Glioblastoma multiforme

Glioblastomas with a wild-type IDH1 gene have a median overall survival of only 1 year, whereas IDH1-mutated glioblastoma patients have a median overall survival of over 2 years.

Tumors of various tissue types with IDH1/2 mutations show improved responses to radiation and chemotherapy.

Approximately 91% of glioblastoma‘s have IDH-wild type mutations with median overall patient survival of 1.2 years, whereas the remaining 9% of tumors are IDH mutant, with a median overall patient survival of 3.6 years.

The tumor has microvascular proliferation, pseudopalisading necrosis, and overt intratumoral heterogeneity.

The glioblastoma microenvironment consists of non-neoplastic cells, including glial cells, microglia, immune cells, vascular cells, reactive astrocytes and endothelial cells, and GBM stem cells.

GBM has a low number of tumor infiltrating lymphocytes and is phenotypically immunologically cold.

Tumor associated macrophages are the most abundant component of the non-tumoral glioblastoma multiforme tumor microenvironment;serving primarily to clear cellular debris by phagocytosis.

Such tumor associated macrophages are derived from microglia resident brain macrophages and blood monocytes, and are highly immunosuppressive and primarily involves antigen presentation and cellular phagocytosis.

The degree to which macrophasis infiltrate the glioblastoma tumor correlates with a more aggressive clinical course and reduced overall survival.

No contemporary treatments are curative.

Current treatment for newly diagnosed patients include maximum safe surgical resection, followed by radiotherapy with concurrent and adjuvant chemotherapy with without Tumor Treating Fields.

Treatment challenges include tumor heterogeneity, tumor location in a region where it is beyond the reach of local control, and rapid, aggressive tumor relapse.

Treatment of patients with malignant gliomas remains palliative and encompasses surgery, radiotherapy, and chemotherapy.

In approximately 20-40% of patients seizure is the first manifestation.

Some patients exhibit personality changes.

Upon diagnosis standard treatment consists of maximal surgical resection, radiotherapy, and concomitant temozolomide and 6 months of adjuvant chemotherapy with temozolomide.

For patients older than 70 years, less aggressive therapy is sometimes employed, using radiation or temozolomide alone.

Elderly patients with glioblastoma who undergo radiotherapy have improved cancer-specific survival and overall survival compared with those who do not undergo radiotherapy treatment.

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 inpatients with MGMT promoter methylation.

Survival in combined therapy group, temozolomide and radiation, exceeds that of radiation alone throughout the 5-year follow-up.

Survival of patients who receive 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.

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.

Carmustine (BCNU)-impregnated biodegradable polymer wafers are recommended for use as a surgical adjunct when cytoreductive surgery is indicated.

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.

Patients typically receive a dose of 60 Gy in 30 fractions.

In elderly patients hypofractionated radiotherapy of 40 GY in 15 fractions has comparable overall survival, decreased corticosteroid requirements, and improved compliance.

The addition of radiotherapy to surgery has been shown to increase survival from 3-4 months to 7-12 months.

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.

Radiation is usually administered 5 days per week in doses of 1.8-2.0 Gy.

Radiation 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.

The 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.

Tumor recurrence after whole-brain radiation therapy occurs within 2 cm of the original site in 90% and in 78% of patients with the use of focal radiation therapy.

Multifocal recurrence occur in 5-6% of patients.

Interstitial brachytherapy is of limited use and is rarely used, requiring

implantation of radioactive seeds, a large dose of radiation is delivered to the tumor volume, with rapid fall-off of radiation in surrounding tissue.

For interstitial brachytherapy, 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 compared with the conventional focal external beam radiation therapy.

Up to 40% of patients treated with interstitial brachytherapy require another surgery for removal of tissue damaged by radiation necrosis.

Radiosensitizers, such as newer chemotherapeutic agents,[56] targeted molecular agents, and antiangiogenic agents may increase the therapeutic effect of radiotherapy.

Radiotherapy for recurrent glioblastoma multiforme is controversial, though some studies have suggested a benefit to stereotactic radiosurgery or fractionated stereotactic reirradiation.

This re-irradiation may take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery.

