Neurologic Manifestations of Glioblastoma Multiforme 

Updated: Nov 07, 2021
Author: Gaurav Gupta, MD, FAANS, FACS; Chief Editor: Stephen A Berman, MD, PhD, MBA 

Overview

Practice Essentials

Glioblastoma multiforme (GBM) is the most common and most aggressive of the primary brain tumors. The previous World Health Organization (WHO) classification of primary brain tumors lists GBM as a grade IV astrocytoma based entirely on the histopathological findings.[1] However, the 2021 WHO grading system considers only isocitrate dehydrogenase (IDH) wild-type diffuse gliomas in adults with histopathological features consistent with the previous definition as GBM.[2]  

Signs and symptoms

Headache is one of the most common symptoms of GBM, especially if the tumor is arising in the posterior fossa. Incidence varies between 23% and 56%.[3, 4]

Seizures are the other common non-specific manifestation of any brain tumor, seen in ~20% cases of GBM at presentation.

Progressive focal neurological deficits can develop typically over weeks to months in GBM patients

Diagnosis

The preferred workup for GBM is diagnostic neuroimaging studies. 

Brain MRI with and without gadolinium contrast is the most sensitive and specific study. GBM tumors characteristically have low-signal intensity on T1-weighted images and high-signal intensity on T2-weighted images. With contrast, the tumors usually enhance. The enhanced T1-weighted images typically have a central hypodensity surrounded by a thick enhancing rim of the tumor.

CT scan can be ordered with or without contrast when MRI is contraindicated or unavailable. On CT scan, GBMs have a variable, inhomogeneous hypodense or isodense appearance with surrounding edema. GBMs tend to infiltrate along the white matter tracts and frequently involve and cross the corpus callosum.

Management

Although the prognosis of GBM is uniformly poor, treating patients in an attempt to improve the quality of life is worthwhile. The current standard of care includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy with temozolomide.

Background

Glioblastoma multiforme (GBM) is the most common and most aggressive of the primary brain tumors. The previous World Health Organization (WHO) classification of primary brain tumors lists GBM as a grade IV astrocytoma based entirely on the histopathological findings.[1]  However, the 2021 WHO grading system considers only isocitrate dehydrogenase (IDH) wild-type diffuse gliomas in adults with histopathological features consistent with the previous definition as GBM.[2]  See the image below.

T1-weighted axial gadolinium-enhanced MRI demonstr T1-weighted axial gadolinium-enhanced MRI demonstrates an enhancing tumor of the right frontal lobe. Image courtesy of George Jallo, MD.

 

Pathophysiology

Glioblastoma multiforme (GBM) tumors are highly malignant, infiltrate the brain extensively, and grow rapidly; at times they may become enormous before turning symptomatic. They can arise de novo or by malignant transformation of a previously low-grade astrocytoma. Malignant transformation occurs by the sequential accumulation of genetic or molecular alterations and abnormal regulation of growth factor signaling pathways within the astrocytes[5] . Primary GBM usually presents with amplified and mutated epidermal growth factor receptors, whereas secondary GBM can have increased signaling through the PDGF-A receptor. There are many other molecular alterations defined in this cancer, including  an amplification of the MDM2 gene, PTEN mutations, P53 mutations, IDH1 mutations, MET amplification, homozygous deletion of CDKN2A, and many more. The genomic and molecular landscape of GBM has evolved exponentially over the past few years.[6]  The transition from a lower grade GBM to a higher grade is associated with inactivation of the retinoblastoma (RB1) gene and hyperactive MDM2.[7]

Many environmental risk factors are linked to the development of GBM such as exposure to therapeutic ionizing radiation or vinyl chloride or pesticides, smoking, and working in petroleum refining and synthetic rubber manufacturing industries.[6]  Excessive use of mobile phones was also initially implicated in the pathogenesis. However, a meta-analysis published in 2007 did not show any association with the incidence of tumor development in people who used cell phones for at least 10 years.[8]

Certain hereditary syndromes are associated with GBM such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), Li-Fraumeni syndrome, hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome), Turcot syndrome/brain tumor-polyposis syndrome (BTPS), multiple endocrine neoplasia type 1 (MEN1), nevoid basal cell carcinoma syndrome (NBCCS), Gorlin-Goltz syndrome, and tuberous sclerosis complex (TSC).[6]

