Glioblastoma Multiforme Treatment & Management

Updated: Jul 28, 2021
  • Author: Jeffrey N Bruce, MD; Chief Editor: Herbert H Engelhard, III, MD, PhD, FACS, FAANS  more...
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Treatment

Approach Considerations

The treatment of glioblastomas remains difficult in that no contemporary treatments are curative. [56]  While overall mortality rates remain high, improved understanding of the molecular mechanisms and gene mutations combined with clinical trials are leading to more promising and tailored therapeutic approaches. Multiple challenges remain, including tumor heterogeneity; tumor location in a region where it is beyond the reach of local control; and rapid, aggressive tumor relapse. Therefore, the treatment of patients with malignant gliomas remains palliative and encompasses surgery, radiotherapy, and chemotherapy. See Brain Cancer Treatment Protocols for summarized information.

Upon initial diagnosis of glioblastoma multiforme (GBM), standard treatment consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide. [57, 58, 8]  At some institutions, transferring the patient to another facility may be necessary if the proper consultations cannot be obtained. In most cases, surgical resection can be performed on an urgent, but not emergent, basis. Patients with glioblastomas who undergo surgical resection typically spend the night after surgery in an intensive care unit, followed by an inpatient stay of 3-5 days. The final length of stay depends on each patient's neurological condition.

Postoperative antibiotics usually are continued for 24 hours, and deep vein thrombosis prophylaxis is continued until patients are ambulatory. Anticonvulsants are maintained at therapeutic levels throughout the inpatient stay, while steroids are reduced gradually, tailored to each patient's clinical status. Many patients benefit from occupational therapy and physical therapy or rehabilitation.

While patients are in the hospital, they should receive postoperative imaging to determine the extent of surgical resection. Surgical resection is evaluated best within 3 days of surgery by using contrast-enhanced MRI. Contrast enhancement during this period accurately reflects residual tumor. If not performed preoperatively, complete evaluations by consulting physicians, including a neuro-oncologist and radiation oncologist, should be considered postoperatively.

For patients older than 70 years, less aggressive therapy is sometimes employed, using radiation or temozolomide alone. [59, 10, 24]  A study by Scott et al found that elderly patients with glioblastoma who underwent radiotherapy had improved cancer-specific survival and overall survival compared with those who did not undergo radiotherapy treatment. [25]

Evidence suggests that in patients over 60 years old, treatment with temozolomide is associated with longer survival than treatment with standard radiotherapy, and for those over 70 years old, temozolomide or hypofractionated radiotherapy is associated with prolonged survival than treatment with standard fractionated radiotherapy. The improvement in survival with temozolomide is enhanced in patients with MGMT promoter methylation. [26]  Data from a randomized phase III trial suggests that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. [60]

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. [61]   

Median time to recurrence after standard therapy is 6.9 months. [62]  For recurrent glioblastoma multiforme, surgery is appropriate in selected patients, and various radiotherapeutic, chemotherapeutic, biologic, or investigational therapies are also employed. [63, 32]

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Surgical Care

Because glioblastomas cannot be cured with surgery, the surgical goals are to establish a pathological diagnosis, relieve mass effect, and, if possible, achieve a gross total resection to facilitate adjuvant therapy. [64] Most glioblastomas recur in and around the original tumor bed, but contralateral and distant recurrences are not uncommon, especially with lesions near the corpus callosum.

The indications for reoperation after initial treatment with surgery, radiation therapy, and chemotherapy are not firmly established. Reoperation is generally considered in the face of a life-threatening recurrent mass, particularly if radionecrosis rather than recurrent tumor is suspected as the cause of clinical and radiographic deterioration. Positron emission tomography (PET) scans and magnetic resonance (MR) spectroscopy have proven useful in discriminating between those 2 entities.

Although no formal studies have been performed, observations indicate that variables, such as young age, prolonged interval between operations, and extent of the second surgical resection, have prognostic significance. [65]

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%. [66]

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). [67]

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. [44] An analysis of 28 studies found a mean duration of survival advantage of total over subtotal resection for glioblastoma multiforme (14 vs 11 mo). [43, 68]

Li and colleagues compared the survival of patients having 100% removal of the contrast-enhancing tumor, with or without additional resection of the surrounding FLAIR abnormality region to that of patients undergoing 78% to < 100% extent of resection of the enhancing mass. The median survival time for patients acheiving complete resection (15.2 months) was significantly longer than that for patients undergoing less than complete resection (9.8 months; P < 0.001). The patients who underwent resection of ≥ 53.21% of the surrounding FLAIR abnormality beyond the 100% resection achieved significant prolongation of survival (median survival times 20.7). [69]

