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Chemoprevention of lung cancer is proving difficult and frustrating, requiring new approaches.

The long-awaited results from EUROSCAN (i.e., the European Study on Chemoprevention With Vitamin A and NAcetylcysteine), the randomized two-by-two factorial trial of vitamin A (retinyl palmitate) andN-acetylcysteine in patients with treated cancers of the lung or head and neck, show no benefit from either agent alone or from the combination. Among 2592 participants who received maximal tolerable doses for 2 years with a mean follow-up of 49 months, 916 experienced recurrence, second primary tumor, or death. The findings were analyzed exhaustively (1). Hypothesis-driven chemoprevention of lung cancers, when put to the test of randomized large-scale clinical trials, so far has been disappointing, unlike important successes with selective estrogen receptor modulators for breast cancer and nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for familial colonic polyps. Once the carcinogenic processes have been initiated, prevention of cancers is much more difficult than one would like. The most reliable methods of reducing the incidence of cancers depend on avoidance of known carcinogenic agents, including UV radiation, tobacco, alcohol, various infectious agents, medical exposures to certain pharmaceuticals and hormones, ionizing radiation, and environmental and occupational exposures to a moderately long list of chemicals (2). Working groups of the U.S. National Cancer Institute (NCI) have emphasized the importance of developing a solid scientific basis from mechanistic studies in vitro and in vivo to guide selection of potential chemopreventive agents and justify their use in phase I, II, and III trials. Priority should be given to population subgroups with particular host or environmental risk factors, including demonstrable genetic susceptibility to specific cancers, persons with precancerous lesions, and cancer patients at risk for second primary tumors. Clinically validated intermediate end points would be very useful; the aim is a reduction in the incidence of cancers, not just of precancerous lesions or biochemical responses. Retinoids are among the most promising classes of chemopreventive agents. Their many proliferation-suppressing, differentiation-enhancing cellular effects and actions on specific receptor targets in the nucleus have given them an extraordinary laboratory basis for clinical testing (3). Retinoids have reduced tumor incidence and tumor mass and have extended tumor latency when animals were treated before, during, or—most importantly—after exposure to initiating and/or promoting agents