THE CLINICAL-EVALUATION OF CANCER PREVENTION AGENTS

The clinical development of cancer chemoprevention agents is similar t o that of cytotoxic agents, On the basis of promising preclinical stud ies, agents with potential efficacy are introduced to the clinic as a phase I trial to study the dose-toxicity relationship of the agent and its human pharmacology. If doses projected to have biological activit y have acceptable side effects, the agent proceeds to a phase II trial , which enrolls a larger number of participants and administers the ag ent for a longer time period (up to 5 years). Phase IIb trials test th e effect of these agents on potential biomarkers of carcinogenesis to get some indication if the agent has activity, The phase II trial also pilots study design, mechanisms of recruitment, and adherence for fut ure phase III trials, The phase III trial of a chemopreventive agent d etermines its effect on cancer incidence, Close attention is also paid to long-term side effects. The unique features of cancer prevention a gents and their evaluation must be considered in this stepwise clinica l evaluation, These features include (i) populations recruited to prev ention trials are healthy; (ii) in this population there is a low tole rance for side effects; and (iii) the clinical end point of the trial, cancer, is statistically an uncommon event, The evaluation of beta-ca rotene and retinol as studied in the Carotene and Retinol Efficacy Tri al (CARET) is used to illustrate this stepwise clinical development.