Chemoprevention of colorectal cancer: Past, present, and future

Abstract

Chemoprevention began to be considered as a potential strategy for lowering the incidence of cancer and cancer-related deaths in the 1970s. For clinical chemoprevention trials against cancer, including colorectal cancer (CRC), well-established biomarkers are necessary for use as reliable endpoints. Difficulty in establishing validated biomarkers has delayed the start of CRC chemoprevention development. Chemoprevention trials for CRC have only recently been initiated thanks to the identification of reliable biomarkers, such as colorectal adenomas and aberrant crypt foci. Some promising agents have been developed for the prevention of CRC. The chemopreventive effect of selective cyclooxygenase 2 inhibitors has been shown, although these inhibitors are associated with cardiovascular toxicity as a crucial adverse effect. Aspirin, which is a unique agent among non-steroidal anti-inflammatory drugs (NSAIDs) showing minimal gastrointestinal toxicity and no cardiovascular risk, has prevented adenoma recurrence in some randomized controlled trials. More recently, metformin, which is a first-line oral medicine for type 2 diabetes, has been shown to be safe and to prevent adenoma recurrence. A recommendation of the United States Preventive Services Task Force published in 2016 provides a Grade B recommendation for the use of aspirin for chronic prophylaxis against diseases, including CRC, in certain select populations. However, the roles of other agents have yet to be determined, and investigations to identify novel "post-aspirin" agents are also needed. The combined use of multiple drugs, such as aspirin and metformin, is another option that may lead not only to stronger CRC prevention, but also to improvement of other obesity-related diseases.

Keywords: aspirin; calcium; chemoprevention; colorectal cancer; metformin.

Figure 1

Timeline of progress in chemoprevention. ACF, aberrant crypt foci; CRC, colorectal carcinoma; EPA, eicosapentaenoic acid; RCT, randomized controlled trial

Figure 2

Forest plot of placebo‐controlled randomized trials examining chemoprevention for colorectal adenoma. We found 12 reports of placebo‐controlled trials for the chemoprevention of colorectal adenoma. One of them used a two‐arm study design. Thus, we ultimately included 13 comparisons. A random‐model meta‐analysis that collectively evaluated all the treatment regimens suggested that the incidence of adenoma was marginally decreased with an OR of 0.71 (95% CI, 0.58‐0.87; I2 = 83%). According to the subgroup analyses, metformin (OR, 0.42; 95% CI, 0.21‐0.85), non‐aspirin NSAIDs (OR, 0.52; 95% CI, 0.40‐0.66; I2 = 74%), and aspirin (OR, 0.74; 95% CI, 0.63‐0.87; I2 = 3%) decreased the incidence of adenoma. However, calcium and vitamin D did not decrease the risk of adenoma