation and isocitrate dehydrogenase status is not indicated.
  • Programmed death ligand (PDL) 1/mismatch repair enzyme activity is not a useful component of standard diagnostic testing.
  • If epidermal growth factor receptor amplification was not previously measured, its assessment at progression may be of diagnostic value.
  • Large panel sequencing may be considered in patients who are eligible for or interested in molecularly guided therapy or clinical trials.
  • Benefit may be derived from treatment with temozolomide (TMZ; especially with progression after > 5 months off TMZ).
  • Fotemustine is suggested in elderly patients with methylated MGMT promoter status.
  • Tumor treatment fields (TTFs) with other chemotherapy may be considered for adult patients.
  • The following are not suggested: (1) TMZ combined with other cytotoxic agents as standalone therapy; (2) other chemotherapeutic agents (including platinum compounds and topoisomerase inhibitors); (3) other cytotoxic therapies (eg,  perillyl alcohol or ketogenic diet) as standalone therapy; and (4) oncolytic virotherapy.
  • Re-irradiation should be considered for patients with pGBM; it can be safely used in elderly patients.
  • Bevacizumab does not provide increased overall survival when used to treat pGBM. There is not sufficient evidence to identify benefits and harms associated with its use in combination with other agents.

Palliative care

European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma include the following recommendations for treatment of complicating signs and symptoms[128] :

  • Headache – Corticosteroids (dexamethasone) are the mainstay of treatment for headache in patients with gliomas. Analgesics and co-analgesics could also be considered in the treatment of headache (in accordance with the World Health Organization cancer pain ladder).
  • Seizures – If oral administration of antiepileptic drugs is not an option, intranasal midazolam and buccal clonazepam are a feasible way to treat seizures in the end of life phase, when patients often have difficulty swallowing.
  • Venous thromboembolism (VTE) – VTE prophylaxis with low molecular weight heparin should be started postoperatively within 24 hours. No data support extending primary VTE prophylaxis beyond the postoperative period; in brain tumor patients who have experienced VTE, the duration of secondary prophylaxis should be planned individually, but is lifelong in most patients.
  • Fatigue – There is to date no proof of efficacy for any pharmacologic or nonpharmacologic intervention for fatigue in glioma patients.
  • Mood and behavioral disorders – Limited evidence supports the use of several pharmacological interventions (eg, methylphenidate, donepezil) for mood disorders in glioma patients. Multimodal psychosocial intervention may improve depressive symptoms.
  • Neurorehabilitation – Brain tumor patients may benefit from postoperative early rehabilitation, as well as rehabilitation after tumor-specific treatment.
  • Cognition – Medical treatment to prevent or treat cognitive decline in brain tumor patients is not recommended. However, cognitive rehabilitation has modest positive effects and should be considered, especially in young glioma patients with relatively favorable prognosis.


Medication Summary

The alkylating agent temozolomide is used for treatment of newly diagnosed glioblastoma multiforme, and the monoclonal antibody bevacizumab is used for treatment of recurrences. In addition, several medications are used for supportive care. Vasogenic cerebral edema is typically managed with corticosteroids (eg, dexamethasone), usually in combination with some form of antiulcer agent (eg, famotidine).

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. A guideline from the Society for Neuro-Oncology and European Society of Neuro-Oncology recommends against routine prophylaxis with antiepileptic drugs (AEDs) in patients with newly diagnosed brain tumors and found insufficient evidence to recommend prescribing AEDs to reduce the risk of perioperative or postoperative seizures in patients undergoing surgery for brain tumors.[129]

Antineoplastic agents

Class Summary

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.

Carmustine (BiCNU)

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

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.

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.

Lomustine (CCNU, Gleostine)

Although its mechanism of action is not completely understood, lomustine causes inhibition of DNA & RNA synthesis resulting from carbamylation of DNA polymerase, alkylation of DNA, and alteration of RNA proteins.


Class Summary

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.

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.

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.


Class Summary

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.


Questions & Answers


What is glioblastoma multiforme (GBM)?

What are common symptoms of glioblastoma multiforme (GBM)?

What are the neurologic signs and symptoms of glioblastoma multiforme (GBM)?

What causes glioblastoma multiforme (GBM)?

How is glioblastoma multiforme (GBM) diagnosed?

How is glioblastoma multiforme (GBM) treated?

What are surgical options for the treatment of glioblastoma multiforme (GBM)?

What is the role of radiotherapy in the treatment of glioblastoma multiforme (GBM)?

What is the efficacy of chemotherapy for the treatment of glioblastoma multiforme (GBM)?

Which medications are used in the treatment of glioblastoma multiforme (GBM)?

What is glioblastoma multiforme (GBM)?