Epidemiology

Frequency

Among primary brain tumors, malignant astrocytomas are the most common in all age groups. (However, among all brain tumors, metastases are the most common.) Glioblastoma multiforme (GBM) tumors are the most common primary brain tumors in adults, accounting for 12–15% of intracranial tumors and 50–60% of primary brain tumors. Approximately three per 100,000 people develop the disease each year, although the regional frequency may be higher.[9, 10]  GBM constitutes 45.2% of all malignant brain tumors, 54.4% of all high-grade gliomas, and 80% of all primary malignant brain tumors.[6]  Several authors have reported a true increase in the incidence of brain tumors, especially among the elderly, and many have attributed the observed changes to developments in diagnostic imaging or changes in the classification system.[11]

Mortality/Morbidity

Morbidity is from the tumor location, progression, and pressure effects. The overall prognosis for GBM has changed little in the past 2 decades, despite major improvements in neuroimaging, neurosurgery, radiation treatment techniques, adjuvant chemotherapy, and supportive care. Few patients with GBM survive longer than 3 years and only a handful survive 5 years. Previously reported long-term survivors of GBM may be patients diagnosed with GBM who harbor low-grade glioma, pleomorphic xanthoastrocytoma, ganglioglioma, or other lesions. 

Race-, sex-, and age-related demographics

High-grade astrocytomas (HGAs) are slightly more common in whites than in blacks, Latinos, and Asians. GBM is slightly more common in men than in women; the male-to-female ratio is 3:2. While GBM occurs in all age groups, its incidence is increasing in elderly patients.  A true increase in the incidence of primary brain tumors exists, which cannot be explained by the aging population, better imaging techniques, or earlier detection at surgery.[6, 9]

Prognosis

With optimal treatment, the median survival of patients with glioblastoma multiforme (GBM) is about 12 to 15 months.[12] However, only 3–7% of patients survive for more than 5 years.[13]  In the United States between 2012 and 2016, five-year survival was 6.8%.[13]  The overall prognosis for GBM has changed little since the 1980s, despite major improvements in neuroimaging, neurosurgery, radiotherapy, and chemotherapy techniques.[14]  Despite all the advancements in the treatment, a prospective trial demonstrated a median survival of only 16.6 months with 34% of patients surviving at 2 years.[15]

Various prognostic factors implicated in survival include age, performance status, histological grade of the tumor, specific molecular markers (MGMT methylation, mutation of IDH1, IDH2 or TERT, 1p19q codeletion, overexpression of EGFR, etc.), and the extent of resection.[16]

Various studies demonstrated that patients with GBM who are younger than 40 years have an 18-month survival rate of 50%, while those aged 40–60 years have an 18-month survival rate of 20%, and those older than 60 years have a rate of only 10%. In some series, age appears to be an even more important prognostic factor than histology.

The survival of patients with GBM decreases as KPS decreases. Patients with a KPS of more than 70 have an 18-month survival rate of 34%, while those with a Karnofsky Performance Scale (KPS) score of less than 70 have an 18-month survival rate of 13%. Additional factors such as the extent of surgical resection, seizures as the initial presentation, and tumor location with superficial tumors have been variably associated with outcome.[14]

An animal study in rats investigated the use of monoclonal antibodies 8H9 as interstitial infusion showed a significant volumetric response and prolonged survival (54 d for untreated rats vs 120 d for treated rats) as a potential target therapy for high-grade gliomas.[17]

A study by Wang et al demonstrated that overexpression of EphA7 was predictive of adverse outcomes in patients with primary and recurrent GBM, independent of microvascular density (MVD) expression. Moreover, the high density of both MVD and EphA7 expression predicted the disease outcome more accurately than EphA7 alone.[18]

A study by Liang et al demonstrated that nuclear FABP7 was preferentially expressed in infiltrative gliomas only and associated with poor prognosis in EGFR-overexpressing glioblastoma. The study suggested that FABP7 immunoreactivity could be used to monitor the EGFR-overexpressed GBM progression.[19]

