Influence of antioxidants and the CYP1A1 isoleucine to valine polymorphism on the smoking--lung cancer association.

To evaluate the association between CYP1A1 genotype and lung cancer risk and to assess the effect of CYP1A1 genotype and antioxidant supplementation on the smoking--lung cancer relationship we conducted a case-control study nested within a large cancer prevention trial cohort. Controls (n = 324) were matched to cases (n = 282) on age (+/- 5 years), intervention group and study clinic in a 1:1 ratio, using incidence density sampling. Genotype was determined by a PCR-based method and logistic regression was used to calculate relative risk estimates. Overall, we found no association between CYP1A1 genotype and lung cancer risk. CYP1A1 genotype did not modify the effect of smoking on lung cancer risk. However, in an examination of subgroups defined by randomized intervention assignment our findings suggest that alpha-tocopherol supplementation may reduce the risk of lung cancer associated with cumulative smoking exposure regardless of CYP1A1 genotype with the greatest effect seen among those with the variant CYP1A1 allele.

Effects of long-term alpha-tocopherol supplementation on serum hormones in older men.

BACKGROUND: alpha-tocopherol supplementation significantly reduced risk of prostate cancer in the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study. Sex hormones are thought to be involved in the etiology of prostate cancer. We examined whether long-term supplementation with alpha-tocopherol modified serum hormone levels. METHODS: Men who were cancer-free consumed > or = 90% of the study capsules, and who had both baseline and follow-up blood available, were eligible for the study. One hundred men who received alpha-tocopherol were matched on age, study center, and length of time between blood draws to 100 men who received a placebo. Multivariate linear regression models which allowed for a separate intercept for each matched pair were used to evaluate the effect of alpha-tocopherol supplementation on follow-up hormone concentrations. RESULTS: Compared to men who received a placebo, we found significantly lower serum androstenedione (P = 0.04) and testosterone (P = 0.04) concentrations among men who received alpha-tocopherol, after controlling for baseline hormone level, follow-up serum cholesterol concentration, body mass index, smoking, and fasting time. Geometric mean (95% confidence interval; CI) androstenedione concentration among men who received alpha-tocopherol was 145 ng/dl (CI, 137-153) after adjusting for covariates, compared to 158 ng/dl (CI, 148-167) among men who received a placebo. Mean testosterone concentrations for men who received alpha-tocopherol and placebo were 539 (CI, 517-562) and 573 (CI, 549-598) ng/dl, respectively. CONCLUSIONS: These results suggest that long-term alpha-tocopherol supplementation decreases serum androgen concentrations, and could have been one of the factors contributing to the observed reduction in incidence and mortality of prostate cancer in the alpha-tocopherol treatment group of the ATBC Study.

Diet and prostate cancer risk in a cohort of smokers, with a specific focus on calcium and phosphorus (Finland).

BACKGROUND: Calcium, phosphorus, fructose, and animal protein are hypothesized to be associated with prostate cancer risk, potentially via their influence on 1,25-dihydroxyvitamin D3. We examined these nutrients and overall diet and prostate cancer risk in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC Study). MATERIALS AND METHODS: The ATBC Study was a randomized 2 x 2 trial of alpha-tocopherol and beta-carotene on lung cancer incidence conducted among Finnish male smokers; 27,062 of the men completed a food-use questionnaire at baseline, and comprise the current study population. There were 184 incident clinical (stage 2-4) prostate cancer cases diagnosed between 1985 and 1993. We used Cox proportional hazards models to examine associations between dietary intakes and prostate cancer. RESULTS: We did not observe significant independent associations for calcium and phosphorus and prostate cancer risk. However, men with lower calcium and higher phosphorus intake had a multivariate relative risk of 0.6 (95% CI 0.3-1.0) compared to men with lower intakes of both nutrients, adjusting for age, smoking, body mass index, total energy, education, and supplementation group. Of the other foods and nutrients examined, none was significantly associated with risk. DISCUSSION: This study provides, at best, only weak evidence for the hypothesis that calcium and phosphorus are independently associated with prostate cancer risk, but suggests that there may be an interaction between these nutrients.

Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland)

BACKGROUND: Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and beta-carotene might be associated with reduced risk of colorectal cancer. METHODS: We tested the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a double-blind, placebo-controlled trial among 29,133 50-69-year-old male cigarette smokers. Participants were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or a placebo daily for 5-8 years. Incident colorectal cancers (n = 135) were identified through the nationwide cancer registry, and 99% were histologically confirmed. Intervention effects were evaluated using survival analysis and proportional hazards models. RESULTS: Colorectal cancer incidence was somewhat lower in the alpha-tocopherol arm compared to the no alpha-tocopherol arm, but this finding was not statistically significant (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.55-1.09; log-rank test p = 0.15). Beta-carotene had no effect on colorectal cancer incidence (RR = 1.05, 95% CI 0.75-1.47; log-rank test p = 0.78). There was no interaction between the two substances. CONCLUSION: Our study found no evidence of a beneficial or harmful effect for beta-carotene in colorectal cancer in older male smokers, but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect. The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk.

