Lung cancer chemoprevention: a randomized, double-blind trial in Linxian, China. Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity. Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements.
We examined the effect of supplementation with four different combinations of vitamins and minerals in the prevention of lung cancer mortality among 29,584 healthy adults from Linxian, China. In accord with a partial factorial design, the participants were randomly assigned to take either a vitamin/mineral combination or a placebo for 5.25 years. The combinations tested in this trial were as follows: factor A, retinol and zinc; factor B, riboflavin and niacin; factor C, ascorbic acid and molybdenum; factor D, beta-carotene, alpha-tocopherol, and selenium. Lung cancer deaths (n = 147) identified during the trial period (1986-1991) and 10 years after the trial ended (1991-2001) were the study outcome. No significant differences in lung cancer death rates were found for any of the four combinations of supplements tested in this study, using log-rank tests (all P values are >0.20) or Cox proportional hazards models adjusted for age, sex, commune, and other treatments. No significant interactions were seen for age, sex, or smoking status. Supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian, China. We studied the relation of serum vitamin A (retinol), beta-carotene, vitamin E, and selenium to the risk of lung cancer, using serum that had been collected during a large blood-collection study performed in Washington County, Maryland, in 1974. Levels of the nutrients in serum samples from 99 persons who were subsequently found to have lung cancer (in 1975 to 1983) were compared with levels in 196 controls who were matched for age, sex, race, month of blood donation, and smoking history. A strong inverse association between serum beta-carotene and the risk of squamous-cell carcinoma of the lung was observed (relative odds, 4.30; 95 percent confidence limits, 1.38 and 13.41). Mean (+/- SD) levels of vitamin E were lower among the cases than the controls (10.5 +/- 3.2 vs. 11.9 +/- 4.90 mg per liter), when all histologic types of cancer were considered together. In addition, a linear trend in risk was found (P = 0.04), so that persons with serum levels of vitamin E in the lowest quintile had a 2.5 times higher risk of lung cancer than persons with levels in the highest quintile. These data support an association between low levels of serum vitamin E and the risk of any type of lung cancer and between low levels of serum beta-carotene and the risk of squamous-cell carcinoma of the lung. Epidemiologic evidence indicates that diets high in fruits and vegetables are associated with a reduced risk of several cancers, including cancers of the esophagus and stomach. Vitamins and minerals in these foods may contribute to the reduced cancer risk. The people of Linxian County, China, have one of the world's highest rates of esophageal/gastric cardia cancer and a persistently low intake of several micronutrients.
                We sought to determine if dietary supplementation with specific vitamins and minerals can lower mortality from or incidence of cancer as well as mortality from other diseases in Linxian.
                Individuals of ages 40-69 were recruited in 1985 from four Linxian communes. Mortality and cancer incidence during March 1986-May 1991 were ascertained for 29,584 adults who received daily vitamin and mineral supplementation throughout this period. The subjects were randomly assigned to intervention groups according to a one-half replicate of a 2(4) factorial experimental design. This design enabled testing for the effects of four combinations of nutrients: (A) retinol and zinc; (B) riboflavin and niacin; (C) vitamin C and molybdenum; and (D) beta carotene, vitamin E, and selenium. Doses ranged from one to two times U.S. Recommended Daily Allowances.
                A total of 2127 deaths occurred among trial participants during the intervention period. Cancer was the leading cause of death, with 32% of all deaths due to esophageal or stomach cancer, followed by cerebrovascular disease (25%). Significantly (P = .03) lower total mortality (relative risk [RR] = 0.91; 95% confidence interval [CI] = 0.84-0.99) occurred among those receiving supplementation with beta carotene, vitamin E, and selenium. The reduction was mainly due to lower cancer rates (RR = 0.87; 95% CI = 0.75-1.00), especially stomach cancer (RR = 0.79; 95% CI = 0.64-0.99), with the reduced risk beginning to arise about 1-2 years after the start of supplementation with these vitamins and minerals. No significant effects on mortality rates from all causes were found for supplementation with retinol and zinc, riboflavin and niacin, or vitamin C and molybdenum. Patterns of cancer incidence, on the basis of 1298 cases, generally resembled those for cancer mortality.
