US Pharm. 2010;35(5)(Oncology suppl):3-10.
ABSTRACT: Glioblastoma multiforme (GBM) is the most deadly brain cancer affecting humans. Each year about 11,000 patients are diagnosed with GBM. It is unclear how GBM arises, but when present, survival is roughly 8 to 15 months. Until recently, therapy for GBM consisted of surgery, radiation therapy, and salvage chemotherapy. With the emergence of the importance of angiogenesis in tumor survival, more targeted therapies have become available. This article reviews the pathophysiology of GBM, standards of care for newly diagnosed GBM, and possible future therapies for GBM.
Glioblastoma multiforme (GBM) is the most deadly of all brain tumors. Each year about 17,000 individuals are diagnosed with a brain tumor, with about 60% of those being gliomas.1 GBM is the most common glioma in humans, with the majority of cases occurring in male adults. In 60% of all GBM cases, the tumor arises de novo, while the other 40% of GBM cases arise through the malignant progression of a lower-grade brain tumor. Survival time is extremely poor for patients diagnosed with GBM. In newly diagnosed GBM, mean survival is 8 to 15 months; however, with recurrent GBM the mean survival is only 3 to 9 months. Overall, the 5-year survival rate is only 5%.2 Despite the poor prognosis associated with GBM, recent developments in chemotherapy have demonstrated increased survival time for these patients.
Pathophysiology of GBM
GBM arises from glial cells, or their precursors, within the central nervous system. Most commonly, the tumor occurs in the subcortical white matter of the cerebral hemispheres within the corticotemporal region of the brain. Compared to the other astrocytic neoplasms, GBM is unique due to the presence of necrosis and vascular proliferation. Furthermore, GBM is extremely complex due to the genetic mutations that occur (TABLE 1).3 Of all the mutations, upregulation of vascular endothelial growth factor (VEGF) appears to be of utmost importance. VEGF is implicated in angiogenesis, the process of forming new blood vessels. In GBM, VEGF ligands and receptors exist in extremely high concentrations compared to those in lower-grade tumors and even normal brain tissue.4 The resulting increase in vascular permeability, endothelial gaps, and fenestrations allows for rapid growth of the tumor.
Risk Factors and Screening
Unlike the case with lung, breast, or colon cancer, there are no clear risk factors or screening procedures for the development of GBM, though trends have been identified (TABLE 2).
Staging of Gliomas
Currently, there are no standards for the staging of gliomas. The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system has not been shown to predict outcomes in glioma patients.5 Instead, tumor histology, location, and biology are much more important for determining patient outcomes. The World Health Organization (WHO) has developed a grading system for gliomas, which more accurately predicts outcomes. This system grades the tumor based on hypercellularity, mitosis rates, presence of necrosis, and vascular proliferation (TABLE 3).6
According to the National Comprehensive Cancer Network (NCCN) guidelines, all patients newly diagnosed with GBM should receive an MRI to help determine the course of therapy.7 If it is determined that the tumor can be safely resected, then removal via surgery is the first step. Once the tumor is removed, carmustine (BCNU) wafers may be placed in the cranial cavity to provide localized chemotherapy. Implantation of BCNU wafers is sometimes not done, as it may limit ability for participation in clinical trials. After surgery, all patients undergo fractional external beam radiation therapy.7 Questions exist if chemotherapy should be administered at this point.
