Abstract

Randomized cancer chemoprevention studies began in earnest about 30 years ago. Many of the trials have been negative, showing no substantial benefit. Certainly antioxidants (beta-carotene, alpha tocopherol, ascorbic acid, selenium) have been ineffective, and retinoids do not seem promising at this point.

There have been several chemoprevention successes, however. Aspirin has been reduces the risk of invasive colorectal cancer (after a latent period of about 10 years), and seems to inhibit carcinogenesis at other sites as well. There are even indications that aspirin reduces all cause mortality (largely through a decrease in cancer deaths). Selective estrogen response modulators have demonstrated efficacy against breast cancer. Several randomized studies have reported that calcium supplementation reduces the risk of colorectal adenomas, and effects on colorectal cancer itself seems likely from associations in observational studies. Difluoromethylornithine combined with sulindac showed promising findings in one trial.

Particularly interesting are the surprises that have emerged. Though highly touted as a possible chemopreventive agent, beta-carotene actually increased the risk of lung cancer in two of three large trials. The same studies also found increased risks of cardiovascular disease and all cause mortality with the intervention. An adenoma trial suggested that folic acid – another promising chemopreventive agent -- increased risk of adenomas as well as prostate cancer. COX-2 inhibitors held great promise as cancer prevention agents and did decrease colorectal adenoma risks in several trials -- but increased risk of cardiovascular disease. Another adenoma trial reported that calcium supplementation reduced risk of prostate cancer. Selenium supplementation increased risk of non-melanoma skin cancer in a skin cancer prevention trial.

Although the mechanisms underlying the successes and the reasons for the surprises aren’t entirely clear, understanding these successes and surprises will help us devise better preventive interventions and give us insight into the pathobiology of cancer (and cardiovascular disease).