                The findings indicate that vitamin and mineral supplementation of the diet of Linxian adults, particularly with the combination of beta carotene, vitamin E, and selenium, may effect a reduction in cancer risk in this population.
                The results on their own are not definitive, but the promising findings should stimulate further research to clarify the potential benefits of micronutrient supplements. Lung cancer cases diagnosed during the period 1975 through 1993 and matched controls were identified in the rosters of Washington County, Maryland residents who had donated blood for a serum bank in 1974 or 1989. Plasma from participants in the 1989 project was assayed for ascorbic acid; serum or plasma was assayed for participants in either project for alpha- and beta-carotene, cryptoxanthin, lutein/zeaxanthin, lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Among the total group of 258 cases and 515 controls, serum/plasma concentrations were significantly lower among cases than controls for cryptoxanthin, beta-carotene, and lutein/zeaxanthin with case-control differences of -25.5, -17.1, and -10.1%, respectively. Modest nonsignificant case-control differences in a protective direction were noted for alpha-carotene and ascorbic acid. There were only trivial differences for lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Findings are reported for males and females and for persons who had never smoked cigarettes, former smokers, and current smokers at baseline. These results and those from previous studies suggest that beta-carotene is a marker for some protective factor(s) against lung cancer; that cryptoxanthin, alpha-carotene, and ascorbic acid need to be investigated further as potentially protective factors or associates of a protective factor; and that lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity are unlikely to be associated with lung cancer risk. Until specific preventive factors are identified, the best protection against lung cancer is still the avoidance of airborne carcinogens, especially tobacco smoke; second best is the consumption of a diet rich in fruits and vegetables. Observational studies suggested that a diet high in fruits and vegetables, both of which are rich with antioxidants, may prevent cancer development. However, findings from randomized trials of the association between antioxidant use and cancer risk have been mostly negative.
                From 8171 women who were randomly assigned in the Women's Antioxidant Cardiovascular Study, a double-blind, placebo-controlled 2 x 2 x 2 factorial trial of vitamin C (500 mg of ascorbic acid daily), natural-source vitamin E (600 IU of alpha-tocopherol every other day), and beta carotene (50 mg every other day), 7627 women who were free of cancer before random assignment were selected for this study. Diagnoses and deaths from cancer at a specific site were confirmed by use of hospital reports and the National Death Index. Cox proportional hazards regression models were used to assess hazard ratios (represented as relative risks [RRs]) of common cancers associated with use of antioxidants, either individually or in combination. Subgroup analyses were conducted to determine if duration of use modified the association of supplement use with cancer risk. All statistical tests were two-sided.
                During an average 9.4 years of treatment, 624 women developed incident invasive cancer and 176 women died from cancer. There were no statistically significant effects of use of any antioxidant on total cancer incidence. Compared with the placebo group, the RRs were 1.11 (95% confidence interval [CI] = 0.95 to 1.30) in the vitamin C group, 0.93 (95% CI = 0.79 to 1.09) in the vitamin E group, and 1.00 (95% CI = 0.85 to 1.17) in the beta carotene group. Similarly, no effects of these antioxidants were observed on cancer mortality. Compared with the placebo group, the RRs were 1.28 (95% CI = 0.95 to 1.73) in the vitamin C group, 0.87 (95% CI = 0.65 to 1.17) in the vitamin E group, and 0.84 (95% CI = 0.62 to 1.13) in the beta carotene group. Duration and combined use of the three antioxidants also had no effect on cancer incidence and cancer death.
                Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality. The association between prostate cancer and baseline vitamin E and selenium was evaluated in the trial-based cohort of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 29,133). During up to 9 years of follow-up, 317 men developed incident prostate cancer. Multivariate Cox proportional hazards models that adjusted for intervention group, benign prostatic hyperplasia, age, smoking, and urban residence were used to evaluate associations between prostate cancer and exposures of interest. There were no significant associations between baseline serum alpha-tocopherol, dietary vitamin E, or selenium and prostate cancer overall. The associations between prostate cancer and vitamin E and some of the baseline dietary tocopherols differed significantly by alpha-tocopherol intervention status, with the suggestion of a protective effect for total vitamin E among those who received the alpha-tocopherol intervention (relative risk was 1.00, 0.68, 0.80, and 0.52 for increasing quartiles; P = 0.07). In the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, alpha-tocopherol supplementation decreased prostate cancer incidence, whereas beta-carotene increased the risk of lung cancer and total mortality. Postintervention follow-up provides information regarding duration of the intervention effects and may reveal potential late effects of these antioxidants.
                To analyze postintervention effects of alpha-tocopherol and beta-carotene on cancer incidence and total and cause-specific mortality.
                Postintervention follow-up assessment of cancer incidence and cause-specific mortality (6 years [May 1, 1993-April 30, 1999]) and total mortality (8 years [May 1, 1993-April 30, 2001]) of 25 563 men. In the ATBC Study, 29 133 male smokers aged 50 to 69 years received alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5 to 8 years. End point information was obtained from the Finnish Cancer Registry and the Register of Causes of Death. Cancer cases were confirmed through medical record review.
                Site-specific cancer incidence and total and cause-specific mortality and calendar time-specific risk for lung cancer incidence and total mortality.
                Overall posttrial relative risk (RR) for lung cancer incidence (n = 1037) was 1.06 (95% confidence interval [CI], 0.94-1.20) among recipients of beta-carotene compared with nonrecipients. For prostate cancer incidence (n = 672), the RR was 0.88 (95% CI, 0.76-1.03) for participants receiving alpha-tocopherol compared with nonrecipients. No late preventive effects on other cancers were observed for either supplement. There were 7261 individuals who died by April 30, 2001, during the posttrial follow-up period; the RR was 1.01 (95% CI, 0.96-1.05) for alpha-tocopherol recipients vs nonrecipients and 1.07 (95% CI, 1.02-1.12) for beta-carotene recipients vs nonrecipients. Regarding duration of intervention effects and potential late effects, the excess risk for beta-carotene recipients was no longer evident 4 to 6 years after ending the intervention and was primarily due to cardiovascular diseases.
                The beneficial and adverse effects of supplemental alpha-tocopherol and beta-carotene disappeared during postintervention follow-up. The preventive effects of alpha-tocopherol on prostate cancer require confirmation in other trials. Smokers should avoid beta-carotene supplementation. Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality.
                We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention.
                CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests.
                According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations.
                CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the incidence of lung cancer, other cancers, and death in 18,314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group.
                After the intervention ended, CARET participants returned the study vitamins to their study center and provided a final blood sample. They continue to be followed annually by telephone and mail self-report. Self-reported cancer endpoints were confirmed by review of pathology reports, and death endpoints were confirmed by review of death certificates. All statistical tests were two-sided.
                With follow-up through December 31, 2001, the post-intervention relative risks of lung cancer and all-cause mortality for the active intervention group compared with the placebo group were 1.12 (95% confidence interval [CI] = 0.97 to 1.31) and 1.08 (95% CI = 0.99 to 1.17), respectively. Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up. By contrast, the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the intervention was stopped. During the post-intervention phase, females had larger relative risks of lung cancer mortality (1.33 versus 1.14; P = .36), cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause mortality (1.37 versus 0.98; P = .001) than males.
                The previously reported adverse effects of beta-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to asbestos persisted after drug administration was stopped although they are no longer statistically significant. Planned subgroup analyses suggest that the excess risks of lung cancer were restricted primarily to females, and cardiovascular disease mortality primarily to females and to former smokers.
There is no evidence for recommending supplements of vitamins A, C, E, selenium, either alone or in different combinations, for the prevention of lung cancer and lung cancer mortality in healthy people. There is some evidence that the use of beta-carotene supplements could be associated with a small increase in lung cancer incidence and mortality in smokers or persons exposed to asbestos.