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.

Adjuvant and concomitant temozolomide with radiation is associated with significant improvement in median progression-free survival over radiation alone: 6.9 vs 5 mo and overall survival 14.6 vs 12.1 mo.

Lomustine–Temozolomide Clinically Beneficial Over Temozolomide Alone for MGMT-Methylated Glioblastoma.

The likelihood of being alive in 2 years is 26% vs 10% for temozolomide plus or minus radiation.

Gliadel wafers 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.

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.

Patients with and without MGMT promoter methylation treated with temozolomide, the groups have median survivals of 21.7 versus 12.7 months, and 2-year survival rates of 46% versus 13.8%, respectively.

Carmustine (BCNU) and cis -platinum (cisplatin) have been the primary chemotherapeutic agents used against malignant gliomas.

Most agents in use have no greater than a 30-40% response rate, and most fall into the range of 10-20%.

Data 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.

The blood-brain barrier effectively excludes many agents from the CNS.

The delivery of chemotherapeutic agents via an intraarterial route rather than intravenously has no survival advantage.

Chemotherapy for recurrent glioblastoma multiforme provides modest, if any, benefit.

Carmustine wafers may increase 6-month survival, though ta significant association between the treatment group and serious intracranial infections may occur.

Bevacizumab when used with irinotecan, improves 6-month survival in recurrent glioma patients to 46% compared with 21% in patients treated with temozolomide or bevacizumab alone.

Anti-angiogenic agents help to decrease peritumoral edema.

A small proportion of glioblastomas responds to gefitinib or erlotinib, tyrosine kinase inhibitors.

The presence in glioblastoma cells of mutant EGFR and PTEN was associated with responsiveness to tyrosine kinase inhibitors.

Bevacizumab therapy may improve survival.

The Optune device uses low-intensity, intermediate-frequency, alternating electric fields referred to as 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 via array placement is based on the individual patient’s magnetic resonance imaging results.

Optune, also known as the NovoTTF-100A System, was initially approved to include use of the device in conjunction with temozolomide chemotherapy in the first-line setting in which median overall survival was 19.4 months with use of the device plus temozolomide, versus 16.6 months with chemotherapy only.

TTF are low intensity, intermediate frequency, alternating electrical fields, delivered via a device, that physically interferes with cell division, by causing misalignment of the microtubule subunits in the mitotic spindle during the metaphase to anaphase transition, and by dielectrophoretic movement of intracellular, macromolecules and organelles during telophase.

Triggers an environment of immunosuppression in both peripheral blood and tumor which shortens time to progression and limited survival of patients.

Less than 10% of patients are alive at 5 years after diagnosis.

In a few years more than half of patients with glioblastoma will be older than 65 years.

Various histologic subtypes exist: fibrillary, most common, gemistocytic, giant cell, small cell, and granular type forms.

The most frequently diagnosed malignant primary brain tumor.

More than 90% of all primary de novo lesions.

Secondary GBM occurs through progression of a low-grade astrocytoma or anaplastic astrocytoma, and generally occurs in younger patients.

Primary and secondary glioblastoma is or indistinguishable morphologically, but genetically different.

Primary GBM is associated with a high frequency of EGFR gene amplification, whereas secondary GBM is characterized by p53 mutations.

EGFR mutation variant III (EGFRvIII) expressed in approximately 30% of patients and is associated with a poor prognosis.

EGFR aberrations with gene amplification seen in more than 40% of GBMs, which may be associated with poorer prognosis.

When sarcomatous elements are present the process is termed gliosarcoma.

Standard treatment surgical debulking, followed by radiotherapy, with or without chemotherapy.

Maximal surgical removal of the tumor, six weeks of postoperative radiation therapy, and concomitant alkylating agent temozolomide 75 mg/m² daily, followed by adjuvant temozolomide 150-200 mg a meter square for five days every 28 days, is the present standard of care.

With the introduction of temozolomide two year survival rate of glioblastoma has doubled from about 12- to about 25%.

Almost 100% glioblastoma’s recur usually within 6-8 months.

Five-year survival rate for glioblastoma multiforme is about 10%.