According to the NCCN guidelines, a patient’s Karnofsky Performance Status (KPS) determines whether chemotherapy is used to treat the GBM (TABLE 4).6,7 KPS classifies patients based on their functional status in performing normal activities without assistance. A score of 70 indicates that one can care for oneself but cannot carry out certain activities of daily living such as working.6 For all patients with a KPS score >70, even if BCNU wafers were implanted at surgery, the NCCN recommends the use of temozolomide with radiation therapy (FIGURE 1). For patients with a KPS score <70, the NCCN recommends that patients with BCNU wafers receive radiation therapy or chemotherapy; however, those without BCNU wafers may receive any combination of chemotherapy, radiation, or both.7 Besides temozolomide, no other antineoplastic agent has demonstrated any meaningful effect on survival in GBM patients.8 In fact, most chemotherapy is reserved as a final attempt to help prolong survival in these patients after first-line failure. In addition to the tumor treatment, many patients also require antiepileptic drugs and corticosteroids to manage symptoms produced by the growth of the tumor. Usually as the tumor grows, patients will require increasing doses of corticosteroids and antiepileptic drugs. This can lead to many drug interaction problems and increased side effects.3
Unfortunately, there is an extremely high recurrence rate with GBM.3 Once GBM has recurred, therapy is determined by the patient’s KPS score and whether the tumor is local or diffuse.6 Due to extremely low survival rates with GBM recurrence, therapy varies from additional surgery to remove the tumor to any variation of systemic chemotherapy, reirradiation, or best supportive care (FIGURE 2).
The development of VEGF inhibitors has offered a new chemotherapy option for patients with GBM. Recently, bevacizumab (Avastin) was approved by the FDA for the treatment of GBM after disease progression in patients who received standard therapy.9 Currently, bevacizumab does not have a place in the NCCN guidelines for therapy. However, with angiogenesis being an important mediator of tumor survival, implementation of bevaciz-umab as therapy for these patients may provide long-term survival and improved quality of life.10
Temozolomide (Temodar): Temozolomide is an oral alkylating agent that targets the O6, N7 position of guanine. This results in damage to the DNA and prevents DNA replication, thereby destroying the cancer cells. Temozolomide is a prodrug that is rapidly converted through nonenzymatic processes to the active metabolite 5-(3-methyltriazen-1-yl)-
During the concomitant phase of temozolomide dosing, patients are at an increased risk for the development of Pneumocystis jiroveci pneumonia (PCP) due to possible severe myelosuppression. Therefore, all patients receiving radiation therapy with the 42-day concomitant therapy of temozolomide are required to receive PCP prophylactic therapy.11 Aside from the increased risk for PCP, the dose-limiting toxicity of temozolomide is severe myelosuppression, which can lead to aplastic anemia. There are set dose reductions in place for patients based on their absolute neutrophil count, platelet counts, and whether the patient experiences any grade 3 or 4 nonhematologic toxicity excluding nausea/vomiting and alopecia.11
Prior to temozolomide, there was little that could be done for patients with GBM. Other chemotherapy regimens had little to no response in increasing survival.8 Patients treated with irinotecan, for example, had 0% to 15% response rates.12 In 2005, a study by Stupp et al demonstrated that in patients with newly diagnosed GBM, those who received temozolomide plus radiation therapy versus radiation therapy alone had clinically meaningful and statistically significant survival.13 Using the approved doses and schedules for temozolomide, this study showed that survival rates at 2 years were increased by 27% in the combination group, compared to only 10% in the radiation monotherapy group. Patients in the combination group also had longer disease-free progression compared to just radiation alone. The most common adverse event reported was severe myelosuppression. Besides myelosuppression, the authors also reported that many patients experienced moderate-to-severe fatigue and pneumonia.13 Prior to this trial, the mainstay of therapy for patients with GBM was surgery and radiation therapy. With the results from this phase III study, the NCCN changed the guidelines to include the use of temozolomide as first-line chemotherapy only for newly diagnosed GBM.14
Bevacizumab (Avastin): GBM is considered one of the most vascularized cancerous tumors. A unique quality of this tumor is that it over-expresses VEGF, which leads to increased microvascular density and increased angiogenesis.10 Bevaciz-umab is a humanized monoclonal antibody that binds to and neutralizes VEGF, thereby preventing its association with its receptors. This disrupts new vessel formation and leads to inhibition of tumor growth.12 The dose of bevacizumab used in GBM is 10 mg/kg every 2 weeks, with the duration of therapy up to the discretion of the oncologist and patient.9
Several phase II and retrospective studies have been published demonstrating the positive effects of using bevacizumab in GBM.15-19 Vredenburgh et al published one of the first studies examining the use of bevaciz-umab for patients with GBM.20 In this phase II trial, 35 patients with recurrent GBM were given bevaciz-umab and irinotecan. At 6 months, the overall survival was found to be 77%. Further, 20 of the 35 patients had at least a partial response as determined by MRI scans using the Macdonald Criteria, which determine disease progression. Since patients with recurrent GBM have such a dismal prognosis, this was one of the first trials to show positive response rates and increased duration of life.20
Most recently, Friedman et al published a phase II trial looking at bevacizumab monotherapy versus combination therapy of bevacizumab and irinotecan in patients with recurrent GBM.12 Prior to this study, all of the phase II trials looked only at using bevacizumab in combination with another chemotherapy agent, usually irinotecan. A total of 167 patients were randomized to receive either bevacizumab alone or in combination with irinotecan. Results from this trial showed an estimated 6-month progression-free survival of 42.6% in the bevacizumab monotherapy group and 50.3% in the combination therapy group. In addition, 24 of the patients in the monotherapy group and 31 patients in the combination therapy group had an objective response to therapy as measured by tumor reduction on MRI. It is also important to note that there was no investigator-determined clinical progression of disease in any patient on therapy.