Studies are focusing attention on identifying molecular markers like anaplastic oligodendroglioma to predict response or resistance to specific treatments. One such interest is the expression of the MGMT (O6 -methylguanine–DNA methyltransferase) gene. The protein product of this gene, 06 alkyl guanine DNA-alkyl-transferase (AGAT), is shown to be a major mechanism for tumor resistance to alkylating agents.[6, 20]  Recent clinical trials for malignant gliomas now often include the determination of MGMT expression status. Several other molecular markers, such as epidermal growth factor receptor, platelet-derived growth factor receptor, vascular endothelial growth factor receptor, loss of chromosome 10, mutation or loss of the p53 gene, expression of the YKL-40 gene, and loss or mutation of PTEN gene, are being investigated.[6]

Studies are also focusing on new targets such as receptor blockade. Glutamatergic system alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-blocker talampanel, may be beneficial in this disease. In one study, talampanel was added to standard radiation and temozolomide in adults with newly diagnosed glioblastoma to estimate the overall survival as well as talampanel toxicity as a secondary measure. The study concluded that talampanel was well tolerated, and compared with European Organization for Research and Treatment of Cancer (EORTC) data, median survival seemed superior (20.3 vs 14.6 mo, respectively). Therefore, talampanel can be added to radiation therapy and temozolomide without significant additional toxicity.[21]

Patient Education

During the course of diagnosis, treatment, and follow-up care, educate the patient and family about the course and prognosis of the tumor to help them cope with the physical and emotional burden. Set this goal during discussion with the patient in the presence of family members, nurses, physicians, social services, and spiritual services. In addition, frequent contacts, regular follow-up care, and involvement of support groups are necessary.

For patient education resources, see the Cancer Center and Brain Cancer.

 

Presentation

History

Though the initial presentation of glioblastoma multiforme (GBM) is very non-specific, more than half of cases present to the emergency department with acute symptoms.[22]  Because of the rapidity of growth, GBM patients present with features of acutely raised intracranial tension (ICT). Many times, it is difficult to localize the symptoms due to extensive invasion, edema, hydrocephalus, and vascular compromise.[23]

Headache is one of the most common symptoms, especially if the tumor is arising in the posterior fossa. Incidence varies between 23% and 56%.[3, 4]  However, only 1–2 in 100 patients with headaches will harbor a brain tumor and GBMs are most common in supratentorial locations. Headache can be initially localized depending on the location and typically progresses over time to become holocranial. It is more common in the early morning, aggravated by lying down, coughing, and the Valsalva breathing maneuver. Also, it is usually associated with persistent nausea, vomiting, and blurring of vision in most patients.[22, 23, 3, 24]

Seizures are the other common non-specific manifestation of any brain tumor, seen in ~20% cases of GBM at presentation. Over the course of the disease, another 20% of these patients may develop seizures. However, some seizures can have peculiar features aiding the tumor localization. Patients can present with focal seizures, generalized seizures (GTCS), and complex partial seizures with preceding visual or gustatory or auditory auras. Many patients may have post-seizure transient motor weakness of the affected limbs (Todd’s paresis).[25]  New-onset seizures are found to be one of the main predictors of survival in studies.[4]

Progressive focal neurological deficits can develop typically over weeks to months in GBM patients. However, they can rarely present with acute deficits secondary to cerebrovascular ischemia or hemorrhage within the tumor.[23, 3, 25]

As an intra-axial tumor, GBMs can cause varied neurological, psychiatric, and cognitive disabilities depending on the location and extent of the tumor within the brain. Patients can present with motor weakness, cranial nerve palsies, ataxia or cerebellar symptoms, and other focal neurological deficits. Occasionally, these patients can present with solely psychiatric symptoms like mood disorders, schizophrenia, anorexia, and neurobehavioral disorders. Among patients presenting with purely psychiatric symptoms, depression is the most common presentation seen in more than 60% of patients followed by manic-like states and anxiety. Psychotic symptoms were noted in 35% of patients. Mood disorders were seen in patients with tumors of the frontal lobe, temporal lobes, and limbic structure. Psychotic symptoms are common with temporal lobe tumors and rarely with the frontal lobes and corpus callosum. Neurological disorders of diminished motivation (DDM) are the most common confusing disease. These patients present with a continuum of impairments in goal-directed behaviors arising from damage to dopaminergic neurons within the frontal lobes, basal ganglia, thalamus, substantia nigra, and mesolimbic structures. DDM encompasses apathy in its milder form, followed by abulia, and at the extreme end may present as akinetic mutism. These can resemble the psychomotor retardation of depression. However, they can be distinguished by lack of sadness, negative thoughts, irritability, and vegetative symptoms.[23]