Serum tocopherols, selenium and lung cancer risk among tin miners in China.

OBJECTIVE: To evaluate the association of prediagnostic serum antioxidants and lung cancer risk we conducted a case-control study nested in an occupational cohort of tin miners. METHODS: Male workers free of cancer enrolled in the cohort. During up to 6 years of follow-up, 339 lung cancer cases were diagnosed and, among these cases, those who donated blood prospectively (n = 108) were eligible for this study. For each case, two controls alive and free of cancer at the time of case diagnosis were matched on age and date of blood collection. RESULTS: Overall, we observed no association between serum alpha-tocopherol, gamma-tocopherol or selenium levels and lung cancer risk. However, a significant gradient of decreasing lung cancer risk with increasing serum alpha-tocopherol was apparent for men less than 60 years old (odds ratio by tertile: 1.0, 0.9, 0.2; trend p = 0.002). Alpha-tocopherol was also protective in men who reported no alcohol drinking (OR by tertile: 1.0, 0.6, 0.3; trend p = 0.008). CONCLUSION: Although there were no significant overall associations between prospectively collected serum alpha-tocopherol, gamma-tocopherol or selenium and incidence of lung cancer, results from this study suggest that higher alpha-tocopherol levels may be protective in men less than 60 years old and in those who do not drink alcohol.

The effect of beta-carotene supplementation on serum vitamin D metabolite concentrations.

In the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study, a large randomized placebo-controlled trial designed to test the cancer prevention effects of alpha-tocopherol (50 mg/day) and beta-carotene (20 mg/day), participants receiving supplemental beta-carotene had significantly higher rates of lung cancer than those not receiving beta-carotene. It has been hypothesized that the supplemental beta-carotene may have interfered with the synthesis of vitamin D and that the resulting lower concentrations of vitamin D contributed to the elevated cancer incidence. We evaluated whether supplementation with beta-carotene altered the serum concentrations of either 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D in the ATBC Study, by comparing on-study changes between baseline and follow-up serum samples among 20 randomly selected matched pairs of subjects from the beta-carotene and placebo groups. In a matched-pair analysis, the difference between the changes in both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the beta-carotene supplement and placebo groups were small and statistically nonsignificant. These results provide no evidence that beta-carotene supplementation interferes with the endogenous production of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D and suggest that it is unlikely that an interaction between supplemental beta-carotene and vitamin D metabolites contributed to the modest increase in lung cancer incidence observed in the ATBC Study.

Serum alpha-tocopherol and subsequent risk of lung cancer among male smokers.

BACKGROUND: Higher blood levels of alpha-tocopherol, the predominant form of vitamin E, have been associated in some studies with a reduced risk of lung cancer, but other studies have yielded conflicting results. To clarify this association, we examined the relationship between prospectively collected serum alpha-tocopherol and lung cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. METHODS: The ATBC Study was a randomized, clinical trial of 29 133 white male smokers from Finland who were 50-69 years old and who had received alpha-tocopherol (50 mg), beta-carotene (20 mg), both, or neither daily for 5-8 years. Data regarding medical histories, smoking, and dietary factors were obtained at study entry, as was a serum specimen for baseline alpha-tocopherol determination. alpha-Tocopherol measurements were available for 29 102 of the men, among whom 1144 incident cases of lung cancer were diagnosed during a median observation period of 7.7 years. The association between alpha-tocopherol and lung cancer was evaluated with the use of multivariate proportional hazards regression. RESULTS: A 19% reduction in lung cancer incidence was observed in the highest versus lowest quintile of serum alpha-tocopherol (relative risk = 0.81; 95% confidence interval = 0. 67-0.97). There was a stronger inverse association among younger men (<60 years), among men with less cumulative tobacco exposure (<40 years of smoking), and possibly among men receiving alpha-tocopherol supplementation. CONCLUSIONS: In the ATBC Study cohort, higher serum alpha-tocopherol status is associated with lower lung cancer risk; this relationship appears stronger among younger persons and among those with less cumulative smoke exposure. These findings suggest that high levels of alpha-tocopherol, if present during the early critical stages of tumorigenesis, may inhibit lung cancer development.