In a cohort study of 761 patients with newly diagnosed glioblastoma, Molinari et al reported longer overall survival with maximal resection of contrast-enhanced tumor plus, in younger patients, resection of non–contrast-enhanced tumor as well. Best overall survival was in two subgroups of temozolomide-treated patients: those with IDH-mutated tumors (n = 28) and those with IDH–wild-type tumors who were younger than 65 years and had a median of 100% of contrast-enhanced tumor resected and a median of 90% of non–contrast-enhanced tumor resected, resulting in no more than 5.4 mL of residual non–contrast-enhanced tumor. Overall survival in those subgroups was 37.3 months, compared with 16.5 months in comparable young patients who had more than 5.4 mL of residual non–contrast-enhanced tumor after resection. [70]

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. [71]

Oral aminolevulinic acid (ALA; Gleolan) was approved by the US Food and Drug Administration (FDA) in 2017 as an adjunct for visualization of malignant tissue during surgery in patients with malignant glioma (suspected WHO grades III or IV on preoperative imaging). During surgery, an operating microscope adapted with a blue-emitting light source and filters for excitation light of wavelength 375-440 nm, and observation at wavelengths of 620-710 nm is used to visualize PpIX (an ALA metabolite) accumulation in tumor cells that shows up as red fluorescence. [72]

Fluorescence-guided surgery (FGS), an emerging technology that combines detection devices with fluorescent contrast agents, may provide more complete and precise resection of gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate for FGS of glioma and other tumor types. In a phase 1 study, tozuleristide (BLZ-100) provided a viable fluorescence signal in both high- and low-grade glial tumors, but did not bind to normal tissues. Signal intensity in high-grade tumors was found to improve with increasing doses of tozuleristide, regardless of the time of dosing relative to surgery. [73, 74]

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Medical Care

In an evidence-based clinical practice guideline formulated to address the impact of cytotoxic chemotherapy on disease control and survival in adults with progressive glioblastoma, Olson et al make the following recommendations [75] :

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

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

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

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

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

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

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

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

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

Anticonvulsant medications are usually maintained, and levels are checked intermittently. Steroids are tapered to lower doses for radiation therapy and then tapered further if possible. While taking steroids, patients should be maintained on an antiulcer agent.

Radiation therapy

Radiation therapy in addition to surgery or surgery combined with chemotherapy has been shown to prolong survival in patients with glioblastoma multiformes compared with surgery alone. [76, 77] The addition of radiotherapy to surgery has been shown to increase survival from 3-4 months to 7-12 months. [62, 78]

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. [79]

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. [80, 81]

Jablonska et al reported that in patients with poor clinical factors other than advanced age, the combination of hypofractionated radiation therapy and temozolomide produced results comparable to those seen with standard fractionation. In the 17 patients in the study, poor clinical factors included postoperative neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Patients received 40, 45, and 50 Gy in 15 fractions to 95% of the planning target volume (PTV), clinical target volume (CTV), and gross tumor volume (GTV), respectively. Treatment was delivered using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). [82]

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. [83, 84]

Two studies investigated tumor recurrence after whole-brain radiation therapy and found that the tumor recurred within 2 cm of the original site in 90% and 78% of patients, supporting the use of focal radiation therapy. Multifocal recurrence occurred in 6% of patients in one study and in 5% of patients in a second trial.

Delivery of external beam radiation therapy typically requires a waiting period of 3–5 weeks after tumor resection, to allow for wound healing and recovery, and tumor regrowth may occur during that time. Interstitial brachytherapy, in which radioactive seeds are placed intraoperatively, after tumor resection, allows immediate initiation of radiation therapy. [85] 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. [86]

Radiosensitizers, such as newer chemotherapeutic agents, [87] targeted molecular agents, [39, 40] and antiangiogenic agents [40] may increase the therapeutic effect of radiotherapy. [88]

Radiotherapy for recurrent glioblastoma multiforme is controversial, though some studies have suggested a benefit to stereotactic radiosurgery or fractionated stereotactic reirradiation. [89, 90, 91]  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. [57]

Fleischmann et al reported that in patients undergoing re-irradiation for recurrent glioblastoma, concomitant treatment with bevacizumab significantly reduced the rate of radiation toxicity, both in the short and the long term. Bevacizumab was given in a dose of 10 mg/kg on days 1 and 15 of re-irradiation therapy. [92]

Chemotherapy – Antineoplastic agents

Temozolomide is an orally active alkylating agent that is indicated for newly diagnosed glioblastoma multiforme and for maintenance therapy; is also used in recurrent glioblastoma. It was approved by the United States Food and Drug Administration (FDA) in 2005. Studies have shown that the drug was well tolerated and provided a survival benefit. Adjuvant and concomitant temozolomide with radiation was associated with significant improvements in median progression-free survival over radiation alone (6.9 vs 5 mo), overall survival (14.6 vs 12.1 mo), and the likelihood of being alive in 2 years (26% vs 10%).

MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that contributes to temozolomide resistance. Methylation of the MGMT promoter, found in approximately 45% of glioblastoma multiformes, results in an epigenetic silencing of the MGMT gene, decreasing the tumor cell's capacity for DNA repair and increasing susceptibility to temozolomide. [93] Note the following:

  • In older patients, MGMT promoter methylation is a favorable prognostic factor and predicts response to temozolomide. When patients with and without MGMT promoter methylation were treated with temozolomide, the groups had median survivals of 21.7 versus 12.7 months, and 2-year survival rates of 46% versus 13.8%, respectively.
  • MGMT promoter methylation status may help guide treatment decisions. In particular, elderly patients, who are at greater risk of toxicity from combined radiotherapy and chemotherapy, might be treated with radiation therapy alone if their tumors lack MGMT methylation (and hence are less likely to respond to temozolomide) or be treated with chemotherapy alone if MGMT promoter methylation is present. [36]

Data from the University of California at San Francisco indicate that, for the treatment of glioblastomas, surgery followed by radiation therapy leads to 1-, 3-, and 5-year survival rates of 44%, 6%, and 0%, respectively. By comparison, surgery followed by radiation and chemotherapy using nitrosourea-based regimens resulted in 1-, 3-, and 5-year survival rates of 46%, 18%, and 18%, respectively.

Chemotherapy for recurrent glioblastoma multiforme provides modest benefit at best. Agents from several classes are used. According to the National Comprehensive Cancer Network, preferred agents include the following [58] :

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

Carmustine

Carmustine-polymer wafers (Gliadel) were approved by the FDA in 2002. Gliadel wafers are placed on the surface of the resected tumor bed. Though Gliadel wafers are used by some for initial treatment, they have shown only a modest increase in median survival over placebo (13.8 vs. 11.6 months) in the largest such phase III trial, and are associated with increased rates of cerebrospinal fluid leak and increased intracranial pressure secondary to edema and mass effect. [94, 95] 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. [96, 97]

Bevacizumab

The anti-angiogenic agent bevacizumab was approved by the FDA for recurrent glioblastoma in 2009. [98] When used with irinotecan, bevacizumab improved 6-month survival in recurrent glioma patients to 46%, compared with 21% in patients treated with temozolomide. [99, 100]  The anti-angiogenic effect of bevacizumab also decreases peritumoral edema, potentially reducing the necessary corticosteroid dose. The bevacizumab-irinotecan combination for recurrent glioblastoma multiforme has been shown to improve survival over bevacizumab alone. [101]

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. [102, 103]

Electric-field therapy

Tumor-treating fields (also known as alternating electric field therapy) is a noninvasive modality that involves the transcutaneous delivery of low-intensity, intermediate-frequency alternating electric fields that exert biophysical force on charged and polarizable molecules known as dipoles. This modality targets dividing cells in glioblastoma multiforme in several ways, including interference with the mitotic apparatus, DNA repair, and cell permeability. Normal cells are generally not harmed. [104] 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. [105]

The Optune tumor-treating field device, also known as the NovoTTF-100A System, was initially approved in 2011 for use in glioblastoma multiforme that had recurred or progressed after treatment. In 2015, the FDA expanded approval to include use of the device in conjunction with temozolomide chemotherapy in the first-line setting. Approval was based on an open-label, randomized phase 3 trial in 700 patients in which median overall survival was 19.4 months with use of the device plus temozolomide, versus 16.6 months with chemotherapy only. [105]

In a randomized, open-label trial in 695 patients with glioblastoma, the addition of  tumor-treating fields to treatment with temozolomide improved median progression-free survival from 4.0 months to 6.7 months (hazard ratio [HR], 0.63; 95% confidence index [CI], 0.52-0.76; P < 0.001). Median overall survival improved from 16.0 months to 20.9 months (HR, 0.63; 95% CI, 0.53-0.76; P <  0.001). [106, 107]

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Supportive Care

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

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

Vasogenic edema

Brain edema can cause focal neurologic deficits and, by increasing intracranial pressure (ICP), produce headache, nausea, and vomiting. Corticosteroids are used to treat patients with symptoms from peritumoral vasogenic edema. Dexamethasone is the steroid of choice for these patients, because of its potency, long half-life, and high brain penetrance. There is no standard regimen for steroid use in this setting, so dosing must be individualized. Most patients respond to low doses of dexamethasone (eg, 4-16 mg/day, given in 1–2 doses). [108, 8, 9, 108]