Also, differentiating a psychiatric disorder from depression can be challenging especially during the early stages of tumor growth when symptoms are subtle. Late-onset, atypical psychiatric symptoms, negative family history of psychiatric diseases, and symptoms refractory to medications should raise suspicion of underlying organic causes like brain tumor/GBM.[23]

Physical

Physical findings depend on the location, size, and rate of growth of the glioblastoma multiforme (GBM) tumor, as with any other CNS tumor. Tumors in less critical areas (eg, anterior frontal or temporal lobe) may present with subtle personality changes and memory problems. Similarly, motor weakness and sensory hemineglect are the hallmarks of tumors arising in the frontal or parietal lobes and thalamic regions. Sensory neglect is more prominent in right hemispheric lesions. Note the following:

  • Seizures are a common presentation of small tumors in the frontoparietal regions (simple motor or sensory partial seizure) and temporal lobe (simple or complex partial seizure).

  • Occipital lobe tumors may present with visual field defects. Although these tumors are less frequent than tumors originating at other sites, patients generally are unaware of the slow onset of a cortically based hemianopsia.

  • Brainstem GBMs are rare in adults. However, they may present with bilateral crossed neurological deficits (eg, weakness on one side with contralateral cranial nerve palsy). Alternatively, they may present with rapidly progressive headache or altered consciousness.

 

DDx

 

Workup

Laboratory Studies

Routine laboratory workup results in glioblastoma multiforme (GBM) often are negative, but excluding a metabolic or infective process is important in an otherwise healthy patient who presents with new-onset seizures or mental status changes for the first time.

Imaging Studies

The preferred workup for glioblastoma multiforme (GBM) is diagnostic neuroimaging studies. 

MRI

Brain MRI with and without gadolinium contrast is the most sensitive and specific study. GBM tumors characteristically have low-signal intensity on T1-weighted images and high-signal intensity on T2-weighted images. With contrast, the tumors usually enhance. The enhanced T1-weighted images typically have a central hypodensity surrounded by a thick enhancing rim of the tumor. See the images below.

T1-weighted axial gadolinium-enhanced MRI demonstr T1-weighted axial gadolinium-enhanced MRI demonstrates an enhancing tumor of the right frontal lobe. Image courtesy of George Jallo, MD.
T2-weighted image demonstrates notable edema and m T2-weighted image demonstrates notable edema and midline shift. This finding is consistent with a high grade or malignant tumor. Image courtesy of George Jallo, MD.

CT scan

CT scan can be ordered with or without contrast when MRI is contraindicated or unavailable. Consider the following:

  • On CT scan, GBMs have a variable, inhomogeneous hypodense or isodense appearance with surrounding edema.

  • GBMs tend to infiltrate along the white matter tracts and frequently involve and cross the corpus callosum.

  • Approximately 4–10% of GBMs and 30–50% of AAs do not enhance, while a significant percentage of low-grade gliomas do not enhance.

Other Tests

Functional neuroimaging such as positron emission tomography (PET scan), single-photon emission computed tomography (SPECT), or MR spectroscopy may help differentiate a glioblastoma multiforme (GBM) tumor from other benign mass lesions, brain abscess, or toxoplasmosis. However, the definitive diagnosis is confirmed by stereotactic or open brain biopsy. See the image below.

Magnetic resonance spectroscopy is representative Magnetic resonance spectroscopy is representative of a glioblastoma multiforme.

Consider the following:

  • Functional imaging is commonly used to differentiate between treatment-related radiation necrosis and tumor recurrence.

  • Functional imaging is also used in defining the margins of the tumor for surgical resection and planning for the radiation fields.

  • Additionally, functional imaging may be helpful in determining the most abnormal region of the tumor to improve the diagnostic accuracy in case a small biopsy sample is taken.