The effect of alpha-tocopherol and beta-carotene supplementation on colorectal adenomas in middle-aged male smokers.

Epidemiological and experimental studies have indicated that dietary factors such as vitamin C, vitamin E, and beta-carotene are associated with the risk of colorectal cancer. This study was carried out within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study), whose participants were randomly assigned to four supplementation groups: (a) alpha-tocopherol (AT), 50 mg/day; (b) beta-carotene (BC), 20 mg/day; (c) both AT and BC; and (d) placebo. We included the 15,538 ATBC Study participants who had been randomized within the areas of three major cities in southern Finland. Cases of colorectal adenoma (n = 146) were identified by the pathology laboratories in the study areas, and these participants' medical records were collected and reviewed. Alpha-tocopherol supplementation increased the risk for adenomas (relative risk, 1.66; 95% confidence interval, 1.19-2.32), whereas beta-carotene supplementation had no effect on the risk (relative risk, 0.98; 95% confidence interval, 0.71-1.35). Slightly more prediagnosis rectal bleeding and intestinal pain occurred in those adenoma cases who received alpha-tocopherol supplements than in those who did not. Thus, some bias may have resulted, with alpha-tocopherol supplementation leading to more colonoscopies and, thus, to an increased detection of incident polyps in this group. This is further supported by the trial finding that alpha-tocopherol supplementation did not increase the risk of colorectal cancer.

Association between serum alpha-tocopherol and serum androgens and estrogens in older men.

There is evidence supporting a role for sex hormones in the etiology of prostate cancer. Supplementation with alpha-tocopherol reduced prostate cancer in the alpha-Tocopherol, beta-Carotene Prevention Study (ATBC Study). The objective of this study was to assess the relation of baseline levels of serum alpha-tocopherol and serum sex hormones in older men. A cross-sectional analysis of serum alpha-tocopherol and sex hormone concentrations was conducted within a subset of the ATBC Study. Serum was collected in the morning after an overnight fast at baseline from 204 men ages 50-69 years participating in the ATBC Study and free of prostate cancer. Hormones were measured by radioimmunoassay, and alpha-tocopherol was measured by high-performance liquid chromatography by standard procedures. Multivariate linear regression was used to evaluate the association of serum alpha-tocopherol with nine androgens and estrogens after controlling for age, body mass index, hormone assay batch, and serum cholesterol. Serum alpha-tocopherol was significantly inversely associated with serum androstenedione, testosterone, sex hormone-binding globulin, and estrone. The difference in hormone concentration per milligram of alpha-tocopherol was 1.8-2.6% for these four hormones. These results indicated that alpha-tocopherol is related to concentrations of several sex hormones in older men and may have implications for the observed protective effect of supplemental vitamin E in relation to prostate cancer in the ATBC Study.

Tea and coffee consumption and risk of colon and rectal cancer in middle-aged Finnish men.

The association between coffee and black tea consumption and the subsequent risk of colon and rectal cancer was investigated within a Finnish clinical trial cohort. One hundred eleven cases of colon cancer and 83 cases of rectal cancer were diagnosed over a median of 9.0 years of follow-up. Proportional hazards regression models were used to derive adjusted relative risk (RR) and 95% confidence intervals (CI) for the association between coffee and tea consumption and cancer incidence. After controlling for confounders, coffee was not significantly associated with colon or rectal cancer. A positive association was seen for increased consumption of tea drinking and colon cancer. Compared with persons who did not drink tea, those who consumed <1 cup/day had an RR of 1.40 (95% CI = 0.84 - 2.33) and those who consumed > or = 1 cup/day had an RR of 2.09 (95% CI = 1.34-3.26, p for trend = 0.001). In contrast, tea consumption had little effect on rectal cancer incidence. This study does not support the hypothesis that coffee and tea protect against colorectal cancer risk. However, given the strength of the tea-colon cancer association and the significant gradient of risk we observed across level of intake, further epidemiologic research of this relationship in other populations seems warranted.

The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study.

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).

Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance.

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Alcohol consumption and risk of colorectal cancer in a cohort of Finnish men.

We investigated the association between self-reported alcohol ingestion and colorectal cancer in a cohort of male smokers in Finland. Among 27,109 men aged 50 to 69 years, 87 colon and 53 rectal cases were diagnosed during the five to eight years of follow-up. Among drinkers, colorectal cancer risk increased with the amount of alcohol consumed (P trend = 0.01) with risk increasing by 17 percent for each drink consumed. Both beer and spirits contributed to this increased risk. Further analyses revealed that the positive association with alcohol was primarily for colon cancer (P trend = 0.01). Interestingly, risk of colorectal cancer associated with drinking (cf self-reported abstinence) changed with follow-up time, suggesting an inverse association for alcohol early in follow-up, and a positive association after about three-and-a-half years of follow-up. Follow-up time did not modify the positive association with amount of alcohol among drinkers, however. Results also indicated that beta-carotene supplementation may attenuate the effect of alcohol on colorectal cancer risk among drinkers. In conclusion, this study supports a role for alcohol in colon carcinogenesis and suggests that similar studies should evaluate carefully the effects of lifetime drinking habits and recent abstinence.

