The COX-2 inhibitors celecoxib and rofecoxib have each been shown to inhibit and cause regression of adenomas in FAP.[117,126,127] An effect of similar magnitude has been seen in trials with COX-2 inhibitors with respect to new adenoma formation in individuals with sporadic or nonfamilial adenomas.[128,129,130,131,132] These much larger trials, involving older subjects (>50 years), revealed a significant increase in drug-related serious adverse events, specifically heart attack and stroke.[131,132] These risks were duration- and dose-dependent, but not clearly related to the presence of underlying cardiovascular risk factors. Publication of these findings led to termination of many cancer prevention trials and temporary suspension of COX-2 trials in FAP. Regulatory approval of celecoxib was withdrawn in some countries. There is some evidence that nonselective NSAIDs may carry cardiovascular risk as well, clouding the future for NSAIDs (with the possible exception of aspirin) in colon cancer chemoprevention.[133,134,135] Polymorphisms in CYP2C9 have been associated with decreases in metabolism of celecoxib. This result, by yielding variable drug levels, could explain differences in both efficacy and side effects of this class of drugs. The possibility of genetically determined variation in response to chemopreventive agents in general may be worth monitoring in future studies. Whether the greater risk of CRC in FAP, compared with the general population, will tilt the risk-benefit equation in FAP families in favor of COX-2 inhibitors and other NSAIDs remains to be seen.
There are emerging data to suggest that omega-3-polyunsaturated fatty acid eicosapentaenoic acid may also be beneficial in reducing polyp burden in individuals with FAP. (Refer to the Interventions/FAP section in the Major Genetic Syndromes section of this summary for more information.)
Use of folic acid supplements for more than 15 years has been shown in one observational study to be associated with a 75% lower CRC rate (RR, 0.25; 95% CI, 0.13–0.51). It is hypothesized that since folate is required for DNA synthesis, suboptimal amounts might cause abnormalities in DNA synthesis or repair. Randomized controlled trials are under way to test the hypothesis that folic acid supplements prevent cardiovascular disease (through their effect on homocysteine). When completed, the trials may have enough statistical power, singly or together, to provide stronger evidence on the effect of folic acid supplements on CRC.
It has been suggested that calcium, by binding bile acids in the bowel lumen, might inhibit their carcinogenic effects.[72,137] A randomized controlled trial of calcium supplementation, with a daily intake of 1,200 mg of elemental calcium for 4 years, reduced the risk of recurrent adenomas in presumably average-risk people with adenomas by 19% (adjusted risk ratio, 0.81; 95% CI, 0.67–0.99). It is uncertain whether this finding applies to people with genetically increased risk of CRC. Similarly, the observational evidence that estrogens are associated with a lower incidence of CRC does not include information specifically about people with a genetically increased risk of CRC.[84,138,139,140]