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CANCER CHEMOPREVENTION TRIALS: 17 LARGE PHASE III OR PHASE IV

Executive Summary

CANCER CHEMOPREVENTION TRIALS: 17 LARGE PHASE III OR PHASE IV trials are currently being conducted, 12 of which are underway in the U.S., according to an estimate by Frank Meyskens, MD, (University of California, Irvine) in a Sept. 20 New England Journal of Medicine editorial. Researchers are studying more than 100,000 subjects "at high risk for cancers of the skin, colon, cervix, breast, lung, and other organs, who are being treated with retinol, beta carotene, isotretinoin, 4-hydroxy-phenyretinamide, and other compounds," he said. Meyskens' editorial accompanied two reports on cancer chemoprevention in the NEJM. One isotretinoin study by Waun Ki Hong, MD, et al., found that "daily treatment with high doses of isotretinoin is effective in preventing second primary tumors in patients who have been treated for squamous-cell carcinoma of the head and neck." Hong et al. concluded, however, that isotretinoin treatment is not effective in preventing recurrences of the original tumor. The study was supported in part by grants from the National Cancer Institute and Hoffmann-La Roche. Isotretinoin is the active ingredient in Roche's Accutane. Forty-nine patients "disease-free after primary treatment for squamous-cell cancers of the larnyx, pharnyx, or oral cavity" were given isotretinoin daily for 12 months at a dosage of 50 to 100 mg per square meter of body surface. The placebo group comprised 51 subjects. At 32 months, two patients (4%) in the isotretinoin group had second primary tumors, compared to 12 (24%) in placebo. Four patients, all from the placebo group, developed multiple second primary tumors. The survival rates of the two groups were not significantly different, the researchers report. Toxic effects in isotretinoin patients were "predominantly mild or moderate." However, dose reduction or temporary discontinuation of isotretinoin therapy was necessitated by severe skin dryness (12% of isotretinoin patients), cheilitis (2%), hypertriglyceridemia (6%) and conjunctivitis (8%). One-third of the 49 isotretinoin patients did not complete the study due to drug toxicity or noncompliance. Meyskens also commented on a beta carotene study conducted by Robert Greenberg, MD, et al. reported in the same issue. The study assesses the ability of beta carotene to prevent basal-cell and squamous-cell skin cancers. Also published in the Sept. 20 NEJM, the Greenberg study found that beta carotene treatment "does not reduce the occurrence of new skin cancers...in persons with a previous nonmelanoma skin cancer." Meyskens said that the researchers "thoroughly address possible reasons for the negative results, but they do not consider an important alternative possibility: that the high levels of beta carotene may have interfered with the actions of other key micronutrients." Meyskens cites a study of mice that experienced a 40% decrease in plasma alpha tocopherol levels after irradiation with ultraviolet light and administration of beta carotene; he concludes that "measurement of plasma alpha tocopherol levels in subjects in the current trial would therefore be of great interest." The five-year study assigned 1,805 patients to a daily 50 mg dose of either beta carotene or placebo. After one year, the treatment group of 913 patients had a median plasma beta carotene level of 3021 nmol per liter, compared to 354 in 892 placebo patients. The subjects were 70% male, reflecting "the higher risk of skin cancer among men" and partial patient recruitment from VA hospitals, the study notes. The researchers cautioned that the study results should not be used to conclude that beta carotene offers no therapeutic value in the treatment of any cancers. "Epidemiologic studies suggest that beta carotene is associated with a lower risk of many types of epithelial neoplasms," particularly lung cancer, the study points out.
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