Rationale and strategies for chemoprevention of cancer in humans.

The potential for chemical intervention (chemoprevention) as a means of halting or delaying the process of carcinogenesis is assessed as a strategy for reducing the incidence of human cancer. The process of carcinogenesis is dissected into its constituent steps, thereby exposing sites for intervention. These sites are then critically discussed with regard to the existence of chemicals active at these sites using data gained from the laboratory and from epidemiological studies, intrinsic problems or advantages associated with intervention at specific sites in the carcinogenic process, and practical aspects of intervention in humans. The design and potential long-term positive and negative consequences of chemoprevention clinical trials are critically discussed, with the objective of exposing the major differences that exist between clinical trials in cancer chemoprevention and those in cancer chemotherapy. Results of completed prevention trials and details of ongoing trials are presented and discussed. Based on the laboratory, epidemiological, and clinical evidence presented, it is concluded that chemoprevention offers excellent prospects as a means of reducing cancer incidence. Among currently available agents, the retinoids possess the best combination of properties. However, much more research is needed to optimize drugs and protocols and to develop interim end points for assessing response. The authors finally caution that overambitious claims for the prospects for chemoprevention may lead to reduced emphasis on the need for changes in life-style (principally in smoking and diet) that are viewed as having the greatest potential for reducing cancer incidence.