Glioblastoma Multiforme Treatment & Management
- Author: Jeffrey N Bruce, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC more...
The treatment of glioblastomas remains difficult in that no contemporary treatments are curative. While overall mortality rates remain high, recent work leading to an understanding of the molecular mechanisms and gene mutations combined with clinical trials are leading to more promising and tailored therapeutic approaches. Multiple challenges remain, including tumor heterogeneity, tumor location in a region where it is beyond the reach of local control, and rapid, aggressive tumor relapse. Therefore, the treatment of patients with malignant gliomas still remains palliative and encompasses surgery, radiotherapy, and chemotherapy. See Brain Cancer Treatment Protocols for summarized information.
Upon initial diagnosis of glioblastoma multiforme (GBM), standard treatment consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide.[24, 25] For patients older than 70 years, less aggressive therapy is sometimes employed, using radiation or temozolomide alone.[26, 27, 28] A study by Scott et al found that elderly patients with glioblastoma who underwent radiotherapy had improved cancer-specific survival and overall survival compared with those who did not undergo radiotherapy treatment.
Recent evidence suggests that in patients over 60 years old, treatment with temozolomide is associated with longer survival than treatment with standard radiotherapy, and for those over 70 years old, temozolomide or hypofractionated radiotherapy is associated with prolonged survival than treatment with standard fractionated radiotherapy. The improvement in survival with temozolomide isenhancedinpatientswithMGMTpromotermethylation.
Stupp et al reported the final results of the randomized phase III trial for patients with glioblastoma who were treated with adjuvant temozolomide and radiation with a median follow-up of more than 5 years. Stupp et al previously reported improved median and 2-year survival when temozolomide was added to radiation therapy in glioblastoma. Survival in the combined therapy group (ie, temozolomide and radiation) continued to exceed that of radiation alone throughout the 5-year follow-up (p< 0.0001). Survival of patients who received adjuvant temozolomide with radiotherapy for glioblastoma is superior to radiotherapy alone across all clinical prognostic subgroups.
Median time to recurrence after standard therapy is 6.9 months. For recurrent glioblastoma multiforme, surgery is appropriate in selected patients, and various radiotherapeutic, chemotherapeutic, biologic, or experimental therapies are also employed.[47, 37] A study by Wernicke et al report that prostate-specific membrane antigen is expressed in the vasculature of GBM vessels and represents a potential novel therapeutic vascular target. Future clinical trials are planned.
Clinical practice guideline
In an evidence-based clinical practice guideline formulated to address the impact of cytotoxic chemotherapy on disease control and survival in adults with progressive glioblastoma, Olson et al make the following recommendations :
Temozolomide is recommended over procarbazine in patients who have a first relapse of glioblastoma after treatment with nitrosourea chemotherapy or who had no prior cytotoxic chemotherapy at the time of initial therapy (level II recommendation)
Carmustine (BCNU)-impregnated biodegradable polymer wafers are recommended for use as a surgical adjunct when cytoreductive surgery is indicated; the associated toxicities must be taken into account (level II recommendation
Various agents of uncertain benefit may be considered for use, depending on the treating clinician's clinical judgment; prior treatment exposure, systemic health, and tolerance must be taken into account; enrollment in clinical trials of these agents is encouraged (level III recommendation)
Radiation therapy [50, 51, 35, 52]
Radiation therapy in addition to surgery or surgery combined with chemotherapy has been shown to prolong survival in patients with glioblastoma multiformes compared to surgery alone. The addition of radiotherapy to surgery has been shown to increase survival from 3-4 months to 7-12 months.[46, 53]
Dose response relationships for glioblastomas demonstrate that a radiation dose of less than 4500 cGy results in a median survival of 13 weeks compared with a median survival of 42 weeks with a dose of 6000 cGy. This is usually administered 5 days per week in doses of 1.8-2.0 Gy.
The responsiveness of glioblastoma multiformes to radiotherapy varies. In many instances, radiotherapy can induce a phase of remission, often marked with stability or regression of neurologic deficits as well as diminution in the size of the contrast-enhancing mass. Unfortunately, any period of response is short-lived because the tumor typically recurs within 1 year, resulting in further clinical deterioration and the appearance of an expansile region of contrast enhancement.[54, 36]
Two studies investigated tumor recurrence after whole-brain radiation therapy and found that the tumor recurred within 2 cm of the original site in 90% and 78% of patients, supporting the use of focal radiation therapy. Multifocal recurrence occurred in 6% of patients in one study and in 5% of patients in a second trial.
Interstitial brachytherapy is of limited use and is rarely used. By implantation of radioactive seeds, a large dose of radiation is delivered to the tumor volume, with rapid fall-off of radiation in surrounding tissue. The tumor must be unilateral and smaller than 5 cm in diameter. In one study, patients treated with interstitial brachytherapy had a significantly better median survival (2 mo) compared with the conventional focal external beam radiation therapy. Following interstitial brachytherapy, up to 40% of patients require another surgery for removal of tissue damaged by radiation necrosis.
