VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer

Most brain tumors secrete high levels of vascular endothelial growth factor, which can lead to an abnormally permeable tumor vasculature. This hyperpermeability causes vasogenic cerebral edema and increased interstitial fluid pressure, which can prevent adequate penetration of chemotherapy agents to the tumor. This Review focuses on the pathophysiology of vasogenic edema and the potential utility of agents that target angiogenesis, and particularly the vascular endothelial growth factor pathway. Most brain tumors oversecrete vascular endothelial growth factor (VEGF), which leads to an abnormally permeable tumor vasculature. This hyperpermeability allows fluid to leak from the intravascular space into the brain parenchyma, which causes vasogenic cerebral edema and increased interstitial fluid pressure. Increased interstitial fluid pressure has an important role in treatment resistance by contributing to tumor hypoxia and preventing adequate tumor penetration of chemotherapy agents. In addition, edema and the corticosteroids needed to control cerebral edema cause significant morbidity and mortality. Agents that block the VEGF pathway are able to decrease vascular permeability and, thus, cerebral edema, by restoring the abnormal tumor vasculature to a more normal state. Decreasing cerebral edema minimizes the adverse effects of corticosteroids and could improve clinical outcomes. Anti-VEGF agents might also be useful in other cancer-related conditions that increase vascular permeability, such as malignant pleural effusions or ascites. Key Points Peritumoral vasogenic cerebral edema is a significant cause of morbidity and mortality in patients with brain tumors VEGF is secreted by brain tumors and has an important role in increasing vascular permeability and, thus, contributing to peritumoral edema Peritumoral edema increases interstitial fluid pressure, which leads to poor penetration of chemotherapeutics and treatment resistance Antiangiogenic agents, particularly those that target the VEGF pathway, have been shown to reduce peritumoral edema in phase II studies of patients with brain tumors, and have been shown to improve progression-free survival and overall survival Anti-VEGF therapy exerts its effects by restoring vascular permeability and normalizing tumor blood vessels Anti-VEGF agents could also be useful in other cancer-related conditions that increase vascular permeability, such as malignant pleural effusions or ascites