Chemoprevention of colorectal cancer: two steps forward, one step back?

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in the Western world. The poor survival rate has prompted the emphasis on prevention of this disease. Removal of adenomas at colonoscopy is highly effective and is the cornerstone of screening/surveillance strategies. However, screening efforts have had limited impact owing to low compliance with guidelines. Chemoprevention aims to prevent the development or recurrence of precancerous lesions and cancers with the use of compounds that block the carcinogenic process. A major advantage was the establishment and understanding of the multistage process of CRC carcinogenesis. Progress has been remarkable because of the availability of reliable animal models and clinical studies using colonic adenomas as a reliable and economic target for testing chemopreventive agents. Nonsteroidal anti-inflammatory drugs have drawn the most attention. Sulindac and celecoxib were shown to be effective in promoting polyp regression in high-risk individuals with familial adenomatous polyposis. In the more common sporadic setting, the Adenomatous Polyp PRevention On Vioxx (rofecoxib), Adenoma Prevention with Celecoxib and Prevention of Sporadic Adenomatous Polyps (celecoxib) trials have demonstrated a significant reduction in adenoma recurrence, but important concerns were raised regarding cardiovascular toxicity associated with selective cyclo-oxygenase-2 inhibitors. These landmark studies are very important, as they are a proof-of-concept that we can prevent CRC. More clinical studies are required to better select high-risk patients with safer regimens. Potential advantage versus risk for a given chemopreventive agent will have to be assessed on an individual basis. Currently, the only approved agent for chemoprevention is celecoxib in high-risk individuals with familial adenomatous polyposis.