Experimental studies are underway in which focal radiation is delivered directly to tumors through an implanted balloon containing interstitial radiation. MRI and MR spectroscopy can be used to monitor therapy. Clinical outcomes from these studies are not yet available.
Radiotherapy for recurrent glioblastoma multiforme is controversial, though some studies have suggested a benefit to stereotactic radiosurgery or fractionated stereotactic reirradiation.[58, 59, 60] In adult patients with progressive glioblastoma, American Association of Neurological Surgeons/Congress of Neurological Surgeons (AANS/CNS) guidelines recommend that when the target tumor is amenable for additional radiation, re-irradiation should be performed to improve local tumor control. This re-irradiation may take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery.
Chemotherapy – Antineoplastic agents [62, 63, 64, 65, 66, 67]
Although the optimal chemotherapeutic regimen for glioblastoma is not defined at present, several studies have suggested that more than 25% of patients obtain a significant survival benefit from adjuvant chemotherapy. Meta-analyses have suggested that adjuvant chemotherapy results in a 6-10% increase in 1-year survival rate.[68, 69]
Temozolomide is an orally active alkylating agent that is used for persons newly diagnosed with glioblastoma multiforme. It was approved by the United States Food and Drug Administration (FDA) in March 2005. Studies have shown that the drug was well tolerated and provided a survival benefit. Adjuvant and concomitant temozolomide with radiation was associated with significant improvements in median progression-free survival over radiation alone (6.9 vs 5 mo), overall survival (14.6 vs 12.1 mo), and the likelihood of being alive in 2 years (26% vs 10%).
Nitrosoureas: BCNU (carmustine)-polymer wafers (Gliadel) were approved by the FDA in 2002. Though Gliadel wafers are used by some for initial treatment, they have shown only a modest increase in median survival over placebo (13.8 vs. 11.6 months) in the largest such phase III trial, and are associated with increased rates of CSF leak and increased intracranial pressure secondary to edema and mass effect.[70, 71]
MGMT is a DNA repair enzyme that contributes to temozolomide resistance. Methylation of the MGMT promoter, found in approximately 45% of glioblastoma multiformes, results in an epigenetic silencing of the gene, decreasing the tumor cell's capacity for DNA repair and increasing susceptibility to temozolomide. Note the following:
When patients with and without MGMT promoter methylation were treated with temozolomide, the groups had median survivals of 21.7 versus 12.7 months, and 2-year survival rates of 46% versus 13.8%, respectively.
Though temozolomide is currently a first-line agent in the treatment of glioblastoma multiforme, unfavorable MGMT methylation status could help select patients appropriate for future therapeutic investigations. 
O6-benzylguanine and other inhibitors of MGMT as well as RNA interference-mediated silencing of MGMT offer promising avenues to increase the effectiveness of temozolomide and other alkylating antineoplastics, and such agents are under active study. [73, 74, 39]
Carmustine (BCNU) and cis -platinum (cisplatin) have been the primary chemotherapeutic agents used against malignant gliomas. All agents in use have no greater than a 30-40% response rate, and most fall into the range of 10-20%.
Data from the University of California at San Francisco indicate that, for the treatment of glioblastomas, surgery followed by radiation therapy leads to 1-, 3-, and 5-year survival rates of 44%, 6%, and 0%, respectively. By comparison, surgery followed by radiation and chemotherapy using nitrosourea-based regimens resulted in 1-, 3-, and 5-year survival rates of 46%, 18%, and 18%, respectively.
A major hindrance to the use of chemotherapeutic agents for brain tumors is the fact that the blood-brain barrier (BBB) effectively excludes many agents from the CNS. For this reason, novel methods of intracranial drug delivery are being developed to deliver higher concentrations of chemotherapeutic agents to the tumor cells while avoiding the adverse systemic effects of these medications.
Pressure-driven infusion of chemotherapeutic agents through an intracranial catheter, also known as convection-enhanced delivery (CED), has the advantage of delivering drugs along a pressure gradient rather than by simple diffusion. CED has shown promising results in animal models with agents including BCNU and topotecan.[75, 76, 77]
Initial attempts investigated the delivery of chemotherapeutic agents via an intraarterial route rather than intravenously. Unfortunately, no survival advantage was observed.
Chemotherapy for recurrent glioblastoma multiforme provides modest, if any, benefit, and several classes of agents are used. Carmustine wafers increased 6-month survival from 36% to 56% over placebo in one randomized study of 222 patients, though there was a significant association between the treatment group and serious intracranial infections.[78, 79]
Genotyping of brain tumors may have applications in stratifying patients for clinical trials of various novel therapies.
The anti-angiogenic agent bevacizumab was approved by the U.S. Food and Drug Administration for recurrent glioblastoma in May 2009. When used with irinotecan, bevacizumab improved 6-month survival in recurrent glioma patients to 46% compared with 21% in patients treated with temozolomide.[81, 82] This bevacizumab and irinotecan combination for recurrent glioblastoma multiforme has been shown to improve survival over bevacizumab alone. Anti-angiogenic agents also decrease peritumoral edema, potentially reducing the necessary corticosteroid dose.
