Antiangiogenic therapies for high-grade glioma

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Abstract
High-grade gliomas are highly vascularized tumors that represent attractive targets for antiangiogenic therapies. In this article, Norden et al. discuss the rationale for targeting angiogenesis in high-grade gliomas and review the published clinical trial evidence, focusing primarily on therapies that target vascular endothelial growth factor and its receptors. High-grade gliomas (HGGs) are vascular tumors that represent attractive targets for antiangiogenic therapies. In this Review, we present the rationale and clinical trial evidence for targeting angiogenesis in HGGs, focusing predominantly on agents that target vascular endothelial growth factor (VEGF) and its receptors. Bevacizumab, a humanized monoclonal antibody against VEGF, was recently approved by the FDA for treatment of recurrent glioblastoma. Bevacizumab prolongs progression-free survival and controls peritumoral edema, but its effects on overall survival remain to be determined. Other inhibitors of VEGF, VEGF receptors and other proangiogenic signaling pathways are being evaluated. Antiangiogenic therapies are well tolerated, although potentially serious adverse events can occasionally occur, and resistance to antiangiogenic therapy inevitably develops. Mechanisms of resistance include upregulation of alternative proangiogenic pathways, and increased perivascular tumor growth. Tumor progression on antiangiogenic agents is a challenging problem for which no effective salvage therapy has been identified. Combining these agents with radiation therapy, cytotoxic chemotherapy, other targeted molecular agents, or anti-invasion therapies could be helpful. The international Response Assessment in Neuro-Oncology Working Group has developed consensus treatment response criteria for HGG that account for the complex effects of antiangiogenic drugs.