Malignant gliomas, including the most common subtype of glioblastoma, are rapidly growing destructive tumors that extensively invade locally but rarely metastasize. The current standard of care, including maximum safe resection followed by radiation therapy and temozolomide chemotherapy, achieves median progression-free and overall survivals of only 6.9 and 14.7 months, respectively.1 After progression, salvage therapies have historically achieved radiographic response and 6-month progression-free survival rates of 5% to 15%, respectively.2–4 Several factors contribute to poor treatment response, including frequent de novo and acquired resistance, heterogeneity across and within tumors, complex and redundant intracellular pathways regulating proliferation and survival, and restricted central nervous system (CNS) delivery because of the blood–brain barrier and high interstitial peritumoral pressures.5,6
Given this background, recent clinical studies have shown substantive radiographic responses and improved progression-free survival with bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF),7 among patients with recurrent malignant glioma.8–11 However, initial enthusiasm has been tempered by relatively modest improvements in overall survival, difficulties in assessing response after anti-VEGF therapeutics, and an inability to identify effective therapy after bevacizumab failure. Nonetheless, initial results have sparked a flurry of studies attempting to more effectively exploit this therapeutic strategy. This article reviews the development, current status, and future challenges of VEGF-targeting therapeutics for patients with recurrent glioblastoma.
Drs. Turner, Peters, Desjardins, Gururangan, Sampson, McLendon, Herndon, Jones, Allan Friedman, and Bigner, have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in their article or their competitors. Dr. Reardon has disclosed that he is a consultant for and on the speakers' bureau for Merck & Co., Inc./Schering-Plough Corporation and Roche/Genentech, Inc. Dr. Kirkpatrick has disclosed that he receives research support from Genentech, Inc. Dr. Vredenburgh has disclosed that he is a consultant for Roche, and is on the advisory board and speakers' bureau for Genentech, Inc. Dr. Henry Friedman has disclosed that he is on the advisory board and speakers' bureau for Genentech, Inc.
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