Glioblastoma

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Practice Essentials

Glioblastoma (GBM), formerly known as glioblastoma multiforme, is the most common and malignant of adult gliomas.[1]  Gliomas are primary neoplasms of the central nervous system that arise from glial cells or their progenitors. See the image below.



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Coronal section of a glioblastoma in the left temporal lobe with typical coloration: thickened tan cortex overlying a large central region of yellowis....

In the fifth edition of the World Health Organization (WHO) Classification of Central Nervous System (CNS) Tumors, published in 2021,[2] glioblastoma was redefined according to molecular testing with respect to isocitrate dehydrogenase (IDH) status. Previously, glioblastoma had included high-grade IDH-wildtype and IDH-mutant neoplasms. The term glioblastoma is now exclusively used to describe adult IDH-wildtype tumors. Highest-grade IDH-mutant tumors have been reclassified as astrocytoma IDH-mutant CNS WHO grade 4. The term glioblastoma multiforme is no longer used, and the term glioblastoma is no longer applied to pediatric tumors.[3]

The 2021 WHO classification defines glioblastoma as an adult grade 4 diffuse astrocytic glioma that is IDH-wildtype and H3-wildtype and has one or more of the following histologic or genetic features[3, 2] :

For more information on the new diagnostic criteria, see Background.

Throughout this article, glioblastoma will refer exclusively to glioblastoma IDH-wildtype CNS WHO grade 4 unless stated otherwise. Astrocytoma IDH-mutant CNS WHO grade 4 is discussed in Astrocytoma.

Glioblastoma has three distinct histologic variants: giant cell glioblastoma, gliosarcoma, and epithelioid glioblastoma (see Workup/Histologic Findings).[3]

Signs and symptoms

The clinical history of a patient with GBM is usually short (< 3 months in > 50% of patients).[4] The most common presenting signs and symptoms are seizure and cognitive disorder.[5] Other presenting symptoms include the following[6] :

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

See Presentation for more detail.

Diagnosis

Because GBM is now a molecular diagnosis, genetic studies for IDH and H3 status are essential, and genetic studies for TERT promoter mutation, EGFR gene amplification, and +7/-10 chromosome copy number changes are important as well. Tumor genetics are also useful for predicting response to adjuvant therapy.

Imaging studies of the brain are essential for diagnosis. Magnetic resonance imaging (MRI), with and without contrast, is the study of choice.[19, 20] Other possible studies include the following[21] :

Cerebral angiography is not necessary

Other diagnostic measures that may be considered include the following:

Staging is not practiced. 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. GBM is not known to metastasize outside of the central nervous system. 

See Workup for more detail.

Management

No current treatment is curative. Standard treatment consists of biopsy or resection followed by early (< 48 h) postoperative MRI or CT and medical care.[22] Choice of therapy is based on patient age, performance status, and MGMT methylation status, as follows:

Surgical options include biopsy, subtotal resection, and gross total resection (associated with better survival). Because GBM cannot be cured surgically, the surgical goals are as follows[23] :

In some cases, stereotactic biopsy is followed by RT (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). In several studies, the extent of surgery has been shown to affect length of survival.[24, 25, 26, 27, 28, 29, 30]

Key points regarding RT for GBM include the following: 

The optimal chemotherapeutic regimen for GBM is not yet defined, but adjuvant chemotherapy appears to yield a significant survival benefit in some patients.[42, 43, 44, 45, 31, 46, 34] Agents used include the following:

Because GBM cannot be cured, regular follow-up to monitor for progression/recurrence is essential and consists of brain MRI 2-8 weeks after RT, then every 2-4 months for 3 years, then every 3-6 months indefinitely.[23]

See Treatment and Medication for more detail.

For patient education resources, see the Brain Cancer Resource Center as well as the patient education article Brain Cancer from the American Brain Tumor Association (ABTA).

Background

Of the estimated 83,750 primary brain and other central nervous system tumors diagnosed in the United States in 2021, approximately 20,800 (or 24.84%) were gliomas.[47] Gliomas arise from glial cells (ie, astrocytes, oligodendrocytes, ependymal cells) or their precursors and comprise a heterogeneous group of neoplasms that differ in location within the central nervous system, age and sex distribution, growth potential, extent of invasiveness, morphologic features, tendency for progression, and treatment response.[48] Glioblastoma (GBM), formerly known as glioblastoma multiforme, is by far the most common and most malignant of the glial tumors, accounting for approximately 45-55% of all gliomas and 12-15% of all primary brain tumors.[48, 49, 50, 47]

Previously, in the 2016 revision of the fourth edition of the World Health Organization (WHO) Classification of Central Nervous System (CNS) Tumors, glioblastomas were divided into three classes according to isocitrate dehydrogenase (IDH) mutation status: IDH wildtype; IDH mutant; and not otherwise specified (NOS), which was applied to tumors for which IDH evaluation could not be performed.[51, 52]

IDH-wildtype GBMs corresponded closely to the clinically defined “primary” glioblastomas, a historical term describing GBMs that manifested de novo (ie, without evidence of a pre-existing, less-malignant precursor lesion), typically affected older patients, and were associated with a short clinical history and poor prognosis.[4, 53, 54, 52] IDH-mutant GBMs corresponded closely to “secondary” glioblastomas—GBMs that developed through malignant progression from a low-grade astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III), typically affected younger patients, and were associated with a longer clinical history and better prognosis.[4, 53, 54, 52]

In 2021, the fifth edition of the WHO Classification of CNS Tumors updated the diagnostic criteria for glioblastoma to reflect increasing evidence that IDH-wildtype and IDH-mutant glioblastomas constitute distinct disease entities that evolve through different genetic pathways, affect different patient populations, and respond to different therapies.[3, 2] The term “IDH-mutant glioblastoma” was eliminated, and all tumors previously classified as IDH-mutant glioblastoma were reclassified as astrocytoma IDH-mutant CNS WHO grade 4.

To be considered a glioblastoma under the new guidelines, a tumor must be a diffuse astrocytic glioma, must be IDH-wildtype, must affect an adult (the term “glioblastoma” is no longer applied to pediatric tumors), and must possess any one of the following histopathological or molecular features: microvascular proliferation, necrosis, TERT promoter mutation, EGFR gene amplification, or +7/−10 chromosome copy number changes.[2] In keeping with the 2021 classification, throughout this article, the term glioblastoma will refer exclusively to glioblastoma IDH-wildtype CNS WHO grade 4 unless stated otherwise. Astrocytoma IDH-mutant CNS WHO grade 4 is discussed in Astrocytoma.

The fifth edition of the WHO Classification of CNS Tumors recognizes three distinct histologic variants of glioblastoma: giant cell glioblastoma, gliosarcoma, and epithelioid glioblastoma.[2] For more information on the differences between these variants, see Workup/Histologic Findings.

Composed of a heterogeneous mixture of poorly differentiated neoplastic astrocytes, glioblastomas occur most often in the subcortical white matter and deeper grey matter of the cerebral hemispheres.[55, 56, 57] In many cases, tumor infiltration 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” (see the image below) Far less frequently, glioblastoma affects the brainstem, the cerebellum, or the spinal cord; if a tumor is identified in these midline locations, other forms of diffuse glioma should be considered (eg, diffuse midline glioma, H3 K27 altered).[2]



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This typical untreated glioblastoma, here with the classic "butterfly" configuration, is a necrotic hemorrhagic mass. Courtesy of Wikimedia Commons [a....

In contrast to astrocytomas IDH-mutant CNS WHO grade 4, which develop from lower-grade astrocytomas (WHO grade 2 or 3) glioblastomas IDH-wildtype CNS WHO grade 4 manifest de novo, without any evidence of a pre-existing, less-malignant precursor lesion. Patients typically present after a short clinical history (usually less than 3 months).[4] Treatment is palliative and includes surgery, radiotherapy, and chemotherapy.[58, 23, 59]

Pathophysiology

Origin

Single-cell RNA sequencing of human tumors has shown that glioblastomas (as previously defined, including pediatric glioblastomas) are composed of a heterogeneous mixture of poorly differentiated neoplastic cells that recapitulate various neurodevelopmental trajectories (eg, astrocyte-like, neural progenitor–like, and oligodendrocytic progenitor–like) and are affected by interactions with immune cells (mesenchymal-like).[60] While mouse models of glioblastoma have shown that a variety of central nervous system cell types—including astrocytes, neurons, oligodendrocyte precursors, and neural precursors—can transform into malignant cells that recapitulate features of glioblastoma,[61, 62] multiple lines of inquiry suggest that the most likely cell of origin is a neural precursor in the subventricular zone.[63, 64, 65]

Location

Glioblastomas are preferentially located in the subcortical white matter and deeper grey matter of the cerebral hemispheres and affect all cerebral lobes.[55, 56, 57] Reports of the most commonly affected lobes vary, with one study finding that glioblastoma most frequently affects the temporal lobe (followed by the insula, parietal lobes, and near the periventricular area frontally and occipitally),[56] and another showing that glioblastoma most frequently affects the frontal lobe (followed by temporal, parietal, and occipital).[57] Other sites for glioblastoma that are much less common include the brainstem, the cerebellum, and the spinal cord.[66] With lesions in those locations, other forms of diffuse glioma should be considered (eg, diffuse midline glioma, H3 K27 altered). 

