Antiangiogenic Therapy for Glioblastoma: The Challenge of Translating Response Rate into Efficacy

Abstract

OVERVIEW Glioblastoma are one of the mostly vascularized tumors and are histologically characterized by abundant endothelial cell proliferation. Vascular endothelial growth factor (VEGF) is responsible for a degree of vascular proliferation and vessel permeability leading to symptomatic cerebral edema. Initial excitement generated from the impressive radiographic response rates has waned due to concerns of limited long-term efficacy and the promotion of a treatment-resistant phenotype. Reasons for the discrepancy between high radiographic response rates and lack of survival benefit have led to a focus on identifying potential mechanisms of resistance to antiangiogenic therapy. However, equally important is the need to focus on identification of basic mechanisms of action of this class of drugs, determining the optimal biologic dose for each agent and identify the effect of antiangiogenic therapy on oxygen and drug delivery to tumor to optimize drug combinations. Finally, alternatives to overall survival (OS) need to be pursued using the application of validated parameters to reliably assess neurologic function and quality of life. A pathophysiological hallmark of glioblastoma is the ex-pression of VEGF and other pro-angiogenic cytokines, which, in turn, stimulate endothelial cell proliferation, mi-gration, and survival. 1,2 This leads to the formation of a highly abnormal tumor vasculature characterized by hyper-permeable vessels, increased vessel diameter, and abnormally thickened basement membranes. This abnormal vascular network not only promotes tumor growth but may also im-pair the effıcacy of cytotoxic chemotherapy and radiation by enhancing tumor hypoxia and compromising intratumoral delivery of chemotherapy. The utilization of angiogenesis inhibitors for the treatment of glioblastoma has brought hope that blocking this central component of gliomas will inhibit tumor growth and prolong patient survival. Early, uncontrolled studies have been en-couraging. Both the pan-VEGF receptor (VEGFR)-2 tyrosine kinase inhibitor cediranib and the anti-VEGF-A antibody bevacizumab demonstrated impressive radiographic re-sponse rates and prolongation of progression-free survival (PFS) in single arm phase II clinical trials. With a strong tail wind, these agents entered into phase III clinical trials for recurrent (cediranib) and newly diagnosed (bevacizumab) glioblastoma. Although these agents may improve symptoms and allow for reduction in steroid use, to date, they have not demonstrated an improvement in OS compared with standard of care therapy. These data require reflection on po-tential mechanisms by which antiangiogenic therapy could augment benefıt associated with current approaches, and identify mechanisms that may limit the ability of these agents to improve patient survival. In this review and at our presentation at the 2013 American Society of Clinical Oncology Annual Meeting, we will ex-plore the potential biologic mechanisms of action and rea-sons why antiangiogenic therapy should be effective in the treatment of glioblastoma. Point by point, we will describe potential flaws in current approaches to inhibit angiogenesis and possible mechanisms of resistance limiting effıcacy. Finally, we will describe areas that require new insights as well as approaches that may improve understanding and bet-ter exploit these therapies to meaningfully improve patient outcome.