Antiangiogenic therapy for glioblastoma: the challenge of translating response rate into efficacy

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.