Direct or indirect ophthalmoscopy is used to look for papilledema and secondary optic atrophy.

Neuropsychological evaluation can help to localize the pathology as well as rule out psychiatric diseases.

Histologic Findings

High-grade astrocytomas (HGAs) are extremely heterogeneous tumors characterized by varying degrees of increased cellularity, pleomorphism, mitoses, microvascular proliferation, and necrosis.​See the image below.

The 2021 WHO grading of gliomas has significantly changed the way glioblastomas are diagnosed. Instead of solely relying on histological characteristics, both histological and molecular characteristics are considered to diagnose glioblastoma. In adults, any IDH-wildtype diffuse and astrocytic glioma with microvascular proliferation or necrosis or TERT promoter mutation or EGFR gene amplification or +7/-10 chromosome copy number changes is considered as glioblastoma, IDH wildtype. IDH mutant-type gliomas are no longer considered glioblastoma irrespective of the suggestive histological features. Also, the term "glioblastoma" is no longer used in the pediatric setting.[26]

Histopathologic slide demonstrating a glioblastoma Histopathologic slide demonstrating a glioblastoma multiforme.
 

Treatment

Medical Care

Although the prognosis of glioblastoma multiforme (GBM) is uniformly poor, treating patients in an attempt to improve the quality of life is worthwhile. The current standard of care includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy with temozolomide. However, continuous supportive care is a major component of the medical treatment of primary brain tumors.

This care includes treatment of cerebral edema with a potent glucocorticosteroid. Dexamethasone is most commonly used because of its potent impact on edema and minimal mineralocorticoid effects. Steroid therapy often requires prophylactic use of H-2 blockers to prevent gastrointestinal side effects.

Seizures are a major concern with supratentorial tumors. Although seizures are less common with GBM than low-grade glioma, treatment with an appropriate anticonvulsant is uniformly recommended for a documented seizure. However, the use of a prophylactic anticonvulsant is controversial. A 2009 prospective study strongly concluded that the use of prophylactic AEDs in glioma is not justified, as patients without epilepsy and not taking AEDs never developed seizures.[27]  Careful consideration is required in selecting an effective AED with minimal side effects and without cytochrome P450 enhancing activity because enzyme inducers can increase the metabolism and clearance of some chemotherapeutic agents.

Thromboembolic disease is also a major concern for patients with primary brain tumors. Although the incidence of thromboembolic disease has been reported to be as high as 35–40% during the course of the GBM, prophylactic use of anticoagulation has not been recommended because of the increased risk of intracranial hemorrhage.[28]

Besides the symptoms of seizures, headache, and mental status changes, many patients have neurologic deficits and require physical, occupational, and speech therapy. Frequently, patients require emotional and psychological support and benefit from help provided by support groups, local workers, psychiatrists, and organizations such as Brain Tumor Society or National Brain Tumor Foundation.

Surgical Care

In glioblastoma multiforme (GBM), surgery is always an incomplete debulking, since it is a highly infiltrating tumor and cannot be resected completely. The extent of surgical resection depends on the location and eloquence of the brain areas. However, a trial using 5-aminolevulinic acid showed a significantly higher rate of complete resection (65% gross total resection) of enhancing tumor on postoperative MRI performed within 72 hours of surgery versus 35% in the conventional surgery arm. Further analysis of the data has demonstrated that patients who underwent gross total resection, regardless of the treatment arm, had superior survival to those who received subtotal resection.[29, 30]

Radiation therapy

After surgery, a combination of radiation therapy (RT) with temozolomide followed by adjuvant temozolomide therapy remains the most effective adjuvant therapy for the treatment of patients with high-grade astrocytoma/GBM. A phase 3 clinical trial organized by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada showed a modest improvement of overall survival of 14.6 months compared with 12 months in the RT arm.[12]  The standard of care for RT in GBM is focal, fractionated external beam RT. New techniques and technologies continue to be evaluated, but none has clearly shown to be superior to standard external beam radiation therapy (EBRT). Different methods of administering radiation therapy are available.