Linxian nutrition intervention trials. Design, methods, participant characteristics, and compliance.

Two nutrition intervention trials were conducted in Linxian, China, where the esophageal/gastric cardia cancer mortality rates are among the highest in the world and there is suspicion that the population's chronic deficiencies of multiple nutrients are etiologically involved. Both trials were randomized, double-blind, and placebo-controlled, and tested the effect of multiple-vitamin and multiple-mineral supplements in lowering the rates of cancer. In the first trial, the Dysplasia Trial, 3318 individuals with a cytologic diagnosis of esophageal dysplasia received daily vitamin and mineral supplements or placebos for 6 years. The second trial, the General Population Trial, involved 29,584 individuals and used a one-half replicate of a 2(4) fractional factorial design, which enabled the testing of daily supplementation of four different vitamin and mineral combinations and placebo for a period 5 1/4 years. This article describes the design and methods of these studies as well as the baseline characteristics and compliance behavior of the participants in these two trials, the largest cancer chemoprevention studies reported to date.

Long-term therapy with low-dose isotretinoin for prevention of basal cell carcinoma: a multicenter clinical trial. Isotretinoin-Basal Cell Carcinoma Study Group.

BACKGROUND: High-dose isotretinoin has been reported to have a prophylactic effect on nonmelanoma skin cancer, although it is associated with significant toxicity. PURPOSE: To test the effectiveness of the long-term administration of low-dose isotretinoin in reducing the occurrence of basal cell carcinoma at a new site in patients with previously treated basal cell carcinomas and to measure the toxicity associated with this regimen, we conducted a clinical trial at eight cancer centers. METHODS: Nine hundred and eighty-one patients with two or more previously confirmed basal cell carcinomas were randomly assigned to receive either 10 mg of isotretinoin or a placebo daily. Patients were followed for 36 months and monitored at 6-month intervals for skin cancer and toxic effects. RESULTS: After 36 months of treatment, no statistically significant difference in either the cumulative percent of patients with an occurrence of basal cell carcinoma at a new site or the annual rate of basal cell carcinoma formation existed between patients receiving isotretinoin and those receiving the placebo. Elevated serum triglycerides, hyperostotic axial skeletal changes, and mucocutaneous reactions were more frequent in the group receiving isotretinoin than in the control group, and these differences were all statistically significant (P less than .001). CONCLUSION: This low-dose regimen of isotretinoin not only is ineffective in reducing the occurrence of basal cell carcinoma at new sites in patients with two or more previously treated basal cell carcinomas but also is associated with significant adverse systemic effects. IMPLICATION: The toxicity associated with the long-term administration of isotretinoin, even at the low dose used in this trial, must be weighted in planning future prevention trials.

Feasibility of conducting a lung-cancer chemoprevention trial among tin miners in Yunnan, P. R. China.

Tin miners in Yunnan Province in southern China have an extremely high rate of lung cancer, more than one percent per year among those at 'high risk' (40+ years old, with 10+ years of underground mining and/or smelting experience). The extraordinary lung cancer rates result from combined exposure to radon, arsenic, and tobacco smoking (cigarettes and/or bamboo water pipe). A study to determine the feasibility of conducting a large-scale, lung-cancer chemoprevention trial was conducted in 1986 among currently employed or retired miners from the Yunnan Tin Corporation in the city of Gejiu. The study was designed to answer four questions: (i) Could potentially eligible miners be identified and recruited? (ii) Could intervention agents be shipped successfully from the United States to the study area and be appropriately distributed? (iii) Would miners adequately adhere to the study protocol and comply with the intervention regimen? (iv) Could potential adverse effects be monitored and documented? The six-month feasibility study yielded affirmative answers to each of these questions. A roster of over 7,000 high-risk miners was compiled. Four agents (vitamin A, 25,000 IU; beta-carotene, 50 mg; vitamin E, 800 IU; and selenium, 400 micrograms) were administered daily with placebos to 350 miners according to a 2(4) factorial design. Adherence, assessed by pill counts and serum micronutrient levels, was approximately 90 percent. The findings from this preliminary study indicate that a full-scale, lung-cancer chemoprevention trial in this population is feasible.