Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. Intervention trial with selenium for the prevention of lung cancer among tin miners in Yunnan, China. A pilot study. Low plasma selenium as a risk factor for cancer death in middle-aged men. Serum selenium and subsequent risk of cancer among Finnish men and women. Association between serum selenium and the risk of cancer. Plasma selenium concentration and prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma selenium level before diagnosis and the risk of prostate cancer development. The nutritional prevention of cancer: 400 mcg per day selenium treatment. Prospective study of serum selenium concentrations and esophageal and gastric cardia cancer, heart disease, stroke, and total death.
To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.
                A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.
                Seven dermatology clinics in the eastern United States.
                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.
                Oral administration of 200 microg of selenium per day or placebo.
                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.
                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.
                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 This pilot study evaluated the feasibility and effectiveness of conducting a double-blind clinical trial for the prevention of lung cancer with selenium (Se) in Yunnan Tin Corporation, the People's Republic of China, where the incidence rates of lung cancer are extraordinarily high among the miners. Forty healthy miners were randomized to either 300 micrograms of Se in high Se malt cakes or an identical placebo of malt cakes daily for one year. Subjects consumed their usual daily diet. The low Se concentrations in plasma (0.05 +/- 0.008 microgram/mL) and hair (0.442 +/- 0.085 microgram/g) reflected their low dietary Se intake in the control subjects. In Se-supplemented group, the Se status was increased by 178% for serum and 194.8% for hair. The serum GSHpx activity was increased by 155.7%, whereas the lipid peroxide level was reduced by 74.5% compared to the placebo. The results of UDS assay indicated that the lymphocyte DNA damage induced by ultraviolet irradiation and carcinogen 3,4-benzpyrene could be protected by Se supplementation. Se-supplementation did not affect the liver function test (SGPT), as well as the concentrations of hemoglobin, albumin, and cholesterol. Thus, daily intake of 300 micrograms Se in form of Se-malt as a chemopreventive measure is safe and effective to humans with low Se status. In a population study, 10,000 men (aged 46-48 years) were invited to a health screening program. At follow-up, which was up to eight years later, 61 subjects had died from cancer; from 35 of these subjects, plasma samples were available that were obtained at the initial screening. These samples, together with samples from two living controls for each case, were analyzed for selenium, retinol, cholesterol, triglyceride, and a number of plasma proteins. Plasma selenium was significantly lower (p less than 0.05) in cases than in controls (means: 1.06 vs. 1.12 mumol/l). The proportion of cases increased significantly from the highest to the lowest quintile of plasma selenium, and the relative risk for cancer death was 3.8 times higher in the lowest quintile compared with the highest. Mean plasma retinol was similar in cases (2.53 mumol/l) and controls (2.56 mumol/l). Cases and controls also had similar values for plasma cholesterol, triglyceride, uric acid, apolipoprotein B, orosomucoid, prealbumin, retinol-binding protein, and beta 2-microglobulin. Apolipoprotein AI in plasma was lower among cases (p less than 0.025). Cases smoked significantly more than controls did (p less than 0.05). Data indicate that low plasma selenium was a risk factor for cancer death in middle-aged men who lived in the same area. Further studies are necessary to establish whether differences in selenium intake, selenium metabolism, or other factors related to selenium are responsible for the relations observed. At present, the available data do not justify selenium supplementation programs in the whole population. The association between the serum selenium level and the subsequent incidence of cancer was investigated in a longitudinal study of 39,268 men and women participating in the Social Insurance Institution's Mobile Clinic Health Examination Survey in Finland. The baseline examinations, including the collection of blood samples, were performed in 1968-1972. During a median follow-up of 10 years, 1,096 new cancer cases were identified from the files of the Finnish Cancer Registry. Selenium concentrations were measured from the stored serum samples collected from these cancer cases and from two controls per case, matched for sex, municipality, and age. The mean serum selenium level was 59.1 micrograms/L among all male cancer cases and 62.5 micrograms/L among controls. The difference was statistically significant (P less than .001). Corresponding values among women were 63.6 and 63.9 micrograms/L, respectively. Low serum selenium levels were associated with an increased risk of developing cancer at several sites, especially cancers of the stomach and lung among men. The relative risk of lung cancer between the highest and lowest decile of serum selenium was 0.11, and it differed significantly from unity (P less than .001). These findings are in agreement with the hypothesis that low selenium intake may increase the risk of some cancers among men. A matched-pair analysis was conducted with data based on a prospective six-year follow-up of a random population sample to study the association between serum selenium and the risk of cancer. Case-control pairs were from a population, after exclusions, of 8,113 persons examined in 1972 from two counties in eastern Finland. Cases were 31- to 59-year-old men and women initially free of cancer. One control was matched to each case according to age, gender, daily tobacco consumption, and serum cholesterol concentration. The mean serum selenium of the 128 cases was 50.5 micrograms/liter and that of the controls was 54.3 micrograms/liter (p = 0.012 for difference). When the residual variation in tobacco consumption and serum cholesterol as well as that in four other possible confounders was allowed for in a multiple logistic model, serum selenium of less than 45 micrograms/liter was associated with a relative risk of cancer of 3.1 (95% confidence interval, 1.5-6.7, p less than 0.01). These data support the hypothesis that selenium deficiency increases the risk of certain cancers in middle-aged persons. Some evidence indicates that a low selenium intake may be associated with an increased risk of prostate cancer.