What is the pathophysiology of glioblastoma multiforme (GBM)?

What is the role of genetics in the pathophysiology of glioblastoma multiforme (GBM)?

Which genetic tumor markers have been used to classify glioblastoma multiforme (GBM)?

Which genetic abnormalities result in more malignant glioblastomas?

Which genetic alterations are associated with primary glioblastomas?

What is the pathophysiology of glioblastoma multiforme (GBM) in cerebral hemispheres?

What is the etiology of glioblastoma multiforme (GBM)?

What is the prevalence of glioblastoma multiforme (GBM)?

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Which clinical history findings are characteristic of glioblastoma multiforme (GBM)?

What are physical findings characteristic of glioblastoma multiforme (GBM)?


Which conditions should be considered in the differential diagnosis of glioblastoma multiforme (GBM)?


What is the role of lab studies in the workup of glioblastoma multiforme (GBM)?

What is the role of imaging studies in the diagnosis of glioblastoma multiforme (GBM)?

What is the role of MRI in the diagnosis of glioblastoma multiforme (GBM)?

What is the role of positron emission tomography (PET) scans and magnetic resonance (MR) spectroscopy in the diagnosis of glioblastoma multiforme (GBM)?

What is the role of EEG in the workup of glioblastoma multiforme (GBM)?

What is the role of lumbar puncture and CSF studies in the workup of glioblastoma multiforme (GBM)?

Which histologic findings are characteristic of glioblastoma multiforme (GBM)?

How is glioblastoma multiforme (GBM) staged?


What are the treatment options for glioblastoma multiforme (GBM)?

What is included in standard treatment of glioblastoma multiforme (GBM)?

What is the role of temozolomide in the treatment of glioblastoma multiforme (GBM)?

What are the goals for surgery in glioblastoma multiforme (GBM)?

Which factors have prognostic significance in glioblastoma multiforme (GBM)?

What are survival rates for surgery for glioblastoma multiforme (GBM)?

What aids are used to visualize glioblastoma multiforme (GBM) during surgery?

What are the AANS/CNS clinical practice guidelines for use of cytotoxic chemotherapy in the treatment of glioblastoma multiforme (GBM)?

What is standard-of-care therapy for the treatment of glioblastoma multiforme (GBM)?

What is the role of radiation therapy in the treatment of glioblastoma multiforme (GBM)?

What is the role of interstitial brachytherapy in the treatment of glioblastoma multiforme (GBM)?

Which radiation therapies for glioblastoma multiforme (GBM) are under investigation?

What is the efficacy of radiotherapy for the treatment of recurrent glioblastoma multiforme (GBM)?

What are the benfits of concomitant threatment with bevacizumab for patients undergoing re-irradiation for recurrent glioblastoma?

What is the role of antineoplastic chemotherapy in the treatment of glioblastoma multiforme (GBM)?

What are the preferred chemotherapy agents for the treatment of glioblastoma multiforme (GBM)?

What is the role of carmustine-polymer wafers (Gliadel) in the treatment of recurrent glioblastoma multiforme (GBM)?

What is the role of bevacizumab the treatment of glioblastoma multiforme (GBM)?

What is the role of electric-field therapy for the treatment of glioblastoma multiforme (GBM)?

Which complications of glioblastoma multiforme (GBM) may require supportive care?

How is vasogenic edema managed in patients with glioblastoma multiforme (GBM)?

How are seizures managed in patients with glioblastoma multiforme (GBM)?

How is VTE managed in patients with glioblastoma multiforme (GBM)?

Which specialist consultations are needed for the treatment of glioblastoma multiforme (GBM)?

Which therapeutic approaches are under investigation for the treatment of glioblastoma multiforme (GBM)?

What is the role of vaccine therapy in the treatment of glioblastoma multiforme (GBM)?

What is the role of tyrosine kinase inhibitors in the treatment of glioblastoma multiforme (GBM)?

What is the role of checkpoint inhibitor therapy in the treatment of glioblastoma multiforme (GBM)?

What is the role of convection-enhanced delivery (CED) in the treatment of glioblastoma multiforme (GBM)?

Which activity modifications are used in the treatment of glioblastoma multiforme (GBM)?


What are the NCCN guidelines on diagnosis and treatment of glioblastoma multiforme (GBM)?

What are the EANO guidelines for the palliative care of patients with glioblastoma multiforme (GBM)?


Which medications are used in the treatment of glioblastoma multiforme (GBM)?

Which medications in the drug class Corticosteroids are used in the treatment of Glioblastoma Multiforme?

Which medications in the drug class Anticonvulsants are used in the treatment of Glioblastoma Multiforme?

Which medications in the drug class Antineoplastic agents are used in the treatment of Glioblastoma Multiforme?