The study of markers of biological effect in cancer prevention research trials.

Biological markers may provide a valuable tool for the development of cancer prevention agents, for monitoring patient compliance to a selected intervention, or for further defining the carcinogenic process. This discussion focuses on markers of biological effect and the rationale for their use in cancer prevention trials. Recent studies with biological markers are investigating their incorporation into phase-I, -II, and -III chemoprevention clinical trial designs. Their use in clinical studies is expected to increase the number of agents that may be evaluated and to provide valuable information on the biological effectiveness of agents, doses, and schedules. Markers may also provide information to help in selecting high-risk groups for prevention research, and to indicate the pathways inhibited and the stage of carcinogenesis affected. Such information may prove of crucial importance in strengthening the rationale for long-term trials and other ancillary research. Biomarker research for colon carcinogenesis is discussed, including examples of a number of recent trials that may influence future progress in this area of prevention research. A crucial step in this process is marker validation as an aspect of major prospective observational and intervention studies where cancer incidence is the endpoint. We cannot be fully confident of markers as intermediate endpoints until the evidence from clinical trials is sufficiently strong to support major public health initiatives for prevention.

Role of biology and prevention in aerodigestive tract cancers.

Primary prevention aimed at smoking control and chemoprevention for high-risk persons or patients at risk for a second cancer provide strong potential for cancer prevention and control of aerodigestive cancers. The National Cancer Institute (NCI) has a major effort to build this area of research. The Third Upper Aerodigestive Tract Cancer Task Force Workshop, held in 1989 under the auspices of the National Cancer Institute's Organ System Program, reviewed the opportunities for chemoprevention research on aerodigestive epithelial cancers such as the regulation of growth and differentiation in normal and malignant cells. The chemoprevention program's drug development effort is evaluating several promising candidate agents for future clinical testing and the NCI clinical intervention program is supporting several trials of selected chemoprevention agents with demonstrated potential for inhibiting cancers of the lung, bronchus, oral cavity, and esophagus. Of special interest to this program is the assessment of beta-carotene, retinol and related synthetic retinoids, and several vitamin and mineral combinations under study in high-risk international populations. Chemoprevention in the medical setting is a major focus of NCI's Community Oncology Program (CCOP), a network designed not only to increase accrual of patients to trials but also to speed adoption of state-of-the-art therapies. Public health strategies are directed toward control of exposure to tobacco. The focal point for these activities is NCI's Smoking, Tobacco, and Cancer Program (STCP). STCP smoking cessation efforts are targeted at specific populations that are at greater risk for developing cancer including youth, minority and ethnic groups, women, smokeless tobacco users, and heavy smokers. Two of the world's largest controlled intervention trials conducted by the STCP are underway: the Community Intervention Trial for Smoking Cessation (COMMITT), which focuses on 6.5 million heavy smokers in 11 pairs of matched communities in North America, and the American Stop Smoking Intervention Study (ASSIST), a coalition model designed to reach millions of Americans through existing health promoting systems.

Concepts in cancer chemoprevention research.

Cancer prevention through the use of chemical intervention regimens (chemoprevention) is an emerging field with broad potential for impacting on cancer incidence rates in defined high-risk groups and the general population. Information from cancer epidemiologic studies coupled with that from basic research on cancer biology have combined to reveal several categories of agents with potential for clinical application, including natural and synthetic tumor suppressive retinoids and antioxidants. Chemopreventive agents may inhibit the development of cancer by limiting exposure to initiators or promoters through stimulation of inactivation or excretion mechanisms. Biological consequences of exposure to carcinogens may also be interfered with, e.g., by inhibiting the activation of proto-oncogenes or by antagonizing the effects of oncogene expression. Hundreds of compounds with chemopreventive efficacy in vitro have been isolated from foods and plant products. The testing and development of candidate chemopreventives proceeds through a series of preclinical efficacy screens, followed by controlled clinical trials.

Strategies for cancer prevention through diet modification.

Diet and cancer research at the National Cancer Institute has grown from a budget of $2.5 million in 1974 to $55 million in 1988. The emphasis is partially on demonstrations of prevention strategies and chemoprevention trials. Studies to disseminate dietary goals in practical ways are undertaken with the aid of the food industry.