Invasion

Glioblastomas often spread along white matter tracts (eg, the corpus callosum, internal capsule, optic radiation, anterior commissure, fornix, and subependymal regions), but infiltration can also involve cortical and deep gray matter structures (eg, the basal ganglia).[2] 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” (see the image below).



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This typical untreated glioblastoma, here with the classic "butterfly" configuration, is a necrotic hemorrhagic mass. Courtesy of Wikimedia Commons [a....

A subset of glioblastomas (0.5-35% in different studies) manifest as multiple lesions and are referred to as either “multifocal” or “multicentric.”[67, 68, 69, 70] Multifocal glioblastomas spread contiguously between multiple foci, while multicentric glioblastomas are distinct, widely separated lesions. Multifocal glioblastomas appear to be more common than multicentric glioblastoma, as careful histologic analyses have shown that only 2.4% of glioblastomas are truly multiple independent tumors.[71, 72] The genetic and pathologic mechanisms driving multifocality are unclear, but studies have shown that these tumors typically have EGFR gene amplifications as well as TERT promotor and PTEN mutations.[73]

In contrast to low-grade CNS malignancies, glioblastomas contain extensive hypoxic areas—ie, regions where oxygen demand exceeds oxygen supply.[2] These hypoxic areas occur in GBM due to rapid cell proliferation and erratic neovascularization that leads to poor oxygen diffusion.[74] Hypoxia increases tumor aggressiveness, promoting the migration of glioblastoma cells and infiltration of surrounding healthy brain tissue, which in turn makes curative surgical resection impossible.[75]

Although glioblastomas can seed the cerebrospinal fluid via drop metastases or growth along ventricular surfaces, invasion of the dura mater, venous sinuses, and bone is rare.[76, 77, 78, 79, 80, 81] Extracranial metastases are also uncommon, occurring in just 0.4-0.5% of cases.[82, 83] The infrequency of metastasis has been attributed to immune mechanisms that disrupt implantation and growth in conjunction with the short survival of glioblastoma patients.[2, 84, 85, 82, 83] When metastases do occur, they usually manifest at the time of recurrence and infiltrate bones, lymph nodes, liver, and lungs.[82, 83] Historical case studies have also implicated ventricular shunts as a vehicle for rare extraneural metastases.[86, 87]

Microvascular Proliferation

One of the histopathologic hallmarks of glioblastoma is microvascular proliferation—the rapid growth of small-lumen, multilayered blood vessels.[2] (See the image below.) Characterized by the formation of two or more blood vessels that share a common wall of endothelial and smooth muscle cells, microvascular proliferation typically occurs in the hypoxic core of glioblastomas, where new capillaries sprout from pre-existing vessels.[88]



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Hematoxylin and eosin stain of a biopsy specimen of a glioblastoma shows prominent microvascular proliferation (formation of a mulitlayered "glomerulo....

Microvascular proliferation is driven by several mechanisms, including hypoxia-induced endothelial proliferation, secretion of angiogenic factors (eg, vascular endothelial growth factor [VEGF]) by tumor cells, and incorporation of tumor cells into vascular endothelium.[88] The final result of microvascular proliferation is the formation of large-lumen microvessels that often have a glomeruloid shape and visible mitoses.[89, 90] Although interactions between blood vessels and tumor cells during microvascular proliferation are known to promote tumor growth,[91, 92] studies exploring the use of the anti-VEGF monoclonal antibody bevacizumab in the treatment of glioblastoma have produced conflicting results.[93, 94]

Necrosis 

The other defining histopathologic feature of glioblastoma is necrosis, or cell death (see the image below). Several mechanisms have been proposed to explain the occurrence of necrosis in GBM. One hypothesis is that the vessels formed during microvascular proliferation have poorly formed, thrombogenic luminal surfaces. This thrombogenicity is exacerbated by the secretion of pro-coagulation molecules (eg, tissue factor) from glioblastoma cells.[95] As microthrombi form, the surrounding tissue becomes infarcted, leading to necrosis and creating an acidic, hypoxic, and hypoglycemic microenvironment. Nearby glioblastoma cells retreat from this hostile microenvironment, forming the characteristic pseudopalisades of less-proliferative, hypoxia-inducible factor 1-alpha (HIF1-α)–secreting cells.[96, 97]



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Necrosis is another histopathologic hallmark of glioblastoma. As seen here, necrotic areas often create serpentine patterns, and tumor cells form pseu....

Mutations

Of all the astrocytic neoplasms, glioblastomas contain the greatest number of genetic changes. In most cases these result from the accumulation of multiple mutations. Some of the more common genetic abnormalities, including the three diagnostic mutations, are described below.

Epidermal growth factor receptor (EGFR)

The EGFR gene encodes a transmembrane receptor tyrosine kinase involved in the regulation of cell proliferation.[98] Approximately 60% of glioblastomas show evidence of EGFR alterations.[98] While multiple alterations have been identified—including amplification, mutation, fusion, rearrangement, and altered splicing—all clinically relevant changes increase activity of the EGFR gene and, ultimately, promote proliferation, invasion, and resistance to radiotherapy and chemotherapy.[99, 100] The most frequent alteration is EGFR amplification, which occurs in roughly 40% of glioblastomas.[101, 102]

Several trials exploring EGFR-targeted therapy have failed to produce meaningful results, likely due to a combination of the heterogeneity of EGFR alterations in GBM, low drug specificity, and poor brain penetration.[103] However, recent studies have shown that EGFR has pro-survival kinase-independent functions in glioblastoma cells, which has inspired novel approaches to EGFR-targeted therapy.[[104, 105]

Telomerase reverse transcriptase (TERT) promoter

The TERT gene encodes a reverse transcriptase subunit of telomerase, a ribonucleoprotein responsible for repairing telomeres damaged during cellular replication, thereby maintaining telomere length and preventing cell death.[106] Telomere lengthening is required for the infinite proliferation of tumor cells, and thus TERT promoter mutations, which are associated with increased telomerase activity, contribute to tumorigenesis in glioblastoma.[107]

Two TERT promoter mutations—C228T and C250T—result in the upregulation of TERT expression and have been reported in nearly 80% of glioblastomas.[106, 108] While some studies have reported a negative association between TERT promoter mutations and survival in glioblastoma patients,[109, 110] others have failed to report this,[111, 112] and the prognostic significance of TERT remains uncertain.[113] While various telomerase-inhibiting therapies are being explored in preclinical and clinical trials,[114, 115, 116] none has yet been approved for clinical care in glioblastoma.

+7/−10 chromosome copy number changes

Whole chromosome gain (trisomy 7) and whole chromosome 10 loss (monosomy 10) are among the most common numerical chromosome alterations in glioblastoma.[117] They frequently occur in combination (+7/-10); less frequent are isolated gains in chromosome 7 or isolated losses in chromosome 10. The sensitivity and specificity of +7/-10 for glioblastoma are 59% and 98%, respectively.[102] Copy number variations in chromosomes 7 and 10 are some of the earliest events in glioblastoma tumor development.[118] The EGFR gene is located on the short arm of chromosome 7 (7p11.2), and thus, gain of chromosome 7 is associated with EGFR amplification.[118] These mutations are associated with a poor prognosis.[2]

The p14ARF-MDM2-MDM4-p53 pathway

The p53 pathway is an essential component of DNA repair, cell cycle arrest, and apoptosis. Alterations in this pathway are extremely common, occurring in nearly 90% of glioblastomas.[118, 119] Mutations in p53, the classic tumor suppressor gene, are present in 20-25% of glioblastomas.[118, 120] Mutations in MDM4 and MDM2, upstream inhibitors of p53, constitute an alternative mechanism by which tumor cells can escape p53-regulated control of cellular proliferation and occur in roughly 15% of glioblastomas.[118] Furthermore, MDM2 is inhibited by p14ARF, an alternate reading frame protein encoded by the COKN2A locus, which is deleted in approximately 60% of glioblastomas.[118, 119] Curiously, mutations in p14ARF, MDM2, MDM4, and p53 usually occur in isolation from one another.[118]

PTEN and the PI3K-AKT-mTOR pathway

The PI3K pathway, an important regulator of cellular proliferation, is activated by RAS and/or receptor tyrosine kinases (including EGFR—see above) and inhibited by the tumor suppressor gene PTEN, which is located on the long arm of chromosome 10 (10q23.3) and encodes a tyrosine phosphatase. Alterations in this pathway are present in roughly 90% of glioblastomas, and amplifications involving EGFR are especially common.[118, 119] Mutations in or deletion of PTEN are less frequent, occurring in approximately 40% of glioblastomas.[121, 118] PTEN mutations increase resistance to multiple therapies and are strongly associated with shorter survival in glioblastoma patients.[122, 123]

