Controversies in Neuro-Oncology

<p>Malignant gliomas are characterized by an extensive vasculature. The most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF), is therefore a therapeutic target for anti-angiogenic therapy. This chapter focuses on different functional characteristics of VEGF and its receptors in the angiogenesis process. Furthermore, the effects of decreasing or blocking VEGF using the humanized monoclonal antibody to VEGF, bevacizumab (Avastin), are discussed. The possible mechanisms of activity of this agent, as well as potential problems with this drug are also discussed.</p>

<p>Glioblastoma multiforme (GBM) is the most aggressive cancer and has the worst prognosis of all malignant gliomas at diagnosis. At the time of disease recurrence/progression, GBM has an even worse prognosis. Vascular proliferation is an important marker in the histological grading of gliomas. Malignant gliomas overexpress VEGF, the principal mediator of tumor angiogenesis, the levels of which correlate directly with tumor vascularity and grade, and inversely with prognosis. Bevacizumab is a humanized monoclonal antibody against VEGF. Bevacizumab with irinotecan has been approved by the US Food and Drug Administration (FDA) for colorectal cancer. Bevacizumab is also FDA approved as a first line treatment for nonsmall cell lung cancer in combination with carboplatin and paclitaxel, has obtained accelerated approval for metastatic HER2-negative breast cancer patients in combination with paclitaxel, and most recently, accelerated approval for recurrent glioblastoma multiforme as single agent. In the first FDA approved phase II trial for recurrent malignant glioma patients published patients received irinotecan [125 mg/m2 for patients on non enzyme inducing antiepileptic drug (EIAED) or not on an antiepileptic drug, and 340 mg/m2 for patients on EIAED] intravenously (IV) every two weeks in combination with bevacizumab 10 mg/kg IV every two weeks. Thirty-two patients were enrolled and a radiographic response rate of 63% was observed [1 complete response (CR) and 19 partial responses (PRs)]. A 6-month PFS of 38% for all patients and a 6-month overall survival of 72% were observed. Following these findings, multiple studies with irinotecan and other agents more commonly used in malignant gliomas were initiated to evaluate alternative bevacizumab-based regimens for recurrent malignant glioma patients. In the vast majority, all those studies showed an unprecedented increase in PFS and response rate in malignant glioma patients treated with bevacizumab as a single agent or in combination, as well a significant improvement in the quality of life of the patients exposed to bevacizumab. However, the utilization of a bevacizumab based regimen for recurrent malignant gliomas has opened a brand new field in neuro-oncology. Further study is needed to determine optimal managements and enhance the quality of life for these patients.</p>

<p>Bevacizumab is the first new drug approved for malignant glioma in a decade and demonstrates the potential for antiangiogenic therapy in the management of these patients. It has demonstrated improved radiographic response and progression free survival rates compared to historical controls as monotherapy. Bevacizumab has also been shown to improve patient symptoms of disease and decrease steroid requirements contributing to improved quality of life for glioma patients. Optimal combinations with other standard and targeted therapies are under investigation, as well as new imaging techniques to evaluate response to therapy, motivated in part by concerns over suspected increase potential for tumor invasion.</p>

<p>Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), recently received accelerated approval by the US Federal and Drug Adminstration as single-agent for recurrent glioblastomas (GBM). Preclinical studies suggest that inhibition of VEGF and radiotherapy (RT) have a synergistic effect in gliomas. We recently conducted a pilot study of bevacizumab and hypo-fractionated stereotactic RT for patients with recurrent GBM and anaplastic gliomas (AG). Patients received bevacizumab (10 mg/kg IV) every 2 weeks of 28-day cycle and 30 Gy of hypofractionated stereotactic RT in 5 fractions after the first cycle of bevacizumab. Twenty-five patients (20 GBM and 5 AG) were included. For the GBM cohort, overall response rate was 50%, 6-month progression free survival was 65% and median overall survival was 12.5 months. Bevacizumab with hypofractionated RT is an active regimen in malignant gliomas and is currently being studied in newly-diagnosed glioblastomas in combination with temozolomide.</p>

<p>In patients with recurrent malignant glioma, bevacizumab therapy achieves high response rates, prolonged progression-free survival, and reduced corticosteroid requirements. However, progressive disease during bevacizumab therapy is the rule. Resistance to bevacizumab may be mediated by upregulation of alternative pro-angiogenic factors or an infiltrative tumor growth pattern characterized by vascular co-option. Clinically, bevacizumab failure is often followed by rapid progression and death. In patients with progressive disease despite bevacizumab monotherapy, adding cytotoxic chemotherapy has not proven beneficial. Similarly, when patients develop progressive disease despite bevacizumab and chemotherapy, continuing bevacizumab and changing the concurrent chemotherapy agent is not effective. Combining bevacizumab with anti-invasion therapies is an appealing approach that has yet to be investigated in clinical trials. Additional research into mechanisms of resistance to anti-angiogenic therapy is needed in order to develop other promising strategies.</p>

<p>Given the marked upregulation of angiogenesis in glioblastoma, the integration of anti-angiogenic agents into treatment approaches is a highly attractive consideration. Preclinical data support an anti-tumor benefit with anti-angiogenic agents in GBM models. However, translation of these agents into the clinic was initially tempered by concern that anti-angiogenics may be associated with severe complications in brain tumor patients including hemorrhages and strokes. Extensive clinical experience to date provides reassurance that such complications are rare and that anti-angiogenics can be safely administered to brain tumor patients. Furthermore, clinical trials conducted among recurrent GBM patients using either bevacizumab, a humanized monoclonal antibody against the primary mediator of tumor angiogenesis, vascular endothelial growth factor (VEGF), or VEGF-receptor tyrosine kinase inhibitors such as cediranib, demonstrate encouraging evidence of anti-tumor benefit. In particular, durable radiographic responses observed among recurrent GBM patients were sufficiently frequent to lead to accelerated approval by the U.S. Food and Drug Administration for bevacizumab in May, 2009. Ongoing efforts are evaluating additional strategies to augment the anti-tumor benefit of anti-angiogenic agents for recurrent patients as well as the safety and efficacy of these agents among newly diagnosed GBM patients.</p>

<p>Malignant gliomas are one the most aggressive form of brain tumors and the current standard of care, combination chemoradiotherapy, prolongs survival to slightly more than a year after treatment. Current chemotherapeutic strategies produce limited benefit due to the rapid emergence of resistance. New strategies, among other things, are looking to target the prolific vascularization that supports the rapid growth of these malignant brain tumors. Several anti-angiogenic agents are in clinical testing, primarily as “salvage” therapies, after initial disease progression, and among these, the most mature data are for bevacizumab (Avastin), recently approved for salvage by the FDA, having shown success in a few Phase I/II trials. A small number of phase II trials have also provided very preliminary results with the up-front use of this agent, and at least two large Phase III trials are underway to determine whether bevacizumab will provide added benefit to patients with glioblastoma, when added to the initial chemoradiotherapy regimen. This paper lays out the rationale behind using bevacizumab in combination with radiotherapy, and discusses the up-front trials.</p>