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A Randomized Controlled Trial

Larry C. Clark, MPH, PhD; Gerald F. Combs, Jr, PhD; Bruce W. Turnbull, PhD; Elizabeth H. Slate, PhD; Dan K. Chalker, MD; James Chow, MD; Loretta S. Davis, MD; Renee A. Glover, MD; Gloria F. Graham, MD; Earl G. Gross, MD; Arnon Krongrad, MD; Jack L. Lesher, Jr, MD; H. Kim Park, MD; Beverly B. Sanders, Jr, MD; Cameron L. Smith, MD; J. Richard Taylor, MD

JAMA. 1996;276(24):1957-1963.

Abstract
Objective.
—To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.

Design.
—A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.

Setting.
—Seven dermatology clinics in the eastern United States.

Patients.
—A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years.

Interventions.
—Oral administration of 200 µg of selenium per day or placebo.

Main Outcome Measures.
—The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers.

Results.
—After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR, 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred.

Conclusions.
—Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made.

Author Affiliations
for the Nutritional Prevention of Cancer Study Group

Footnotes
Affiliations for the named authors and a complete list of the Nutritional Prevention of Cancer Study Group appear at the end of this article.

Corresponding author: Larry C. Clark, MPH, PhD, Arizona Cancer Center, 2504 E Elm St, Tucson, AZ 85716-3417 (e-mail: selenium@ccit-arizona.edu).

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ABSTRACT | FULL TEXT  

Hydroponic Cultivation Offers A Practical Means of Producing Selenium-Enriched Garlic
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ABSTRACT | FULL TEXT