Surrogate biomarkers for anti-angiogenic therapy for advanced colorectal cancer

Abstract

Vascular endothelial growth factor (VEGF)—over-expressed in colorectal cancer—is associated with disease progression and inferior survival. Based on successful, randomized, phase III trials, anti-VEGF therapeutics have entered clinical practice. Bevacizumab, a VEGF-specific antibody, was the first anti-angiogenic agent to be approved by the Food and Drug Administration to be used in combination with standard chemotherapy in the first and second line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also normalize tumor vasculature thereby leading to greater tumor oxygenation (a known radiosensitizer) and drug penetration. A dose-escalation phase I trial has demonstrated that the combination of bevacizumab at the 5-mg/kg dose with radiochemotherapy was well tolerated by patients with rectal cancers. In addition, results from an array of correlative studies have demonstrated that bevacizumab has antivascular effects and supported the normalization hypothesis. The ongoing phase II study will further elucidate the mechanisms of action and efficacy of bevacizumab in locally advanced rectal cancer.