Prevention of cancer in the next millennium: Report of the Chemoprevention Working Group to the American Association for Cancer Research.

Twenty-five years ago, as the “War on Cancer” began, there was hope and anticipation that the mortality rates for common forms of cancer might be greatly reduced by the year 2000. Although this goal has not been attained, a primary result of the increased funding for cancer research during the past 25 years has been an immense increase in knowledge of the mechanisms whereby normal cells and tissues become malignant. Furthermore, increased funding has led to the inception of programs to use this fundamental knowledge to develop new approaches to synthesize and test new drugs to prevent cancer, as contrasted with classical chemotherapy for treatment of existing disease. This new pharmacological approach to arrest or reverse the process of carcinogenesis, and thus to prevent cancer, is called chemoprevention. Although still in its infancy, the new science of chemoprevention has been established as an important approach to control malignancy. For the first time, it has been shown convincingly that the use of chemopreventive agents in men and women with premalignant lesions can substantially reduce the subsequent development of truly invasive cancer. Chemoprevention is now recognized as both a clinical and basic science. Although encouraging progress toward chemoprevention of human cancer has been made, this field is still in its earliest stages of development. We are nowhere near the ultimate desired goal of possessing some safe and effective agents that could easily be given to the general population for the prevention of cancer, as fluoride can be added to drinking water for prevention of dental caries. Thus, in spite of the advances that have already occurred in chemoprevention of cancer, there is more to be done before these advances can be translated into full human benefit. If we are to meet the desired goal of widespread implementation of chemoprevention of cancer, progress will need to occur in four major areas. First, we need to continue to enlarge the substrate of basic scientific knowledge of mechanisms of carcinogenesis. Understanding the process of carcinogenesis is the foundation for the science of chemoprevention. Second, we need to conduct more clinical studies to validate specific pharmacological agents for chemoprevention of human cancer. Proof of safety and efficacy of new drugs in controlled clinical trials is essential if this field is to progress. Third, we need to develop new and better agents for eventual use for chemoprevention in men and women. Although existing drugs have already had a significant impact, many have a significant downside in a benefit versusrisk analysis. Finally, we need a more broadly based educational effort, directed at both physicians and society as a whole, to achieve better understanding and compliance with the goals of chemoprevention. There are significant misunderstandings and apprehensions about widespread use of chemopreventive agents, centering around the misperception that it is not appropriate to treat “healthy” people with preventive agents. We need an intensive educational effort to convince people that absence of clinical symptoms may not guarantee that ne is “healthy,” and that a more sophisticated understanding of risk actors can be used constructively to develop interventions that have the potential to provide better health. In all of the above considerations, the dictum, primum non nocere, first do no harm, must be operative. There is realistic concern that poorly planned interventions can increase, rather than decrease, risk. However, from a pragmatic perspective, failure to intervene when one has the capacity to prevent disease may also be viewed as harmful. We therefore need the broadest possible societal discussion of the potential benefits and risks of chemoprevention strategies as a whole, as well as sophisticated analysis of each individual proposed preventive agent. It is the hope that the Report of this Working Group will provide a useful framework for the evaluation and discussion of future efforts to prevent cancer. This Report does not address other highly important issues relating to lifestyle, diet, tobacco, and environmental factors in the causation and prevention of cancer. These factors are of immense significance in the total effort to prevent cancer and will be the subject of future review and recommendations by other American Association for Cancer Research Working Groups. It should also be noted that this Report is not intended to be a critique of established approaches to treatment of cancer, such as chemotherapy, surgery, or radiation. Tremendous advances have occurred in the use of all of these modalities, resulting in major benefits to patients worldwide. Nor is this document an archival survey of the entire field of chemoprevention. Many detailed reviews on chemoprevention are referenced in the body of this Report, such as the recent comprehensive surveys by Kelloff (1) or Lippmanet al. (2). Rather, this Report should be viewed as a working document to summarize both progress and problems in chemoprevention, as well as to suggest future efforts to make chemoprevention an essential component within the total effort to control cancer.