                The aim of this study was to investigate the association of plasma selenium concentration with subsequent prostate cancer risk and to examine this association by stage and grade of disease and other factors.
                A nested case-control study was performed among men in the European Prospective Investigation into Cancer and Nutrition (EPIC). The association between plasma selenium concentration and prostate cancer risk was assessed in 959 men with incident prostate cancer and 1059 matched controls.
                Overall, plasma selenium concentration was not associated with prostate cancer risk; the multivariate relative risk for men in the highest fifth of selenium concentration compared with the lowest fifth was 0.96 (95% CI: 0.70, 1.31; P for trend = 0.25). There were no significant differences in the association of plasma selenium with risk when analyzed by stage or grade of disease. Similarly, the association of selenium with risk did not differ by smoking status or by plasma alpha- or gamma-tocopherol concentration.
                Plasma selenium concentration was not associated with prostate cancer risk in this large cohort of European men. Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer.
                A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression.
                After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p <0.001).
                Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer. These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer. Because plasma selenium decreases with patient age, supplementation may be particularly beneficial to older men. Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence. We previously reported an inverse association between prediagnostic serum selenium concentrations and the risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia cancer (GCC) but not gastric noncardia cancer (GNCC) in a nested study from the Nutrition Intervention Trial in Linxian, China.
                We examined the relation between baseline serum selenium and the subsequent risk of death from ESCC, GCC, GNCC, heart disease (HD), stroke, and total death over 15 y of follow-up (1986-2001).
                We measured baseline serum selenium concentrations in 1103 subjects randomly selected from a larger trial cohort. We identified 516 deaths during the 15-y follow up, including 75 from ESCC, 36 from GCC, 116 from HD, and 167 from stroke. Relative risks (RRs) and 95% CIs were estimated by using Cox proportional hazards regression models. Reported RRs estimated the change in risk conferred by a 25% increase in serum selenium relative to the population distribution. All estimates were adjusted for sex, age, smoking, drinking, and serum cholesterol.
                We found significant inverse associations between baseline serum selenium and death from ESCC (RR: 0.83; 95% CI: 0.71, 0.98) and GCC (0.75; 0.59, 0.95). Trends toward inverse associations were noted for death from HD (0.89; 0.78, 1.01; P = 0.07), but no association was noted for total death (0.96; 0.90, 1.02) or stroke (0.99; 0.88, 1.11).
                Population-wide selenium supplementation in the region of China with low serum selenium and high incidences of ESCC and GCC merits serious consideration.
No reliable conclusions can be drawn regarding a causal relationship between low selenium exposure and an increased risk of cancer. Despite evidence for an inverse association between selenium exposure and the risk of some types of cancer, these results should be interpreted with care due to the potential limiting factors of heterogeneity and influences of unknown biases, confounding and effect modification.
The effect of selenium supplementation from RCTs yielded inconsistent results. To date, there is no convincing evidence that selenium supplements can prevent cancer in men, women or children.