Rakesh K. Jain, PhD

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. Based on successful randomized phase III trials, anti-EGFR and anti-VEGF therapeutics have entered clinical practice. Cetuximab (Erbitux), an EGFR-specific antibody, is currently approved in the United States in combination with irinotecan (Camptosar) for patients with metastatic colorectal cancer refractory to irinotecan or as a single agent for patients unable to tolerate irinotecan-based therapy. In retrospective analyses, patients with EGFR-expressing rectal cancer undergoing neoadjuvant radiation therapy had a significantly inferior disease-free survival and lower rates of achieving pathologic complete response. Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, there is a strong rationale to combine cetuximab with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Bevacizumab (Avastin), a VEGF-specific antibody, was the first antiangiogenic agent to be approved in the United States for use 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 and drug penetration. This review will address completed and ongoing trials that have established and continue to clarify the effects of these agents in rectal cancer.

Angiogenesis is an essential step in the growth and spread of solidtumors-the cause of more than 85% of cancer mortality. Inhibitingangiogenesis would therefore seem to be a reasonable approach to preventor treat cancer. However, tumor angiogenesis differs from normalangiogenesis in that the resulting vessels are tortuous, irregularlyshaped, and hyperpermeable. These abnormalities result in irregularblood flow and high interstitial fluid pressure within the tumor, whichcan impair the delivery of oxygen (a known radiation sensitizer) anddrugs to the tumor. Emerging evidence suggests that antiangiogenictherapy can prune some tumor vessels and normalize the structure andfunction of the rest, thereby improving drug delivery and normalizingthe tumor microenvironment. This normalization effect may underliethe therapeutic benefit of combined antiangiogenic and cytotoxic therapies.This paper reviews current and emerging concepts of the mechanismof action of antiangiogenic therapies and discusses the implicationsof these mechanisms for their optimal clinical use.