Clinical cancer chemoprevention

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The substance under test has to be innocuous from a toxicological standpoint, as it is likely to be administered over a considerable period of time and to healthy individuals. Foodstuffs are attractive sources of tumour-suppressive substances, as the effects of long-term exposure are well-documented.

Currently, more than 60 randomized trials of potential chemo-preventive agents have been reported. Only a few of these trials constituted 'definitive trials'. A primary chemopreventive trial with a significantly positive outcome is the retinol study that showed protection against squamous cell skin carcinoma. Tamoxifen has been approved in the US to reduce the risk of breast cancer in high-risk women.

Two definitive trials of p-carotene were significantly negative. In these trials lung cancer incidence was studied in 50 000 individuals. The outcome of these trials made headlines, suggesting that in high-risk groups of smokers and/or workers occupationally exposed to asbestos. p-carotene increases rather than decreases the risk of developing lung cancer. Subgroup analyses of these two trials revealed that the risk of lung cancer was highest among those individuals who continued to smoke at least 20 cigarettes per day and those in the highest quartile of alcohol consumption. It is conceivable that p-carotene suppresses tumours only in those individuals from whom the initiating stimulus has been removed, but not in those who continue to be subjected to it.

These results underline the importance of understanding how chemopreventive agents exert their effects and under which conditions they are beneficial or indeed detrimental, prior to extensive clinical evaluation.

Several trials were 'classically' negative—the investigational agents (among them p-carotene, 13-cis retinoic acid, retinol, selenium, and a-tocopherol) failed to prevent a variety of cancers. Analyses of subsets of populations in some of the trials yielded intriguing positive or negative results. For example, a nutritional supplement of selenium reduced total cancer mortality and incidence of prostate, lung, and colorectal cancer, and recently, a-tocopherol was reported to protect against prostate cancer.

Whenever possible, trials of agents for 'primary prevention' should be preceded by clinical evaluation of their efficacy for 'secondary prevention' of cancer in specific epithelial target sites. These studies are aimed at the reversal or arrest of pre-malignant lesions, or the prevention of second primary tumours in patients cured of an initial cancer. Secondary prevention trials are more cost-effective than large and long-term primary prevention trials. The burden of carcinogenic stimuli on the patient is high and a meaningful endpoint can be measured in a reasonable time frame in a smaller number of patients. Such trials have furnished important leads concerning the benefit of retinoids to prevent pre-malignant lesions and secondary primary malignancies of the head and neck, lung, skin, and liver, and of the non-steroidal anti-inflammatory drug, sulindac, in the prevention of the development of tumours in familial adenomatous polyposis.

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