Other mutations

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.[118, 119]

Etiology

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 (e.g., neurofibromatosis type 1, Turcot syndrome, Lynch syndrome, Li-Fraumeni syndrome).[7, 8]

The only established non-genetic risk factor for glioblastoma is ionizing radiation to the head or neck.[8, 124] Ionizing radiation is the type of radiation produced by atomic bombs, therapeutic radiation, CT scans, MRI scans, and x-rays. However, while survivors of atomic bomb radiation and patients who receive therapeutic radiation for lymphoblastic leukemia are more likely to develop glioblastoma,[125, 126] patients who receive diagnostic irradiation (ie, CT, MRI, x-ray) do not appear to be at increased risk.[127] Regarding the former, higher doses of radiation are associated with a greater risk of developing glioblastoma and a shorter latency period.[9, 10]

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.[11, 12, 13, 14, 15, 17, 18]

Studies of association with head injury, N-nitroso compounds, occupational hazards, and electromagnetic field exposure have been inconclusive.[16]

There is a growing consensus that atopic conditions, including asthma, hay fever, eczema, and food allergies, are protective, reducing the risk of various forms of glioma—including glioblastoma—by nearly 40%.[9, 128, 129] This relationship is thought to be due to increased immune surveillance in patience with allergies, but more research is required to elucidate the underlying mechanisms. 

Epidemiology

Glioblastoma is the most frequent malignant brain tumor in adults, accounting for approximately 12-15% of all primary intracranial neoplasms and 45-55% of all gliomas.[49, 50, 47] The overall incidence of glioblastoma varies worldwide and is highest in North America, Australia, and Northern and Western Europe.[130, 131] In the United States, the average annual age-adjusted incidence rate of GBM is 3.19 per 100,000 persons, and the overall prevalence is 9.23 per 100,000 persons.[49] Recent studies have shown that incidence is increasing in England,[132] but there does not appear to be any trend toward increased incidence in the United States or Canada.[133] These discrepancies may be due to differences in genetics or environmental factors, but they are more likely a reflection of international differences in surveillance procedures, reporting practices, and changes in classifications of glioblastoma over time.[51]

In the United States, glioblastoma is 1.59 times more common in males than females, with an annual age-adjusted incidence of 4.03 and 2.54 per 100,000 persons, respectively.[134] With regard to race and ethnicity, incidence is highest among non-Hispanic whites (3.51 per 100,000 persons) and lowest among Asians or Pacific Islanders (1.18 per 100,000 persons).[134]  

Glioblastoma may manifest in persons of any age but preferentially affects older adults. The incidence rate increases with age, peaking at 75-79 years, and the median age at diagnosis is 64 years.[49, 135]

Although existing epidemiologic data are based on the previous WHO guidelines, implementation of the 2021 WHO guidelines is unlikely to result in a substantial change in incidence rates, because approximately 90% of all GBMs were IDH-wildtype while just 10% were IDH-mutant.[51, 136] However, because IDH-mutant GBM were more common in young people and in women, there will likely be a notable increase in the average age of onset and the incidence for men.[136]

Prognosis

Glioblastomas are among the most malignant of human neoplasms and have one of the worst survival rates of any brain tumor[49] —without therapy, glioblastoma patients have a median survival of 3 months.[137] Although current treatments remain palliative, they do prolong survival, and patients treated with optimal therapy—including surgical resection, radiation therapy, and chemotherapy—have a median survival of approximately 15-18 months.[138, 139]

There has been a significant increase in both 1-year and 5-year survival rates over the past 25 years. From 1997 to 2012, 1-year survival increased from 24.3% to 43.0%, and 5-year survival increased from 2.1% to 5.6%.[139, 140] These trends are likely due to widespread adoption of the current standard therapy in the early-mid 2000s as well as increased screening and earlier detection due to improvements in imaging technology.[141] It is important to note, however, that these data apply to GBM as previously defined by the WHO (ie, as an IDH-wildtype or IDH-mutant grade IV astrocytoma) and that the prognosis for GBM as currently defined has yet to be determined.  

Patient survival depends on a variety of clinical parameters. Younger age, higher Karnofsky Performance Scale (KPS) score at presentation (the KPS is a standard measure of the ability of cancer patients to perform daily tasks), radiotherapy, and chemotherapy all correlate with improved outcome.[142, 143, 141] Clinical evidence also suggests that a greater extent of resection favors longer survival,[144, 145, 146] and tumors deemed unresectable due to location (eg, in the brainstem) portend a poorer prognosis.[147] Despite identification of multiple factors that influence survival, individual prediction of clinical outcome has remained an elusive goal. 

The elderly (ie, persons 65 years of age or older) represent an important subgroup among glioblastoma patients, as they are more likely than their younger counterparts to suffer from medical comorbidities and polypharmacy, delays in diagnosis (early symptoms of GBM may be misinterpreted as signs of dementia or depression), treatment toxicities, precarious living situations with few social supports, and reduced functional and cognitive reserve (corresponding to a lower KPS score).[148, 149] These factors collectively translate to a significantly worse prognosis: among patients over 65, the 5-year survival rate is just 2.1% compared to 4.1% for those 55 to 64 and 6.5% for those 45 to 54.[150]

Because the elderly are underrepresented in clinical trials, there are few data to guide clinical decision-making for this population. However, two reviews of outcomes in elderly patients have been published. One found that gross-total resection confers a modest survival benefit and that treatment with bevacizumab significantly increases overall survival.[93] The second study confirmed that there is a survival advantage for patients who undergo maximal safe resection. It also found that radiotherapy extends survival in selected patients and that temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor MGMT promoter methylation.[151]

Recurrence, or regrowth of tumor after a period of complete remission or stable disease, is nearly universal in glioblastoma and typically occurs within 7 months of initial treatment.[45, 152] Prognosis at recurrence is grim, with an estimated median survival of 22-44 weeks.[45, 31] {ref 308}[153, 154] 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.[155] 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.[155]

While the past few decades have seen marginal improvements in overall survival, new approaches to the management of glioblastoma are clearly needed. 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, and continued enrollment of patients in clinical trials will generate important information on the efficacy of these investigational therapies. More information on these developments can be found under Investigational Approaches.

Patient Education

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

 

History

The clinical history of patients with glioblastoma (GBM) is usually short, spanning less than 3 months in 68% of patients and < 6 months in 84% of patients.[4] Note the following:

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:

Laboratory Studies

Because gliobastoma is currently a molecular diagnosis, genetic studies for IDH and H3 status are essential, and genetic studies for TERT promoter mutation, EGFR gene amplification, and +7/-10 chromosome copy number changes are also important. Furthermore, excluding a metabolic or infectious process with routine laboratory studies is critical in the evaluation of an otherwise healthy patient who presents with new-onset seizures or neurologic deficit.

Researchers are working to identify a biomarker that could be used to diagnose glioblastoma with a noninvasive liquid biopsy taken from blood or cerebrospinal fluid, but this technology has not been fully realized.[159, 160, 161]

Imaging Studies

Imaging studies of the brain are essential to make the diagnosis of glioblastoma (GBM). For complete discussion, see Imaging in Glioblastoma.

On computed tomography (CT) scans, glioblastomas usually appear as irregularly shaped hypodense lesions with thick margins, a peripheral ringlike zone of heterogeneous contrast enhancement, and a penumbra of vasogenic edema. Hemorrhage is occasionally seen, while calcification is uncommon. A marked mass effect is typically evident.[158]

Magnetic resonance imaging (MRI) with and without contrast is the study of choice for the evaluation and diagnosis of glioblastoma (see the images below).[19, 20] 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 non-enhancing low attenuation is vasogenic edema containing varying numbers of invasive tumor cells.[[158] Several pathologic studies have shown that the area of enhancement does not represent the outer tumor border, because infiltrating glioma cells can be identified within, and occasionally beyond, a 2-cm margin.[162]



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A T1-weighted axial MRI without intravenous contrast demonstrates a hemorrhagic multicentric glioblastoma in the right temporal lobe. Effacement of th....



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A T1-weighted axial MRI with intravenous contrast shows heterogeneous enhancement of the lesion within the right temporal lobe. The hypointensity circ....



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A T1-weighted coronal MRI with intravenous contrast demonstrates a glioblastoma within the medial temporal lobe and the stereotypical pattern of contr....



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A T1-weighted sagittal MRI with intravenous contrast demonstrates a glioblastoma.



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On T2-weighted axial MRI, the tumor (glioblastoma) and surrounding white matter within the right temporal lobe show increased signal intensity compare....



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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 ....