Many patients with glioblastoma experience cognitive deficits with memory loss and loss of executive function.

Patients with the glioblastoma may experience mood disorders and personality changes.

Patients with impaired executive functions are more common in tumors involving the frontal lobe.

Phase III trial from EORTC and NCIC in 573 newly diagnosed GBM associated with a median survival of 14.6 months in surgically treated patients with radiation with or with temozolomide, compared to 12.1 months with radiotherapy alone, a 2 year survival rate of 26.5% compared with 10.4% (Stupp R et al).

Because lesions typically have thin tendrils several centimeters into the surrounding brain tissue resection of the entire tumor cannot be accomplished.

Surgery can alleviate symptoms and extend survival and the most aggressive surgery possible is recommended.

To prolong survival 92-98% of the tumor must be resected.

In a retrospective study of more than 400 patients significant survival advantage was noted for patients in whom 98% or more of the tumor volume was resected then for those with lesser extent of resection (Anderson MD).

Compared to sub total resection, gross total resection substantially improved overall and progression free survival, but the quality of evidence is moderate to low (Brown TJ).

All survivors of five years or longer have had aggressive surgical resection of the tumors.

Tumor cell infiltrate into the surrounding brain, limits usefulness of surgical resection.

Median survival with surgery alone 14 weeks and 40 weeks with surgery and radiation therapy.

Median survival with multimodality therapy in the range of 9-12 months.

Patients older than 65 years of age and nose older than 40 with a Karnofsky performance scale below 80 have the worse prognosis(Lamborn KR).

Survival for patients with elevated IgE live longer than those with normal levels.

Low likelihood of a patient receiving surgery, radiation, or chemotherapy decreases with age.

WHO system is the primary means to guide therapy and assess prognosis.

Prognostic factors that are favorable in older patients include a good performance status Karnofsky performance scale greater than 70, or WHO functional status grade I or II, younger age, and extent of surgical resection.

A recent population based study revealed overall survival 42.4% at 6 months, 17.7% at 1 year and 3.3% at 2 years.

Two-year survival rates 8-12%.

Only 5% of patients live greater than 5 years.

35% of patients survive the first year after diagnosis.

Tumor grade, age, extent of resection and performance status at diagnosis are the most important prognostic factors of outcome.

Median survival only 16-24 weeks after recurrence.

Patients who progress through initial treatment have an overall survival of less than 6 months (Wong ET).

Keime-Guibert et al randomized 85 elderly patients to radiation therapy plus supportive care vs. supportive care alone: at a median follow-up of 21 weeks, the median survival for treated group was 29.1 weeks, compared to 16.9 weeks for those treated with supportive care alone.

BCNU added to radiation increases survival rate by approximately 10% at 1 and 2 years.

A meta-analysis of 12 randomized trials with 3004 patients demonstrated that adjuvant nitrosoureas generated slightly longer median survival times, but no difference in long-term survival time in high-grade gliomas (Stewart LA).

Refractory to most chemotherapeutic agents due to unresponsiveness, with occasional short lived responses, rapid development of resistance with genetic transformations and tumor heterogeneity.

Methylguanine methyltransferase thought to be major mechanism of resistance to alkylating agents.

MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme protecting against damage from ionizing radiation and alkylating agents.

Concomitant and adjuvant radio-chemotherapy with the alkylating agent temozolomide is the standard of care in non-elderly patients with glioblastoma.

The above treatment benefit is largely restricted to patients with tumors exhibiting promoter methylation of the O6-methyl guanine-DNA methyltransferase gene (MGMT), which encodes a DNA repair protein associated with alkylator resistance.

When MGMT promoter is methylated cells are unable to repair DNA damage.

Methylated MGMT promoter is present in 40-45% of GBM’s.

Toleration of chemotherapy combined with radiotherapy is reduced in the elderly.

In a phase 3 trial comparing temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma: temozolomide alone is nine inferior to radiotherapy alone in this study (Neuro-oncology Working Group).

In the above study tumor MGMT promoter methylation was seen in 35% of patients tested and MGMT promoter methylation was associated with a longer overall survival than was the unmethylated status,11.9 versus 8.2 months.