All of the phase II trials published to date looking at bevacizumab in GBM have also shown that patients were usually able to maintain a stable dose of corticosteroids or even decrease the dose.12 The reduction in steroid use has improved patients’ quality of life since they are exposed to fewer side effects of corticosteroids. Overall, the use of bevacizumab has been shown to be beneficial in almost all patients with GBM.12
With such promising results, many researchers are looking into using bevacizumab for primary therapy for GBM. For instance, there are 48 clinical trials currently using bevacizumab with or without other therapies for GBM.21 In May 2009, Vredenburgh et al presented an abstract at the American Society of Clinical Oncology meeting detailing the data collected from a phase II study using bevacizumab plus temozolomide and radiation therapy in newly diagnosed GBM followed by adding irinotecan once radiation therapy was concluded.22 The results from this phase II trial showed that 61 out of 75 patients enrolled, or 81% of patients, were still alive and had no progression of their disease at 9 months.
Despite how promising the use of bevacizumab may be for treating GBM, there are many drug-related issues with its use. Currently there are three black box warnings associated with bevacizumab, including gastrointestinal perforation, severe or fatal hemorrhage, and wound-healing complications.9 Additionally, there is a dose-limiting toxicity of hypertension that has been observed in patients receiving this therapy. Other common adverse events include thromboembolism formation, proteinuria/nephrotic syndrome, and reversible posterior leukoencephalopathy syndrome (TABLE 7).23
Currently, 556 clinical trials for GBM are under way.21 With an increased understanding of tumor pathology, researchers are able to focus on developing targeted biological therapies. One of these promising therapies lies within scorpion venom.24 Along with enzymes and histamine, scorpion venom contains the potent neurotoxin chlorotoxin. Chlorotoxin has been found to bind selectively to low-conductance chloride channels in glioma cells. In order for the tumor to invade the surrounding tissues, an influx of chloride into the cell is required. By blocking these channels, tumor invasion is halted.24 To date there has been only one published trial examining the use of chlorotoxin for GBM. In a phase I study, Mamelak et al reported on 18 patients given various doses of chlorotoxin labeled with iodine 131, also referred to as TM-601. This trial reported that at day 180 post injection, 4 patients had stable disease and 1 patient had a partial response. In addition, two of the patients improved further and were disease free for more than 30 months.25 The authors of this trial did not report what doses of TM-601 these patients received or whether any toxicity was seen with this treatment. Therefore, the authors concluded that future study was needed with this compound for GBM. As of right now, there are three phase I/II studies using chlorotoxin (TM-601) for GBM.21
GBM is the most deadly brain tumor that affects humans. With extremely poor prognosis and survival time, therapy is limited. However, the development of targeted therapies, like bevacizumab, has provided increased survival rates for patients with GBM. As research continues into these targeted therapies, there is increasing hope that a cure will be found.
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