Positron emission tomography (PET) is very sensitive at the initial stage of the diagnosis and can be helpful in diagnosing glioblastomas in difficult cases, such as those associated with radiation necrosis or hemorrhage. Compared with standard MRI, PET is better able to identify intra-tumor heterogeneity and delineate tumor extent.[163] Consequently, PET is particularly useful in treatment planning (including, biopsy, surgery, and radiotherapy) and post-treatment monitoring. On PET scans, increased regional glucose metabolism closely correlates with cellularity, and PET volumes have been shown to have a strong prognostic impact.[164, 165]

Magnetic resonance (MR) spectroscopy has also proved somewhat useful in distinguishing recurrent tumor from radiation necrosis and hemorrhage.[166] In solid enhancing portions of glioblastoma, MR spectroscopy demonstrates an increase in the choline-to-creatine peak ratio (CHO:CR), an increased lactate (LAC) peak, and decreased N-acetylaspartate (NAA) peak (see the image below).[167] As this classic “neoplastic spectrum” is broadly indicative of cell turnover, identification of this pattern in non-enhancing T2/FLAIR regions supports a diagnosis of infiltrative tumor over radiation necrosis/hemorrhage.[167, 168] A choline/NAA index greater than 2 with a concurrently elevated LAC peak is associated with a poor prognosis.[169]



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Magnetic resonance (MR) spectroscopy signal representative of glioblastoma (GBM) demonstrating a high peak ratio of choline (CHO) to creatine (CR), a ....

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

Other Tests

Electroencephalography (EEG) changes observed in the setting of glioblastoma and other CNS tumors result mainly from disruptions in the surrounding neural tissue, as tumor is electrically silent. While EEG patterns are not specific to tumor pathology, some general correlations have been established. For example, compared with slow-growing gliomas, glioblastomas are associated with more overall abnormality and greater impairment and disorganization of background rhythms. Glioblastomas also produce the most widespread, slowest, and largest delta waves and, due to the high incidence of necrosis, tend to demonstrate flat polymorphic delta activity (PDA).[170]

Procedures

While lumbar puncture can be useful in narrowing the differential diagnosis, it may be contraindicated in the setting of a severe mass effect due to the risk of herniation secondary to increased intracranial pressure. 

Cerebrospinal fluid (CSF) studies do not currently aid in the diagnosis of glioblastoma, but research is being conducted in monitoring of genetic changes in glioblastoma and the presence of circulating tumor DNA.[159, 160, 161]

Histologic Findings

Macroscopic Appearance

Despite the short duration of symptoms, glioblastomas are often surprisingly large at the time of presentation, occupying much of a cerebral lobe.[2] They are typically unilateral but may cross the corpus callosum.[55, 56, 57] Most glioblastomas of the cerebral hemispheres are clearly intraparenchymal with an epicenter in the white matter, but some extend superficially into cortical gray matter and contact the leptomeninges and dura, occasionally mimicking a metastasis or meningioma.[76, 77]  

Macroscopically, glioblastomas are poorly delineated, with peripheral grayish to pink tumor cells, central yellowish necrosis from myelin breakdown (comprising up to 80% of the total tumor), and multiple red and brown areas of recent and distant hemorrhages.[2] Cysts, when present, typically contain a turbid fluid of liquefied necrotic tumor tissue.[171, 172] See the image below.



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Coronal section of a glioblastoma in the left temporal lobe with typical coloration: thickened tan cortex overlying a large central region of yellowis....

Microscopic Appearance

Glioblastomas are highly cellular tumors composed of poorly differentiated, fusiform, round, or pleomorphic astrocytic cells with marked nuclear atypia and brisk mitotic activity.[172] As discussed in greater detail in Overview/Pathophysiology, microvascular proliferation and necrosis are essential diagnostic features.[2] Necrosis is often, but not always, accompanied by perinecrotic palisading and can be innate, or therapy-induced (ie, radionecrosis) in patients who have received treatment. The distribution of these histologic features varies, but viable tumor cells tend to be located in the periphery whereas necrotic tissue is usually found in the tumor center.[2] Microvascular proliferation occurs throughout the tumor but is most pronounced around necrotic regions and in the infiltrative margins.[2]

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.[173]

The WHO recognizes three histologic patterns characterized by the predominance of a particular cell type: giant cell glioblastoma, gliosarcoma, and epitheliod glioblastoma. These patterns are discussed below. 

Giant cell glioblastoma

Large, multinucleated tumor cells are present in many glioblastomas, but only those in which multinucleated giant cells comprise the dominant histopathological feature are designated giant cell glioblastomas. This subtype is rare, accounting for < 1% of all glioblastomas.[174, 175] Giant cell glioblastomas are characterized by an abundance of multinucleated giant cells set against a background of small, often fusiform cells (see the image below).[176]



View Image

Histology section of a giant cell glioblastoma. Several bizarre, multinucleated giant cells are visible against a background of smaller tumor cells. C....

The giant cells themselves are bizarre: in some cases, they can be as large as 0.5 mm in diameter and contain more than 20 nuclei.[2] Mitoses are often visible in both the giant cells and smaller tumor cells. A common feature is the formation of pseudorosette-like accumulations of tumor cells around the vasculature.[52] Frequently rich in reticulin, giant cell glioblastomas are firm and well-circumscribed; consequently, these tumors may be mistaken for a metastasis or meningioma when attached to the dura.[2] Although the prognosis in patients with giant cell glioblastoma is poor, it may be slightly better than that of ordinary glioblastoma.[175, 177]

Gliosarcoma

The designation of gliosarcoma is reserved for tumors that show prominent mesenchymal metaplasia characterized by alternating areas of glial and mesenchymal differentiation in a biphasic pattern.[2] (See the image below.) This subtype is also rare but slightly more common than giant cell glioblastoma, accounting for roughly 2% of all glioblastomas.[178]



View Image

Histology section of a gliosarcoma with Van Gieson’s stain highlighting connective tissue. The classic alternating pattern of gliomatous (pink) and sa....

Gliosarcomas are characterized by a mixture of sarcomatous and gliomatous tissues. The sarcomatous component often resembles a spindle cell sarcoma, with long bundles of densely packed spindle cells surrounded by reticulin fibers. Some cases show marked pleomorphism and/or additional lines of mesenchymal differentiation, including cartilage, bone, osteoid-chondroid tissue, smooth and striated muscle, and lipomatous features.[179, 180, 181]

The glial component typically appears as reticulin-free islands of astrocytic cells; rarely, primitive neuronal components are present.[182] Due to its high connective-tissue content, gliosarcoma—like giant cell glioblastoma—appears as a firm, well-circumscribed mass that may be similarly mistaken for a metastasis or meningioma when attached to the dura.[2] The prognosis in patients with gliosarcoma is very similar to that of classic glioblastoma.[183]

Epithelioid glioblastoma

Epithelioid glioblastomas, which often resemble metastatic carcinoma or melanoma, are characterized by sharply demarcated, loosely cohesive aggregates of large epithelioid cells with little intervening neuropil. The epithelioid cells are relatively uniform, with distinct cell membranes, abundant eosinophilic cytoplasm, large vesicular nuclei, and prominent macronucleoli.[2] Rosenthal fibers and eosinophilic granular bodies are rare. In some cases, giant cells, lipidization, cytoplasmic vacuoles, desmoplastic response, and xanthoastrocytoma-like histology can be seen.[184, 185, 186] Necrosis is often present but is more commonly zonal than palisading.[2] The prognosis in patients with epithelioid glioblastomas varies with the presence of various genetic alterations including BRAF mutations, COKN2A deletions, and PDGFRA amplification.[185]



View Image

This glioblastoma is composed of large epithelioid cells that are immunoreactive for glial fibrillary acidic protein (GFAP) (hematoxylin and eosin, 40....

Staging

Staging of 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. Despite its rapid infiltrative growth, glioblastomas tend not to invade the subarachnoid space and thus rarely metastasize via cerebrospinal fluid (CSF). Penetration of the dura, venous sinuses, and bone is exceptional, and hematogenous spread to extraneural tissues is very rare in patients who have not had previous surgical intervention.[78, 79, 80, 67, 81] When metastasis does occur, it most commonly affects bones, lymph nodes, liver, and lungs.[82, 83]

Approach Considerations

The treatment of glioblastomas remains difficult in that no contemporary treatments are curative.[187] While overall mortality rates remain high, improved understanding of the molecular mechanisms and genetic 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. Because none of these treatments is curative, the National Comprehensive Cancer Network (NCCN) recommends clinical trials for eligible patients.[22]

Treatment should be tailored to each patient based on age, functional status, and goals of care.[58] Palliative care should be integrated early in the clinical course, and supportive care may be the best option for some patients (eg, those with large or multifocal lesions who have a low Karnofsky Performance Scale score).[23] See Brain Cancer Treatment Protocols for summarized information.

