Chemoprevention

ONE PROMISING APPROACH to cancer prevention is to stop the early stages (initiation) or slow the progression (promotion) to cancer. Chemoprevention requires the identification of chemical substances that have the potential to prevent cancer initiation or progression of premalignant lesions to invasive cancer. Many of the agents evaluated to date have been naturally occurring in foods, others are established drugs that have the potential to prevent cancer (e.g., aspirin).

The National Cancer Institute's (NCI) chemoprevention program, initiated in the early 1980s, has developed into a major effort in which more than 400 potential chemopreventive agents are being studied. Chemoprevention uses a stepwise, systematic research strategy that includes (1) identification of potential new agents that have either efficacy in preventing carcinogenesis in animal models or a [Page 186]high probability, based on epidemiologic studies, of preventing human cancer, (2) preclinical drug development, and (3) phases I, II, and III clinical intervention trials.

Phase II clinical trials evaluate agent efficacy in a larger group of subjects at high risk for specific cancers. They also provide data that characterize dose, safety, and toxicity in the selected population. Two important objectives of phase II trials include (1) identifying biochemical, genetic, cellular, or tissue biomarkers of cancer that can be used to estimate the potential for neoplastic progression and (2) determining whether the chemopreventive agent being tested can affect the modulation of that biomarker. Agents found to have high efficacy and low toxicity in phase II clinical trials are investigated further in large-scale phase III intervention trials conducted with a large number of subjects over an extended period.

Randomized, large-scale phase III clinical trials are generally considered the best means available to test whether a chemopreventive intervention reduces cancer risk. These large trials can take 10 years or longer to complete. This reflects the long time for cancer development and introduces important challenges in prevention trials. With the long time for the intervention there are real changes that the population at large will adopt the intervention (and the control or comparison group will also do this). Second, the intervention group may lose interest and stop taking their medication or chemopreventive agent. Finally, many subjects may be lost from the study. Thus adherence and follow-up often lead to limited ability of prevention trials to identify important actions of the interventions under study.