External beam radiation therapy (EBRT)

The standard dose of external beam radiotherapy is 60 Gy in single daily fractions of 1.7–2 Gy, 5 times a week. This is applied to a limited field that includes the enhancing volume on CT scans with a 2-3 cm margin or a 1–2 cm margin beyond T2-weighted MR images.[31]

Approximately 50% of AAs and 25% of GBMs decrease in size following radiotherapy. This response usually occurs by the end of treatment.

Stereotactic brachytherapy

In patients who have recurrence after conventional radiotherapy, repeat resection of the tumor and brachytherapy may be indicated. Excellent candidates are patients with unifocal, well-defined, supratentorial tumors less than 5 cm in diameter that does not involve the corpus callosum, brain stem, or ependymal surfaces.

Brachytherapy involves using stereotactic techniques to accurately place catheters containing radioactive isotopes within brain tumors, without tumoricidal effect to normal brain tissues.

Typically, brachytherapy delivers an additional 50-60 Gy of radiation, bringing the total dose of radiation up to 110–120 Gy.

Brachytherapy involves a surgical procedure to place the radiation source, which is further difficult in tumors of critical locations. So, only ~25% of patients were candidates for this procedure and hence brachytherapy fell out of favor.[32]

Stereotactic radiosurgery

Stereotactic radiosurgery is a technique used to treat small (< 4 cm), radiographically well-defined lesions with a single high-dose fraction of ionizing radiation in stereotactically directed narrow beams.

Radiosurgery has the advantage over brachytherapy in being noninvasive, allowing treatment of patients with tumors in surgically inaccessible or eloquent areas of the brain or serious coexisting medical illnesses.

Initial retrospective studies of radiosurgical boost to conventional RT were promising. However, an RCT revealed no difference in survival with RTOG 9305. Hence there is no role of stereotactic radiosurgery in primary GBM.[33]

In recurrent GBM, though there are reports of advantages of stereotactic radiosurgery, there is no level I evidence to support this, and many of these studies report a high rate of radiation necrosis. An ongoing RCT is evaluating the use of stereotactic radiosurgery in recurrent GBM.[32]

Boron neutron capture therapy (BNCT)

This modality of treatment is still investigational, not widely available, and costly. The value still is not proven.

An earlier study of intra-operative BNCT (IO-BNCT) by Hatanaka showed unsatisfactory results in patients with tumors located deeper than 4 cm from the brain surface.[34]  Later, non-operative BNCT (NO-BNCT) using epithermal neutron beam and advanced dose planning system also did not show any improvement in the long-term survival of these patients.[35]

BNCT for newly diagnosed or recurrent high-grade gliomas is still being evaluated.

Chemotherapy

Chemotherapy probably has a modest but significant effect in prolonging survival when administered with concurrent radiation therapy after surgery.

Current recommendations in patients age < 70 years with good Karnofsky Performance Scale (KPS) score include maximal safe surgical resection followed by concurrent radiation and chemotherapy with temozolomide, followed by adjuvant chemotherapy with temozolomide.

A phase III randomized trial combining low-dose chemotherapy using the oral alkylating agent temozolomide concurrently with radiation, followed by an additional 6 months of adjuvant temozolomide showed statistically significant survival benefit over radiation alone. The median survival was 14.6 months with radiation therapy plus temozolomide and 12.1 months with radiation therapy alone. The treatment was well tolerated with minimal additional toxicity.[12]

Another phase III randomized trial that included 240 patients compared surgery with implantation of polymer wafers with BCNU (Gliadel wafers) into the tumor bed demonstrated a significant prolongation of survival compared with a placebo wafer. Both groups received radiation therapy. The median survival was 13.9 months in the group treated with Gliadel wafers and 11.6 months in the group treated with a placebo.[36]

A safety and efficacy study by Darakchiev et al, using adjunct combination therapy with BCNU wafers and permanent iodine-125 seeds, resulted in favorable survival in patients with recurrent GBM. The median survival was 69 weeks, and the median progression-free survival was 47 weeks. The incidence of brain necrosis appeared to be higher than with either therapy alone. However, the necrosis was manageable with surgery or hyperbaric oxygen therapy and did not affect the survival.[37]

Stupp et al reported the results of the randomized phase III trial for patients with glioblastoma who were treated with adjuvant temozolomide and radiation with a median follow-up of more than 5 years. Stupp et al previously reported improved median and 2-year survival when temozolomide was added to radiation therapy in glioblastoma.[12]  Survival in the combined therapy group (ie, temozolomide and radiation) continued to exceed that of radiation alone throughout the 5-year follow-up (p < 0.0001). Survival of patients who received adjuvant temozolomide with radiotherapy for glioblastoma is superior to radiotherapy alone across all clinical prognostic subgroups.