Upon initial diagnosis of glioblastoma (GBM), standard treatment consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide.[58, 188, 22] 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. The final length of stay depends on each patient's neurologic 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 in the hospital, patients should receive postoperative imaging to verify the extent of surgical resection, preferably within 24-48 hours of surgery, using magnetic resonance imaging (MRI) with and without contrast.[58] Contrast enhancement during this period accurately reflects residual tumor. MRI should include diffusion-weighted sequences for detection of perioperative ischemia.[189] 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 with radiation or temozolomide (TMZ) alone is sometimes employed, as these patients tend to be less tolerant of toxicities.[190, 42, 191, 192] 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.[193]

Evidence suggests that in patients over 60 years old, treatment with TMZ is associated with longer survival than treatment with standard radiotherapy, and for those over 70 years old, TMZ or hypofractionated radiotherapy is associated with longer survival than treatment with standard fractionated radiotherapy; the improvement in survival with TMZ is enhanced in patients with MGMT promoter methylation.[43] Data from a randomized phase III trial suggest that lomustine-temozolomide plus radiotherapy might be superior to TMZ chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter.[194]

In their highly influential randomized phase III clincal trial comparing combined therapy with TMZ and radiation versus radiation alone in patients with glioblastoma, Stupp et al found that TMZ plus radiotherapy was associated with a greater median and 2-year survival,[31] and survival in the combined therapy group continued to exceed that of radiation alone across all clinical prognostic subgroups throughout the 5-year follow up.[45]

Glioblastomas virtually always recur after standard therapy, with a median time to recurrence of 6.7 months following initial treatment.[152] There is no established standard-of-care salvage therapy, and the NCCN guidelines recommend clinical trials.[22] While surgery may be appropriate in patients with symptomatic or large lesions, only gross total resection (GTR) is associated with a survival benefit.[26, 27, 29] Various other options have been employed, including temozolomide rechallenge, nitrosoureas, bevacizumab, re-irradiation, tumor treating fields, and various investigational therapies.[44, 195, 196] Unfortunately, none of those has been shown to prolong survival in randomized controlled trials.

Surgical Care

Surgical care in glioblastoma should be individually tailored, taking into consideration the indications, risk-benefit ratio, and prognostic impact for each patient. Because glioblastoma cannot be cured with surgery, the surgical goals are to establish a pathologic diagnosis, relieve mass effect, and, ideally, achieve a gross total resection (GTR) to facilitate adjuvant therapy while preventing new permanent neurologic deficits that might jeopardize independence, decrease quality of life, and increase the risk of additional complications that could delay or even preclude additional therapy.[23] While neurologic deficits can sometimes be predicted preoperatively, patients should be counseled that neurosurgical procedures are always associated with some unpredictable risks.[23]

Biopsy

If the patient should refuse surgery or if surgery is not feasible due to the patient’s medical comorbidities and/or involvement of eloquent cortex, a stereotactic or open biopsy should still be performed for histologic diagnosis and molecular testing, which can guide subsequent therapy.[23, 197, 59] To obtain sufficient material for accurate diagnosis and grading, the surgeon should biopsy contrast-enhancing regions of solid tumor mass that contain viable tumor cells, ideally avoiding necrotic areas and surrounding healthy neural tissue.[58]

Extent of Resection

Historically, tumor extent was largely defined using T1-weighted MRI with contrast.[20] However, because glioblastoma is highly invasive, with infiltrating cells extending beyond the main, contrast-enhancing tumor mass, non–contrast-enhancing tumor should also be included in the target resection volume.[58, 162] The goal for glioblastoma surgery is the maximal resection that is safely feasible and leaves the smallest amount of residual postoperative enhancing tumor.[198]

While no randomized clinical trials have been conducted to determine the optimal extent of surgery in glioblastoma, gross total resection (GTR) is generally recommended, as several retrospective studies have shown that GTR is associated with improved progression-free and overall survival in both newly diagnosed[25, 26, 27] and recurrent glioblastomas[28, 29] in both young and elderly patients[27, 30] regardless of molecular status.[24] A sampling of these studies is discussed below: 

Surgical Adjuncts

Numerous preoperative and intraoperative surgical adjuncts have been developed to maximize the extent of resection while minimizing the risk of new neurologic deficits. These include preoperative imaging studies, such as functional MRI (fMRI) and diffusion tensor imaging (DTI) fiber tracking, which are particularly useful when resecting tumors near or within eloquent brain regions.[21, 201, 202] Similarly, awake craniotomy with evoked potentials, electromyography, or brain mapping can be used to monitor and preserve language and other essential cognitive functions when eloquent cortex is involved.[203] Intraoperative MRI may help identify residual tumor and optimize the extent of resection,[204] and intraoperative ultrasound appears to be associated with preservation of quality of life via prevention of new neurologic deficits.[205]

In 2017, the fluorescent dye 5-aminolevulinic acid (5-ALA; Gleolan) was approved by the US Food and Drug Administration (FDA) as an adjunct for visualizing malignant tissue during surgery.[206] Since then, fluorescence-guided surgery (FGS) has been increasingly used to facilitate more complete and precise resection. A randomized trial comparing FGS with 5-ALA to conventional microsurgery with white light found that patients who received FGS had a 6-month progression-free survival (PFS) rate of 46.0%, whereas patients who received conventional surgery had a 6-month PFS rate of 28.3%.[207] Despite those promising data, widespread utilization of FGS has been limited by the cost of 5-ALA and the need for specialized equipment. An alternative fluorescent contrast agent, tozuleristide (BLZ-100), is currently undergoing clinical trials for use in FGS.[208, 209]

Postoperative Imaging

Patients should receive an MRI with and without contrast within 24-48 hours after surgery to verify the extent of resection and to establish a baseline for subsequent interventions.[58, 59] The scan should include diffusion-weighted sequences for detection of perioperative ischemia.[189]  

Recurrence

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.[210] The indications for reoperation after initial treatment are not firmly established, and while there is some evidence that gross total resection of recurrent glioblastoma is associated with improved outcomes,[28, 29] no randomized clinical trials have been conducted to investigate the survival benefit of surgery following recurrence.[59]

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 somewhat useful in discriminating between those entities.[163, 165, 166, 167, 168] Young age, relatively high KPS score, prolonged interval since the previous operation (ie, > 6 months), and complete resection of contrast-enhancing tumor on reoperation are all associated with a better prognosis.[211, 28, 29]

Medical Care

In a 2022 update to its evidence-based clinical practice guideline on cytotoxic chemotherapy in adults with progressive glioblastoma, the Congress of Neurological Surgeons makes the following level III recommendations[212] :

The level II recommendations in the previous guidelines have been removed, as there is insufficient evidence to support suggestions about the use of in situ chemotherapy and nitrosureas following widespread implementation of the Stupp regimen.[46, 212]

According to a 2020 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.[58] In patients ages 18-70 with good functional status, regardless of MGMT promoter methylation, options for subsequent therapy are as follows:

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

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

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

The goal of radiation therapy (RT) for glioblastoma is to improve local control and survival without inducing neurotoxicity (ie, radionecrosis). RT has been an important therapeutic modality since the 1990s, when early clinical trials showed that RT delays neurologic deterioration and increases survival.[32, 33] Subsequent studies confirmed those early results and have shown further that the addition of RT to surgery alone or to surgery with chemotherapy prolongs survival in glioblastoma patients from 3-4 months to 7-12 months.[31, 34]

Most current guidelines recommend starting RT within 3-5 weeks after surgery and administering 50-60 Gy in 30 daily fractions of 1.8-2.0 Gy for 6 weeks in combination with TMZ.[213, 214] These recommendations are based on dose-response relationship data demonstrating that total doses < 45 Gy are associated with a median survival of 13 weeks while a total dose of 60 Gy is associated with a median survival of 42 weeks. Investigations of other doses and dosing schedules have shown that there is no indication for doses > 60 Gy,[215] but hypofractionated RT with a higher dose per fraction and a lower total dose (eg, 40 Gy delivered in 15 fractions of 2.67 Gy over 3 weeks) results in similar survival outcomes in patients older than 65 years and in those with a KPS score < 70.[216]

Furthermore, in patients with poor clinical factors other than advanced age (eg, postoperative neurologic complications, high tumor burden, unresectable or multifocal lesions, low treatment compliance due to social factors, rapidly progressive disease), hypofractionated RT (ie, 40-50 Gy in 15 fractions) combined with TMZ produced results comparable to those seen with standard fractionation.[217] Even smaller total doses (eg, 34 Gy in 10 fractions of 3.4 Gy or 25 Gy in 5 fractions of 5 Gy), may be appropriate in extremely frail patients.[43]

It is very important to limit exposure of critical neural structures to RT, and some clinical and research groups have modified the standard approach to minimize radionecrosis in the brainstem, cervical cord, cochlea, temporal lobes, hippocampi, and ophthalmic and optic structures.[218] However, despite advanced imaging and ongoing research efforts, there is no consensus on the optimal RT volume and margin expansions when these structures are involved.[218, 219]

Stereotactic biopsy followed by RT 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 whose poor medical condition precludes general anesthesia. Median survival after stereotactic biopsy and RT is reported to be from 27-47 weeks.[220]

