NSAIDs and Colorectal Cancer Control: Promise and Challenges.

The chemoprevention of colorectal cancer (CRC) is a realistic option given the low acceptance and cost of screening colonoscopy. NSAIDs, currently not recommended for CRC prevention, are the most promising agents. Here, we review relevant work and assess the chemopreventive potential of NSAIDs. The chemopreventive efficacy of NSAIDs is established by epidemiological and interventional studies as well as analyses of cardiovascular-prevention randomized clinical trials. The modest chemopreventive efficacy of NSAIDs is compounded by their significant toxicity that can be cumulative. Efforts to overcome these limitations include the use of drug combinations; the emphasis on the early stages of colon carcinogenesis such as aberrant crypt foci, which may require shorter periods of drug administration; and the development of several families of chemically modified NSAIDs such as derivatives of sulindac, nitro-NSAIDs and phospho-NSAIDs, with some of them appearing to have higher safety and efficacy than conventional NSAIDs and thus to be better candidate agents. The successful development of NSAIDs as chemopreventive agents will likely require a combination of the following: identification of subjects at high risk and/or those most likely to benefit from chemoprevention; optimization of the timing, dose and duration of administration of the chemopreventive agent; novel NSAID derivatives and/or combinations of agents; and agents that may prevent other diseases in addition to CRC. Ultimately, the clinical implementation of NSAIDs for the prevention of CRC will depend on a strategy that drastically shifts the currently unacceptable risk/benefit ratio in favor of chemoprevention.