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Patients with successfully treated upper aerodigestive tract (UADT) tumors commonly develop second primary tumors (SPTs). These tumors occur more often than chance would predict, arise in both the upper or lower aerodigestive tracts, are frequently preceded by leukoplakia, and are a major cause of treatment-related failure. Measures to control SPTs include primary prevention with tobacco and alcohol abstinence, surveillance endoscopy, and secondary chemoprevention. Chemoprevention is the administration of natural or synthetic substances to suppress or reverse the malignant process. Secondary chemoprevention of the UADT is the suppression or reversal of leukoplakia and/or SPTs. Classic antioxidant micronutrients such as retinoids, carotenoids, and certain other agents have been effective in nonrandomized and randomized clinical trials, but treatment is uncertain and recurrences common. These facts, coupled with recent harmful effects of beta-carotene in two clinical trials, stress the need for additional basic science, translational, and clinical research. Chemoprevention is a promising new technology, but is not currently standard therapy for the secondary prevention of UADT tumors.

Chemoprevention has four goals: (1) inhibition of carcinogens, (2) logical intervention for persons at genetic risk for cancer, (3) treatment of precancerous lesions, and (4) confirmation and translation of leads from dietary epidemiology into intervention strategies. The National Cancer Institute has described a multidisciplinary, cancer science-based program for chemopreventive drug development that addresses these objectives, and has collaborated with the US Food and Drug Administration to provide consensus guidance for applying this approach. A critical component is the identification and characterization of intermediate biomarkers of cancer and their validation as surrogate end points for cancer incidence in clinical chemoprevention trials. More than 40 agents in the program are currently on the clinical development path (preclinical toxicology and phase I clinical safety studies or phase II/III efficacy trials), with the major effort in phase II studies to identify and characterize intermediate biomarkers. The continually advancing knowledge of molecular and tissue-based carcinogenesis mechanisms will provide leads to new chemopreventive agents with increased specificity for carcinogenesis-related activities and, hence, reduced toxicity by virtue of minimal effects on normal cell and tissue functions. Results from the Human Genome Project will help identify and evaluate the potential for chemopreventive intervention in cohorts at genetic risk and will provide specific target lesions for intervention strategies.