10 Questions about the use of bevacizumab in the management of recurrent malignant gliomas.

1 is bevacizumab? Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), a predominant ligand for the VEGF receptors Flt-1 and KDR. The binding of VEGF to its receptors promotes endothelial cell proliferation as well as angiogenesis—-a process required for tumor growth beyond 0.125 mm, which involves the formation of new blood vessels from existing vasculature. The rationale for targeting angiogenesis in brain tumors is based on the highly vascularized nature of malignant gliomas and the increased expression of angiogenic mediators, including VEGF, within brain tumors relative to nonmalignant tissue. Several mechanisms of action have been proposed for antiangiogenic therapies, including the inhibition of tumor-associated neoangiogenesis, a direct effect on VEGFRexpressing tumor cells, potential injury to glioma stem cells by disruption of the microvascular stem cell niche, and the normalization of the tumor-associated vasculature, which leads to improved drug delivery. 2 are the indications for the use of bevacizumab that are approved by the US Food and Drug Administration (FDA)? After demonstrating significant improvements in progression-free survival (PFS) and overall survival (OS), bevacizumab, in combination with intravenous (IV) 5-fluorouracil–based chemotherapy, was initially approved by the FDA in 2004 for the first-line treatment of patients with metastatic colorectal cancer (mCRC). Bevacizumab was subsequently approved in combination with standard chemotherapy for the treatment of advanced non–small-cell lung cancer, metastatic breast cancer, and previously treated mCRC because of its ability to improve PFS and/or OS outcomes in these tumor types. In May 2009, the FDA-granted accelerated approval of bevacizumab as a single agent for the treatment of glioblastoma that has progressed following prior therapy. The accelerated approval was based on an improvement in objective response rate reported in 2 studies—an open-label, multicenter, randomized, noncomparative phase 2 trial, BRAIN, that evaluated bevacizumab with and without irinotecan (Camptosar; Pfizer, New York, NY), a topoisomerase I inhibitor, in 167 patients with glioblastoma at first or second relapse, and the single-arm, singleinstitution NCI 06-C-0064E trial that evaluated bevacizumab monotherapy in 56 patients with glioblastoma that had progressed following treatment with temozolomide and radiation therapy.