A post hoc analysis in a subset of patients in a phase III trial, patients whose tumors had methylation of the promoter region of the methylguanine methyltransferase (MGMT) gene survived longer and derived greater benefit from the addition of temozolomide therapy to RT than those whose tumors were not methylated.[20]

For tumor recurrence, various conventional chemotherapeutic agents, including nitrosoureas, BCNU, and CCNU, and chemotherapies such as cisplatin, carboplatin, etoposide, are used. Selected patients may benefit from tumor resection. Patients with recurrent GBM are encouraged to participate in approved clinical trials to develop effective regimens[6] .

A phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma (RESCUE study) concluded that for patients with recurrent GBM, rechallenging with 50 mg/m2/d continuous dose-intense temozolomide is a valuable option. Patients with recurrence after a treatment-free interval or patients experiencing progression during the first 6 cycles of conventional adjuvant temozolomide therapy benefit the most[38] .

After the initial definitive treatment (surgical debulking) of glioblastoma multiforme (GBM), the patient may need further inpatient care during the ongoing radiation therapy. Chemotherapy usually is performed on an outpatient basis. Continuing outpatient follow-up care is necessary if the patient develops neurological deterioration such as acute motor weakness or depression of consciousness from the effects of therapy, increased intracranial pressure from vasogenic edema, or acute hydrocephalus from ventricular obstruction. Appropriate intervention depends on the nature of the problem (eg, steroid therapy for edema, shunting for hydrocephalus).

Other treatment options

Extensive research is taking place on newer therapeutic options like laser interstitial thermal therapy (LITT), tumor treating fields (TTF), immunotherapy, immune checkpoint inhibitors, T-cell therapy, viral therapy, vaccine therapy, and so on.[39]  These options are beyond the scope of this section. Interested readers are encouraged to read standard neuro-oncological textbooks, journals, and other sources (see References).

Consultations

Treatment of GBM is largely a multispecialty team approach. Therefore, neurology, neurosurgery, neuro-oncology, radiation oncology, psychiatry, and social service consultations should be obtained.

 

Medication

Medication Summary

The goals of pharmacotherapy for glioblastoma multiforme (GBM) are to reduce morbidity and to prevent complications.

Alkylating agents

Class Summary

Alkylating agents lead to DNA double strand breaks and apoptosis.

Local chemotherapy with carmustine wafers significantly prolongs survival in patients with newly diagnosed primary malignant glioma.

Temozolomide (Temodar)

Oral alkylating approved for newly diagnosed GBM and recurrent anaplastic astrocytomas. Converted to MTIC at physiologic pH; 100% bioavailable; approximately 35% crosses blood-brain barrier. Indicated for GBM combined with radiotherapy. Significant overall survival was demonstrated in patients treated with temozolomide and radiation compared with radiotherapy alone.

Carmustine (BiCNU, Gliadel Wafer)

Gliadel is a small wafer that contains the chemotherapeutic drug carmustine. The wafer is designed to release the drug slowly over a period of 2-3 wk after placed in tumor bed. Up to 8 wafers are implanted in the cavity, slowly delivering carmustine directly to tumor site.

Vascular endothelial growth factor inhibitors

Class Summary

These are monoclonal antibodies that target the vascular endothelial growth factor (VEGF) – the principal molecule involved in angiogenesis during embryogenesis and in malignant tumors – thereby inhibiting the growth of GBM 

Bevacizumab (Avastin, Mvasi, Zirabev)

Administered as an intravenous infusion in chemotherapy day unit in the hospital. FDA-approved schedule dose for recurrent glioblastoma is 10 mg/kg every 2 weeks. However, studies show even smaller doses of 5 mg/kg every 2 weeks are also equally effective. Proteinuria and hypertension are the most frequent adverse effects of the drug.