The responsiveness of glioblastoma to RT varies. In many instances, RT 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.[221, 222] Early research on tumor recurrence following whole-brain RT found that the great majority (78-90%) of tumors recur within 2 cm of the original site while just 5-6% of patients develop multifocal recurrence, supporting the use of focal RT.[223, 224] Radiosensitizers, such as newer chemotherapeutic agents,[37] targeted molecular agents,[38, 39] and antiangiogenic agents[39] may increase the therapeutic effect of RT and delay recurrence.[225]

Delivery of external beam radiation therapy (EBRT) 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 RT.[36] 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.[226]

RT for recurrent glioblastoma is controversial, though some studies have suggested a benefit from stereotactic radiosurgery or fractionated stereotactic reirradiation.[227, 228, 229]  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 to additional RT, re-irradiation should be performed to improve local tumor control and maintain or improve the patient’s neurologic status and quality of life prior to further tumor progression.[41] This re-irradiation may take the form of conventional fractionation RT, fractionated radiosurgery, or single-fraction radiosurgery.[188, 41] Fleischmann et al reported that in patients undergoing re-irradiation for recurrent glioblastoma, concomitant treatment with bevacizumab significantly reduced the rate of radiation toxicity in both the short and long term.[230]

Chemotherapy – Antineoplastic agents

Temozolomide

TMZ is an orally active alkylating agent approved by the FDA in 2005 for newly diagnosed glioblastoma, maintenance therapy, and recurrent glioblastoma. For adults < 70 years in good general and neurologic condition with newly diagnosed glioblastoma, standard first-line chemotherapy consists of TMZ (75 mg/m2 daily x 6 wk) during rRT followed by six further cycles of maintenance TMZ (150-200 mg/m2 on days 1-5 every 28 days).[31]

While TMZ is generally well tolerated, common toxicities include nausea and myelosuppression, especially thrombocytopenia and neutropenia; those occur more commonly during the adjuvant therapy period.[59] Increasing the dose of TMZ or extending the duration of chemotherapy beyond six cycles has no benefit,[231] and higher doses are associated with greater toxicity and worse quality of life.[59]

Compared with RT alone, adjuvant and concomitant TMZ with RT is associated with significantly longer median progression-free survival (6.9 vs. 5 mo) and overall survival (14.6 vs. 12.1 mo), and greater likelihood of being alive in 2 years (26% vs 10%).[45, 31]

MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that contributes to TMZ resistance. Methylation of the MGMT promoter, found in approximately 45% of glioblastomas, results in an epigenetic silencing of the MGMT gene, decreasing the tumor cell's capacity for DNA repair and increasing susceptibility to TMZ.[232] Note the following:

In a phase III clinical trial, the addition of tumor treating fields (TTF)—which disrupt cellular proliferation of tumor cells via low intensity, intermediate frequency (200 kHZ), alternating electric fields—to adjuvant TMZ extended progression-free survival by 2.7 months and overall survival  by 4.9 months without reducing quality of life.[233]

Temozolomide plus bevacizumab

In two phase III clinical trials, the addition of bevacizumab—an antiangiogenic monoclonal antibody that targets VEGF—to adjuvant TMZ prolonged progression-free survival but not overall survival.[94, 234] Due to the uncertain clinical significance of this finding as well as increased toxicity (eg, early cognitive decline), bevacizumab has not been approved for the treatment of newly diagnosed glioblastoma. However, it may be useful in patients with large tumors who are highly symptomatic cannot tolerate radiotherapy.[23]

Temozolomide plus lomustine

In a small phase III clinical trial, the addition of lomustine to adjuvant TMZ following RT in newly diagnosed MGMT promoter methylated glioblastoma increased median overall survival from 31.4 months to 48.1 months.[235] However, because lomustine did not increase progression free survival, was associated with greater hematologic toxicity, and might preclude later use of lomustine (which is standard of care at recurrence), the role of lomustine in newly diagnosed glioblastoma remains unclear. 

Chemotherapy for recurrent glioblastoma

Chemotherapy for recurrent glioblastoma provides modest benefit at best. Agents from several classes are used. According to the National Comprehensive Cancer Network, preferred agents include the following[22] :

Carmustine

Approved by the FDA in 2002 for the treatment of newly diagnosed and recurrent glioblastoma, biodegradable polifeprosan 20 with carmustine polymer wafers (Gliadel) are placed on the surface of the resected tumor bed at the time of surgery and then slowly degrade to release carmustine directly into the brain, thereby bypassing the blood-brain barrier.[236, 237]  In a large phase III trial, carmustine wafers were shown to produce a modest increase in median survival over placebo (13.8 vs 11.6 months) but were associated with increased rates of cerebrospinal fluid leak and increased intracranial pressure secondary to edema and mass effect.[236, 238]

Similarly, in a randomized clinical trial of 222 patients, carmustine wafers increased 6-month survival from 36% to 56% over placebo but were associated with serious intracranial infections.[237, 239] At present, carmustine wafers are used only sporadically, partially because of these safety and tolerability issues but also because much of the efficacy data stem from the pre-TMZ era and use of this treatment may preclude patients from enrolling in clinical trials.[58]

Bevacizumab

Bevacizumab, an anti-angiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), was approved by the FDA for recurrent glioblastoma in 2009 based on early phase II clinical data showing improved progression-free survival, though there was no improvement in overall survival.[240, 241, 242] A subsequent phase III clinical trial demonstrated that bevacizumab combined with lomustine improves progression-free survival more than lomustine alone (4.2 vs 1.5 mos), but there was still no benefit in overall survival.[243]

Similarly, bevacizumab combined with irinotecan was found to improve survival over bevacizumab alone.[244] When compared with TMZ alone, the bevacizumab-irinotecan combination also increased 6-month survival from 21% to 46%.[245, 246] Furthermore, the anti-angiogenic effect of bevacizumab reduces peritumoral edema, lowering the necessary corticosteroid dose and thus improving quality of life.[244, 247]

A population-based analysis of 5607 adult patients with glioblastoma in the SEER (Surveillance Epidemiology and End Results) database also found that bevacizumab therapy may improve survival. In the study, glioblastoma patients who died in 2010 (after the FDA approved bevacizumab for this condition) had 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). The survival difference was unlikely due to improvements in supportive care, which did not vary significantly between those who died in 2006 and patients who died 2 years later in 2008.[248, 249]

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 (200 kHZ), alternating electric fields that exert biophysical force on charged and polarizable molecules known as dipoles. This modality targets dividing cells in glioblastoma in several ways, including interference with the mitotic apparatus, DNA repair, and cell permeability.[250] Normal cells are generally not harmed.[251] 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.[252]

The Optune tumor-treating field device, also known as the NovoTTF-100A System, was initially approved in 2011 for use in glioblastoma that had recurred or progressed after treatment. In 2015, the FDA expanded approval to include use of the device in conjunction with TMZ chemotherapy in the first-line setting. Approval was based on an open-label, randomized phase III trial in 700 patients in which median overall survival was 19.4 months with use of the device plus TMZ, versus 16.6 months with TMZ alone.[252] Soon after, a randomized, open-label trial in 695 patients with glioblastoma demonstrated that the addition of tumor-treating fields to treatment with TMZ improved median progression-free survival from 4.0 months to 6.7 months (P < 0.001) and median overall survival from 16.0 months to 20.9 months (P < 0.001) without compromising health-related quality of life.[233, 253, 254]

Supportive Care

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

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).[58, 255, 256]

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. 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.[58]

Several studies have reported that, in addition to reducing brain edema, dexamethasone may exert an antitumoral effect by 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 the future, precision medicine may address this by combining glucocorticoids with agents that inhibit the unwanted signaling pathways activated by glucocorticoids.[257, 258]

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.[255]  Preliminary studies have provided support for the notion that bevacizumab can effectively reduce brain tumor-related steroid-refractory edema.[259, 260]

Seizures

Seizures are one of the most common presenting symptoms of glioblastoma, and roughly half (40-60%) of patients with GBM experience seizures over the course of the disease.[5, 261] 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 administered at the lowest dose possible for seizure control in order to avoid adverse effects and minimize drug-drug interactions.[58, 255] Notably, a recent retrospective study found that preoperative seizures and levetiracetam administration were associated with a significant survival advantage in patients with glioblastoma.[262]

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.[58, 255]

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 radiologic disease stability could be appropriate before considering withdrawal of AED treatment.[255]

Venous thromboembolism

Approximately 20% of glioblastoma patients experience VTE in the year following surgical resection.[58]  This is due to multiple factors, including increased activation of clotting factors and thrombin by glioblastoma, the need for surgical intervention, and high rates of impaired limb mobility.[263, 264]

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.[265] American Society of Clinical Oncology (ASCO) guidelines recommend anticoagulation for patients with primary brain malignancies and an established VTE, although uncertainties remain about the choice of anticoagulant and selection of patients most likely to benefit, due to limited data on this population.[266]

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).[266] 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.[255] Prophylaxis is continued for at least 7 to 10 days postoperatively.[266] Data from a retrospective matched cohort study found no statistically significant difference in the cumulative incidence of ICH in high-grade glioma patients in the LMWH cohort versus the cohort not receiving anticoagulation therapy.[267]

ASCO guidelines include direct oral anticoagulants (DOACs) as an option for VTE prophylaxis and treatment but note an increased risk of major bleeding.[266] 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.[268]

Consultations

To develop a coordinated treatment strategy, patients with glioblastomas should be evaluated by a team of specialists that includes a neurologist, neurosurgeon, neurooncologist, and radiation oncologist.