A small proportion of glioblastomas responds to gefitinib or erlotinib (tyrosine kinase inhibitors). The simultaneous presence in glioblastoma cells of mutant EGFR (EGFRviii) and PTEN was associated with responsiveness to tyrosine kinase inhibitors, whereas increased p-akt predicts a decreased effect.[84, 85, 86] Other targets include PDGFR, VEGFR, mTOR, farnesyltransferase, and PI3K.
Other therapy modalities under investigation include gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.[87, 88, 89, 90, 91, 92]
A population-based analysis of 5607 adult patients with glioblastoma in the SEER (Surveillance Epidemiology and End Results) database found that bevacizumab therapy may improve survival. In the study, glioblastoma patients who died in 2010 (after the FDA approved bevacizumab for this condition) survived significantly longer than those who died of the disease in 2008. Median survival was 8 months for patients who died in 2006, 7 months in 2008, and 9 months in 2010. This difference in survival was highly significant between 2008 (pre-bevacizumab) and 2010 (post-bevacizumab). This survival difference was unlikely due to improvements in supportive care during this time interval, because there was no significant difference between those who died in 2006 and patients who died 2 years later, in 2008.[93, 94]
The Optune device uses low-intensity, intermediate-frequency, alternating electric fields (tumor- treating fields) to target dividing cells in glioblastoma multiforme while generally not harming normal cells. The tumor-treating fields are generated via electrodes placed directly on the scalp. To target the tumor, array placement is based on the individual patient's magnetic resonance imaging results.
Optune, also known as the NovoTTF-100A System, was initially approved in 2011 for use in glioblastoma multiforme that had recurred or progressed after treatment. In October 2015, the FDA expanded approval to include use of the device in conjunction with temozolomide chemotherapy in the first-line setting. Approval was based on an open-label, randomized phase 3 trial in 700 patients, in which median overall survival was 19.4 months with use of the device plus temozolomide, versus 16.6 months with chemotherapy only.
The extent of surgery (biopsy vs resection) has been shown in a number of studies to affect length of survival. In a study by Ammirati and colleagues (1987), patients with high-grade gliomas who had a gross total resection had a 2-year survival rate of 19%, while those with a subtotal resection had a 2-year survival rate of 0%.
In another study of 416 patients, gross total resection, defined as >98% on MRI, conferred a survival advantage over subtotal resection (13 vs 8.8 mo).
In another study of 92 patients, a total tumor resection without any residual disease resulted in a median survival of 93 weeks, whereas the smallest percent of resection (< 25%) and greatest volume of residual tumor (>20 cm3) gradually shortened the survival to 31 weeks and 50 weeks, respectively.
An analysis of 28 studies found a mean duration of survival advantage of total over subtotal resection for glioblastoma multiforme (14 vs 11 mo).[99, 100]
Because these tumors cannot be cured with surgery, the surgical goals are to establish a pathological diagnosis, relieve mass effect, and, if possible, achieve a gross total resection to facilitate adjuvant therapy. Most glioblastomas recur in and around the original tumor bed, but contralateral and distant recurrences are not uncommon, especially with lesions near the corpus callosum. The indications for reoperation of malignant astrocytomas after initial treatment with surgery, radiation therapy, and chemotherapy are not firmly established. Reoperation is generally considered in the face of a life-threatening recurrent mass, particularly if radionecrosis rather than recurrent tumor is suspected as the cause of clinical and radiographic deterioration. PET scans and MR spectroscopy have proven useful in discriminating between these 2 entities.
See the images below.
Although no formal studies have been performed, observations indicate that variables, such as young age, prolonged interval between operations, and extent of the second surgical resection, have prognostic significance.
A study by El Hindy et al found that a common regulatory single-nucleotide polymorphism (-938C>A) is a survival prognosticator and a marker for high-risk in patients with glioblastoma multiforme who undergo gross total resection.
Stereotactic biopsy followed by radiation therapy may be considered in certain circumstances. These include patients with a tumor located in an eloquent area of the brain, patients whose tumors have minimal mass effect, and patients in poor medical condition, precluding general anesthesia. Median survival after stereotactic biopsy and radiation therapy is reported to be from 27-47 weeks.
A study by Jakola et al found that surgical procedures may not significantly alter the quality of life (QOL) in the average patient, however, the use of intraoperative ultrasonography may be associated with a preservation of QOL in that it helps avoid introducing new deficits.
Patients with glioblastomas should be evaluated by a team of specialists, including a neurologist, neurosurgeon, neurooncologist, and radiation oncologist, in order to develop a coordinated treatment strategy.
No dietary restrictions are necessary.
No universal restrictions on activity are necessary for patients with glioblastomas. The patient's activity depends on his or her overall neurologic status. The presence of seizures may prevent the patient from driving. In many circumstances, physical therapy and/or rehabilitation are extremely beneficial. Activity is encouraged to reduce the risk of deep venous thrombosis.
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