Assessing toxicity in cancer chemoprevention trials: the other side of the coin.

Clinical cancer chemoprevention started by studying natural agents presumed to be virtually free of toxicity. Beginning with these agents, however, the history of the major cancer chemoprevention trials has shown that evaluating adverse effects is every bit as important as evaluating preventive efficacy. Clinical trials have taught us invaluable lessons about the nature of serious toxicity in chemoprevention—adverse effects on the primary end point, unanticipated side effects, and anticipated side effects—and about the complex riskbenefit ratios of preventive agents. We now know that there is no free lunch with chemopreventive agents, whether natural or not. This Perspective will discuss the toxicity lessons we have learned and continue to learn from clinical trials of natural and molecular-targeted and other synthetic agents.