Investigational Approaches

The limited efficacy of current therapeutic options for glioblastoma (GBM) has prompted research into alternative approaches. Therapy modalities under investigation include the following:[58, 269]

Genotyping of brain tumors may have applications in stratifying patients for clinical trials of various novel therapies. In about 50% of patients with gliomas, circulating tumor DNA can be sequenced from cerebrospinal fluid, allowing genotyping of the tumor without the need for brain re-biopsy.[159, 160, 161]

Vaccine therapy

Vaccines being studied for treatment of glioblastoma include modified polio vaccine, cytomegalovirus (CMV) vaccine, and autologous tumor lysate-loaded dendritic cell 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. 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 and remained at that rate through 36 months.[277]

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%).[277] Notably, secondary analysis revealed that very low tumor mutational burden was associated with long-term survival in this recurrent GBM recombinant poliovirus trial.[278]

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.[279] Patients are first treated with dose-intensified temozolomide, as the temozolomide induces lymphopenia, which provides an opportunity to retrain the immune system.

In the study by Batich et al, 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.[279]

Autologous tumor lysate-loaded dendritic cell vaccine

Dendritic cells (DCs) initiate an immune response by capturing antigens from their environment, processing them, and presenting them to naive T cells in lymphoid tissues. For creation of an autologous vaccine, monocytes are collected from the patient by leukapheresis for DC culture, and the DCs are then exposed in vitro to lysate of the patient’s tumor. This ensures that the vaccine targets the full repertoire of antigens present on the patient’s tumor. On injection into the patient, the dendritic cells present tumor antigens to the immune system, prime T cells, and mobilize antitumor responses.[280, 281]

In an international phase III trial, autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) resulted in clinically meaningful and statistically significant improvement in overall survival for patients with both newly diagnosed and recurrent glioblastoma, compared with standard of care. The survival benefit of DCVax-L was larger in patient groups that generally fare worse with standard of care, including older patients, patients with substantial residual tumor, and patients with recurrent disease.[281]

For study patients with newly diagnosed GBM, median overall survival for the 232 patients receiving DCVax-L was 19.3 months from randomization (22.4 months from surgery) versus 16.5 months from randomization in control patients (hazard ratio [HR] = 0.80; 98% confidence interval [CI], 0.00-0.94; P = 0.002). Survival at 60 months was 13.0% vs 5.7%, respectively. For the 64 patients with recurrent GBM receiving DCVax-L, median overall survival was 13.2 months from relapse versus 7.8 months in control patients (HR, 0.58; 98% CI, 0.00-0.76; P <  0.001); survival at 30 months after recurrence was 11.1% vs 5.1%, respectively.[281]

Tyrosine kinase inhibitors

A small proportion of glioblastomas responds to the tyrosine kinase inhibitors gefitinib and erlotinib. The simultaneous presence in glioblastoma cells of mutant EGFR (EGFRvIII) and PTEN is associated with responsiveness to tyrosine kinase inhibitors, whereas increased p-akt is associated with a decreased effect.[282, 283, 284] 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.[285]

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.[286]

Interestingly, secondary analysis of IDH-wildtype participants treated with immune checkpoint inhibitors found that very low tumor mutational burden correlated with durable, long-term survival in a subset of recurrent GBM patients.[278, 287]

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). Early preclinical and clinical studies using CED showed that it is safe but suggested it is only somewhat effective and has substantial technical limitaitons.[288]

Seeking to overcome these barriers, in a recent phase 1b clinical trial, Spinazzi et al engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic CED of topotecan into the brain and tested its safety and biological effects in five patients with recurrent glioblastoma. They found that chronic CED of topotecan was well tolerated without substantial complications and significantly reduced proliferating tumor cells in all five patients, suggesting that CED may be an effective drug delivery approach in glioblastoma.[289]

Numerous research teams are exploring the use of focused ultrasound to noninvasively open the blood-brain barrier and enable relatively large agents into the brain parenchyma. In short, focused ultrasound induces microbubble oscillations that mechanically disrupt the endothelial tight junctions that contribute to the blood-brain barrier, thus allowing the delivery of therapeutics such as chemotherapies, targeted drug therapies, or immunotherapies into the brain parenchyma. While preclinical models have produced encouraging data, clinical trials exploring the use of focused ultrasound are in early, exploratory stages. Thus far, clinical trials have demonstrated that the use of focused ultrasound is safe and feasible, but further studies are warranted to evaluate efficacy.[290]

Activity

While seizures may prevent patients with glioblastomas from driving, there are no universal restrictions, and activity levels are largely determined by each patient’s overall neurologic status. In many circumstances, physical therapy and/or rehabilitation are extremely beneficial. In fact, regimented exercise programs have been shown to improve motor function and cognitive functioning and reduce depression, anxiety, headaches, fatigue, and communication deficits in patients with various forms of glioma, including glioblastoma.[291] One study even found that exercise was an independent predictor of survival in patients with recurrent high-grade (grade III and IV) glioma,[292] and an ongoing clinical trial (NCT03390569) is investigating the effects of exercise regimens on progression-free survival, overall survival, and quality of life in GBM patients.

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. 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’s performance status (PS; quantified with the Karnofsky Performance Scale score [KPS]), age, and MGMT promoter methylation status.[22]  

Category 1 recommendations for first-line treatment are as follows:[22]

The American Society of Clinical Oncology (ASCO) and Society of Neuro-Oncology (SNO) have published treatment guidelines for diffuse astrocytic and oligodendroglial tumors in adults.[293] The guidelines contain the following recommendations for treatment of glioblastoma:

Progressive glioblastoma

Congress of Neurological Surgeons guidelines for the management of progressive/recurrent glioblastoma include the following recommendations[294] ;

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[295]

Since the 2017 EANO guidelines, new findings in palliative care in neuro-oncology include the following[297]

Medication Summary

The alkylating agent temozolomide is used for treatment of newly diagnosed glioblastoma, 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, phenytoin, or carbamazepine. 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 (SNO) and European Society of Neuro-Oncology (EANO) 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.[298]

Temozolomide (Temodar)

Clinical Context:  Oral alkylating agent converted to MTIC (3-methyl-(triazen-1-yl)imidazole-4-carboximide) at physiologic pH; 100% bioavailable; approximately 35% crosses the blood-brain barrier. Indicated for glioblastoma combined with radiotherapy.

Carmustine (BiCNU)

Clinical Context:  Alkylates and cross-links DNA strands, inhibiting cell proliferation. Used in glioblastoma and other brain tumors (including brain-stem gliomas, medulloblastomas, astrocytomas, ependymomas, and brain metastases), multiple myeloma, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. Carmustine is lipophilic and readily crosses the blood-brain barrier.

Bevacizumab (Alymsys, Avastin)

Clinical Context:  Binds to vascular endothelial growth factor A (VEGF-A), preventing its interaction with VEGF receptor tyrosine kinases, thus inhibiting tumor cell growth. Indicated in metastatic colorectal cancer, non-squamous non-small cell lung cancer, cervical cancer, and glioblastoma. As a result of promising phase II clinical trials, single-agent bevacizumab gained accelerated approval from the FDA in 2009 for recurrent glioblastoma in patients who had failed other therapeutic options. More recent trials have yielded less encouraging results, however, and there is no consensus on the best bevacizumab regimen in recurrent glioblastoma. Trials involving patients with newly diagnosed glioblastoma have demonstrated that bevacizumab has no significant effect on survival, health-related quality of life, or neurocognitive function but may reduce glucocorticoid requirements.[312]

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. While EGFR is overexpressed in most glioblastomas, and 30% of glioblastomas have mutations that lead to constitutively active mutant EGFRvIII, numerous phase II clinical trials have demonstrated that erlotinib alone is likely insufficient in the treatment of glioblastoma.[313]

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, but gefitinib is an EGFR inhibitor that blocks tyrosine kinases responsible for intracellular phosphorylation associated with transmembrane cell surface receptors. As with erlotinib, gefinitib has been extensively explored in glioblastoma due to the frequency of constitutively active EGFR vIII mutations within glioblastoma, but clinical trials have not shown significant efficacy.[313]

Lomustine (CCNU, Gleostine)

Clinical Context:  Although its mechanism of action is not completely understood, lomustine causes inhibition of DNA and RNA synthesis resulting from carbamylation of DNA polymerase, alkylation of DNA, and alteration of RNA proteins. Despite limited evidence, use of lomustine in recurrent glioblastoma is increasing; lomustine alone is now commonly used as a control arm in clinical trials. Lomustine anti-tumor activity may be restricted to patients with MGMT promoter methylation.[314]

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. Numerous in vitro, in vivo, and clinical trials have yielded conflicting results about the effect of dexamethasone on glioblastoma aggressiveness, but dexamethasone remains the preferred glucocorticoid option for glioblastoma-induced cerebral edema.[257]

Class Summary

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

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)?What is the prognosis of glioblastoma multiforme (GBM)?What is included in patient education about glioblastoma multiforme (GBM)?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 are the differential diagnoses for Glioblastoma?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?Which medications in the drug class Anticonvulsants are used in the treatment of Glioblastoma?Which medications in the drug class Antineoplastic agents are used in the treatment of Glioblastoma?