In the above study event free survival was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy, 8.4 months versus 4.6 months, whereas the opposite was true for patients with no methylation of the MGMT promoter 3.3 months versus 4.6 months.

Method for testing MGMT is a methylation-specific polymerase chain reaction.

MGMT promoter hypermethylation is a predictor of response of the alkylating agent temozolomide in patients with GBM.

GBM patients treated with radiotherapy plus temolozide versus radiotherapy alone patients with methylated MGMT promoter who received combination therapy had longer overall survival than those without methylation (23.4 versus 12.6 months) (Stupp R et al).

When tumors are analyzed for the presence of methyl guanine methyl transferase (MGMT) patients with silenced MGMT had better survival than those whose tumors do not.

The phosphatidylinositol 3′-kinase (P13 kinase) pathway is activated in th majority of patients with GBM, with 15% having PIK3CA or PIK3R1 mutations and 40-50% have loss or mutation of phosphatase and tensin homolog deleted on chromosome 10.

Blood brain barrier prevents adequate delivery of chemotherapy for brain tumors, particularly in the infiltrating component of the malignancy where such cells are intercalated with normal brain tissue.

Efflux pumps located in the blood brain barrier can eliminate drug agents.

Nitrosourea based regimens in an adjuvant setting prolonged survival 6% and 4% at 1 and 2 years, respectively.

EORTC and NCI of Canada study of 573 patients in a study of radiation alone vs. chemoradiotherapy with temozolomide revealed a 2 year survival rate of 10% versus 26.5%, respectively.

Response rate to second line chemotherapy <10%.

Most patients have progression or recurrence at or close to the primary site and distant intracranial or extracranial failures are rare.

Additional biologic barriers to the spread of glioblastoma include the absence of lymphatics within the brain and spinal cord, the dense  surrounding dura and blood brain barrier, and early occlusion  in the venous channels by tumor compression.

Almost all cases of extraneural metastases with glioblastoma occur after neurosurgical procedures.

Necrosis and endothelial proliferation seen on histopathology indicate the presence of severe hypoxia.

Genetic abnormalities include amplification of epidermal growth factor receptor (EGFR), multiple types of EGFR mutations, loss of tumor suppressor protein PTEN, overexpression of platelet derived growth factor (PDGF) receptor alpha and p53 gene mutation.

Overexpression of PDGF and its receptor PDGFR is seen in low-grade astrocytomas and GBM, and is possibly associated with shorter survival.

Aberrant activation of NF-kB seen in glioblastoma.

NK-kB inhibitor alpha (NFKBIA) represses NF-kB and therefore signaling in the NF-kB and EGFR pathways.

NFKBIA is often deleted but not mutated in glioblastomas.

NFKBIA is a gene that inhibits the EGFR signaling pathway.

NFKBIA deletion increase chemotherapy resistance it and shortens survival.

Either the NFKBIA or EGFR abnormality is associated with shorter survival, compared to patients whose lesions have neither genetic defect.

Deletion of NFKBIA has the effect of amplification of EGFR in the pathogenesis of glioblastoma, and is associated with a short survival.

In patients older than 70 years mutations p53 gene are associated with reduced survival, where as in younger individuals such medications are associated with increased survival (Batchelor TT).

May be associated with cancer stem cells, which have an expression of CD 133 and Nestin.

The deletion of the cycin-dependent kinase 2A/p16 (CDKA2A) is a negative prognostic finding and is intensified in patients over the age of 70 (Shih HA).

Loss of the heterozygosity of chromosome 1p is a postive prognositic finder in patients, and has a greater effect in older patients.

Almost all GMs have excessive activation of the epidermal growth factor receptor pathway by amplification or activating mutations of the EGFR oncogene.

A marker for GBM includes oligodendrocyte lineage transcription factor 2 (Olig2), which is specific to the CNS and diffuse gliomas.

Olig2 Suppresses responses to genotoxic damage mediated by tumor suppressor gene p53, which is seen in the majority of high-grade gliomas.

Glioma stem cells produce vascular endothelial growth factor.