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

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

Seizures

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

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

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

Venous thromboembolism

Approximately 20% of glioblastoma patients experience VTE in the year following surgical resection. [8] Prevention and treatment of VTE in these patients is complicated by their increased risk for intracranial hemorrhage (ICH). Therapeutic anticoagulation may increase risk of ICH in patients with primary brain tumors, but lack of long-term anticoagulation has been associated with an increased risk of recurrent VTE in patients with glioblastoma.American Society of Clinical Oncology (ASCO) guidelines recommend anticoagulation for patients with primary brain malignancies and an established VTE, although because of limited data on this population, uncertainties remain about the choice of anticoagulant and selection of patients most likely to benefit. [109]

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). [109] In patients with systemic cancer, prophylaxis is started preoperatively; because of the risk of ICH, however, prophylaxis in glioblastoma patients is started within 24 hours after surgery. [9] Prophylaxis is continued for at least 7 to 10 days postoperatively. [109]

ASCO guidelines include direct oral anticoagulants (DOACs) as an option for VTE prophylaxis and treatment, but note an increased risk of major bleeding. [109] 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. [110]

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Consultations

Patients with glioblastomas should be evaluated by a team of specialists, including a neurologist, neurosurgeon, neurooncologist, and radiation oncologist, in order to develop a coordinated treatment strategy.

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Investigational Approaches

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

  • Targeted molecular therapies
  • Immunotherapy (eg, vaccines, checkpoint inhibitors, oncolytic viruses) [111]
  • Nanomedicines that can cross the blood-brain barrier [112]
  • Stem cells [113]
  • Cannabinoids [114]
  • Ketogenic diet [115]

Genotyping of brain tumors may have applications in stratifying patients for clinical trials of various novel therapies. In about 50% of patients with glionas, circulating tumor DNA can be sequenced from cerebrospinal fluid, allowing genotyping of the tumor without the need for brain re-biopsy. [116]

Vaccine therapy

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

Modified polio vaccine therapy

The poliovirus receptor CD155 is broadly upregulated on the surface of malignant solid tumors, and a preliminary study of intratumoral infusion of a modified poliovirus vaccine has demonstrated benefit in some cases of recurrent  malignant glioma. In a dose-finding and toxicity study, 61 patients with recurrent supratentorial WHO grade IV malignant glioma received seven doses of a live attenuated poliovirus type 1 vaccine with its cognate internal ribosome entry site replaced with that of human rhinovirus type 2. The recombinant nonpathogenic polio–rhinovirus chimera was infused into the glioma via an implanted catheter. [117]

In contrast to overall survival rates in a historical control group, which declined steadily to 14% at 24 months and 4% at 36 months, overall survival in the study patients stabilized at 21% at 24 months, remaining at that rate through 36 months. Adverse events that affected more than 20% of the study patients in the dose-expansion phase included headache (52%), hemiparesis (50%), seizure (45%), dysphasia (28%), and cognitive disturbance (25%). [117]

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

In a study of 11 patients with newly diagnosed glioblastoma received temozolomide, 100 mg/m2/d × 21 days per cycle, and at least three pp65-directed vaccines admixed with granulocyte-macrophage colony-stimulating factor on day 23 ± 1 of each cycle. Despite increased proportions of regulatory T cells (Tregs), median progression-free survival was 25.3 months and overall survival was 41.1 months; three patients remained progression-free more than 7 years after diagnosis. [118]

Tyrosine kinase inhibitors

A small proportion of glioblastomas responds to gefitinib or erlotinib (tyrosine kinase inhibitors). The simultaneous presence in glioblastoma cells of mutant EGFR (EGFRviii) and PTEN was associated with responsiveness to tyrosine kinase inhibitors, whereas increased p-akt predicts a decreased effect. [119, 120, 121] 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. [122]

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. [123]

Drug delivery systems

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

Pressure-driven infusion of therapeutic agents through an intracranial catheter, also known as convection-enhanced delivery (CED), has the advantage of delivering drugs along a pressure gradient rather than by simple diffusion. CED has been used to deliver both conventional chemotherapy drugs (eg, paclitaxel, topotecan) and investigational agents (eg, interleukin-4–Pseudomonas exotoxin fusion protein). Although preclinical and clinical studies involving CED has shown that it is safe, it has proved only somewhat effective, and has technical shortcomings that need to be addressed. [124]

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Activity

No universal restrictions on activity are necessary for patients with glioblastomas. The patient's activity depends on his or her overall neurologic status. The presence of seizures may prevent the patient from driving. In many circumstances, physical therapy and/or rehabilitation are extremely beneficial. Activity is encouraged to reduce the risk of deep venous thrombosis.

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