Author

Jeffrey N Bruce, MD, Edgar M Housepian Professor of Neurological Surgery Research, Vice-Chairman and Professor of Neurological Surgery, Director of Columbia Brain Tumor Center, Director of Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Columbia University Vagelos College of Physicians and Surgeons

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Theracle, Inc. <br/>Received grant/research funds from NIH for other.

Coauthor(s)

Cole M Chokran, AB, MD/MS Candidate, Columbia University Vagelos College of Physicians and Surgeons

Disclosure: Nothing to disclose.

Nina Teresa Yoh, MD, Resident Physician, Department of Neurological Surgery, Columbia University Irving Medical Center, New York-Presbyterian Hospital

Disclosure: Nothing to disclose.

William M Savage, BA, MD Candidate, Columbia University Vagelos 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

Herbert H Engelhard, III, MD, PhD, FACS, FAANS, Affiliated Professor of Bioengineering, University of Illinois at Chicago

Disclosure: Nothing to disclose.

Additional Contributors

Benjamin C Kennedy, MD, Assistant Professor of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania; Director of Epilepsy and Functional Neurosurgery, The Children’s Hospital of Philadelphia

Disclosure: Nothing to disclose.

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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Coronal section of a glioblastoma in the left temporal lobe with typical coloration: thickened tan cortex overlying a large central region of yellowish necrosis stippled with red and brown lesions from new and old hemorrhage. Courtesy of Wikimedia Commons [author Sbrandner, https://commons.wikimedia.org/wiki/File:Glioblastoma_macro.jpg].

This typical untreated glioblastoma, here with the classic "butterfly" configuration, is a necrotic hemorrhagic mass. Courtesy of Wikimedia Commons [author Rodney D McComb, MD and The Armed Forces Institute of Pathology, https://commons.wikimedia.org/wiki/File:Glioblastoma_multiforme.jpg].

This typical untreated glioblastoma, here with the classic "butterfly" configuration, is a necrotic hemorrhagic mass. Courtesy of Wikimedia Commons [author Rodney D McComb, MD and The Armed Forces Institute of Pathology, https://commons.wikimedia.org/wiki/File:Glioblastoma_multiforme.jpg].

Hematoxylin and eosin stain of a biopsy specimen of a glioblastoma shows prominent microvascular proliferation (formation of a mulitlayered "glomeruloid tuft"). Courtesy of Wikimedia Commons [author Jensflorian, https://commons.wikimedia.org/wiki/File:Glioblastoma_endothelial_proliferations.jpg].

Necrosis is another histopathologic hallmark of glioblastoma. As seen here, necrotic areas often create serpentine patterns, and tumor cells form pseudopalisades around the periphery of these necrotic areas. Courtesy of Wikimedia Commons [author Jensflorian, https://commons.wikimedia.org/wiki/File:GBM_pseudopalisading_necrosis.jpg].

A T1-weighted axial MRI without intravenous contrast demonstrates a hemorrhagic multicentric glioblastoma in the right temporal lobe. Effacement of the ventricular system is present on the right, along with mild impingement of the right medial temporal lobe on the midbrain.

A T1-weighted axial MRI with intravenous contrast shows heterogeneous enhancement of the lesion within the right temporal lobe. The hypointensity circumscribed within the enhancement is suggestive of necrosis. This radiologic appearance is typical of a multicentric glioblastoma.

A T1-weighted coronal MRI with intravenous contrast demonstrates a glioblastoma within the medial temporal lobe and the stereotypical pattern of contrast enhancement.

A T1-weighted sagittal MRI with intravenous contrast demonstrates a glioblastoma.

On T2-weighted axial MRI, the tumor (glioblastoma) and surrounding white matter within the right temporal lobe show increased signal intensity compared with 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.

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

Coronal section of a glioblastoma in the left temporal lobe with typical coloration: thickened tan cortex overlying a large central region of yellowish necrosis stippled with red and brown lesions from new and old hemorrhage. Courtesy of Wikimedia Commons [author Sbrandner, https://commons.wikimedia.org/wiki/File:Glioblastoma_macro.jpg].

Histology section of a giant cell glioblastoma. Several bizarre, multinucleated giant cells are visible against a background of smaller tumor cells. Courtesy of Wikimedia Commons (author Jensflorian, https://commons.wikimedia.org/wiki/File:Giant_cell_glioblastoma_HE_X200.jpg].

Histology section of a gliosarcoma with Van Gieson’s stain highlighting connective tissue. The classic alternating pattern of gliomatous (pink) and sarcomatous (yellow-brown) tissue is evident. Courtesy of Wikimedia Commons [author Marvin 101, https://commons.wikimedia.org/wiki/File:Gliosarcoma_Histopathology_200x_EVG.jpg].

This glioblastoma is composed of large epithelioid cells that are immunoreactive for glial fibrillary acidic protein (GFAP) (hematoxylin and eosin, 40× original magnification). Courtesy of Roger E McLendon, MD.

Axial CT scan without intravenous contrast reveals a large right temporal intra-axial mass (glioblastoma). 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 demonstrates a hemorrhagic multicentric glioblastoma in the right temporal lobe. Effacement of the ventricular system is present on the right, along with mild impingement of the right medial temporal lobe on the midbrain.

A T1-weighted axial MRI with intravenous contrast shows heterogeneous enhancement of the lesion within the right temporal lobe. The hypointensity circumscribed within the enhancement is suggestive of necrosis. This radiologic appearance is typical of a multicentric glioblastoma.

A T1-weighted coronal MRI with intravenous contrast demonstrates a glioblastoma within the medial temporal lobe and the stereotypical pattern of contrast enhancement.

A T1-weighted sagittal MRI with intravenous contrast demonstrates a glioblastoma.

On T2-weighted axial MRI, the tumor (glioblastoma) and surrounding white matter within the right temporal lobe show increased signal intensity compared with 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.

Histopathologic slide demonstrating classic glioblastoma (GBM).

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

Hematoxylin and eosin stain of a biopsy specimen of a glioblastoma shows prominent microvascular proliferation (formation of a mulitlayered "glomeruloid tuft"). Courtesy of Wikimedia Commons [author Jensflorian, https://commons.wikimedia.org/wiki/File:Glioblastoma_endothelial_proliferations.jpg].

Necrosis is another histopathologic hallmark of glioblastoma. As seen here, necrotic areas often create serpentine patterns, and tumor cells form pseudopalisades around the periphery of these necrotic areas. Courtesy of Wikimedia Commons [author Jensflorian, https://commons.wikimedia.org/wiki/File:GBM_pseudopalisading_necrosis.jpg].

Coronal section of a glioblastoma in the left temporal lobe with typical coloration: thickened tan cortex overlying a large central region of yellowish necrosis stippled with red and brown lesions from new and old hemorrhage. Courtesy of Wikimedia Commons [author Sbrandner, https://commons.wikimedia.org/wiki/File:Glioblastoma_macro.jpg].

Histology section of a giant cell glioblastoma. Several bizarre, multinucleated giant cells are visible against a background of smaller tumor cells. Courtesy of Wikimedia Commons (author Jensflorian, https://commons.wikimedia.org/wiki/File:Giant_cell_glioblastoma_HE_X200.jpg].

Histology section of a gliosarcoma with Van Gieson’s stain highlighting connective tissue. The classic alternating pattern of gliomatous (pink) and sarcomatous (yellow-brown) tissue is evident. Courtesy of Wikimedia Commons [author Marvin 101, https://commons.wikimedia.org/wiki/File:Gliosarcoma_Histopathology_200x_EVG.jpg].

This glioblastoma is composed of large epithelioid cells that are immunoreactive for glial fibrillary acidic protein (GFAP) (hematoxylin and eosin, 40× original magnification). Courtesy of Roger E McLendon, MD.

This typical untreated glioblastoma, here with the classic "butterfly" configuration, is a necrotic hemorrhagic mass. Courtesy of Wikimedia Commons [author Rodney D McComb, MD and The Armed Forces Institute of Pathology, https://commons.wikimedia.org/wiki/File:Glioblastoma_multiforme.jpg].