GBM is one of the most highly vascular solid tumors.

GBM tumors increase in size and then release pro-inflammatory proteins to adapt to hypoxia that occurs.

Profound immunosuppression exists in patients with GBM with immunosuppression via cell to cell contact, secretion of products that inhibit T cell activity and proliferation and initiate T-cell apoptosis.

Metastases occasionally found in the lungs, pleura, lymph nodes, bone, liver, and heart.

GBM cells may disseminate through hematogenous pathways or cerebrospinal fluid.

Extra neural metastasis most commonly seen following a neurosurgical procedure or ventriculo-peritoneal drainage.

Extra neural metastasis have been seen in transplant patients who have received organs from patients with glioblastoma multiforme.

Rarely extra neural metastases can occur in the absence of any previous surgical procedure.

Diagnosis is achieved through tomographic imaging, particularly MRI.

Glioblastomas typically show contrast enhancement on T1-weighted sequences;T2 – weighted/fluid-attenuated inversion recovery (T2/flare) reveals hyperintense cerebral edema; Central necrosis, and signs of local mass effect may also be present.

Aberrant activation of transcrption factor nuclear factor of κ-light polypeptide gene enhancer in B cells (NF-κB) occurs in GM.

A small group of patients respond to EGFR inhibitors erlotinib and gefitinib.

Often express EGFRvIII, an active genomic deletion variant of EGFR.

The EGFR gene is common in glioblastoma but that does not correlate with responsiveness of EGFR inhibitors.

Responses of more than 50% reported for combination of bevacizumab and irinotecan.

Study AVF3708g bevacizumab at 10mg/kg IV alone or with irinotecan in previously treated patients that failed radiotherapy with temozolomide resulted in a 25.9% objective response with a median response duration of 4.2 months (Kreisl TN).

In the European Organization for Research and Treatment of Cancer/NCI of Canada phase 3 study of 573 patients randomized to receive radiation alone or radiation plus low dose temozolomide at 75 mg meter squared: A longer median survival of 14.6 months versus 12.1 months when temozolomide was added to radiation, a 2 year survival rate of 26.5% in the combination therapy group versus 10% in the radiation only group (Stupp R et al).

NCI 06-C-0064E study of bevacizumab in patients that failed temozolomide and radiotherapy resulted in a 19.6% objective response rate with a median response duration of 3.9 months.

Adding bevacizumab to a first line regimen of radiation and temozolomide significantly improves progression free survival of newly diagnosed GM in a phase II study (Lai A).

Patients receiving temozolomide and bevacizumab during and after RT showed improved progression free survival without improved overall survival compared to a group treated with RT and bevacizumab at recurrence (Lai A et al).

Lomustine–Temozolomide Clinically Beneficial Over Temozolomide Alone for MGMT-Methylated Glioblastoma

Methylation status of the methyl-guanine methyl transferase gene (MGMT) is an independent predictor of response to the combination treatment, and the benefits of adjuvant temozolomide with radiation therapy for glioblastoma persist through 5 years of follow-up, although long-term survival rates remain low.

The original 2-year analysis of the above study showed survival of 27.2% in the combined therapy group versus 10.9% in the radiation alone group: At 5 years, mortality was 89% with temozolomide and 97% with radiation alone. (Stupp R et al).

A Randomized Phase III Clinical Trial of dose-dense temozolomide for newly diagnosed patients, with more than 800 patients randomly assigned to adjuvant standard-dose temozolomide or a dose-dense regimen: The efficacy outcomes were equivalent, but the dose-dense arm had greater toxicity (Wang GM et al).

Rindopepimut plus bevacizumab associated with improved long-term survival in patients with recurrent EGFRvIII positive glioblastoma.

5-Aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas.

Tumor fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumor, leading to improved progression-free survival in patients with malignant glioma.

In a phase 3 non-randomized controlled trial of 331 patients treated with dendritic cell autologous tumor lysate vaccine was associated with a clinically, meaningful and statistical significant improvement in median overall survival for patients, with both newly diagnosed and recurrent glioblastoma multiforme: 22.4 months vs 16.5 months for standard of care (Luau LM).