Familial Adenomatous Polyposis (FAP) is a model for the
adenoma-
carcinoma sequence in several respects. One important area in which FAP serves as a model is
chemoprevention. Early prevention trials mainly utilized
micronutrients and were largely unsuccessful in preventing or causing regression of
adenomas. A new era was ushered in by the recognition that antiarthritic doses of a
nonsteroidal anti-inflammatory agent (
NSAID),
sulindac, could actually induce regression of colorectal
adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal
adenomas, but
sulindac appears to lack significant benefit in regressing duodenal
adenomas or preventing initial occurrence of
adenomas in APC mutation carriers. Due to the well-known side effects of traditional
NSAIDs, selective
COX-2 inhibitors have been studied rather extensively.
Celecoxib has shown benefit in regressing colorectal
adenomas and appears to have some duodenal activity as well.
Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of
NSAID research in
chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic
adenoma prevention trials. Whether
NSAIDs will have a significant future in FAP
chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial
adenomas, a problem with even greater societal impact. The historical development of
chemoprevention in FAP will be presented, with an emphasis on issues of trial design.