Affiliations of authors: J. A. Baron (Departments of Medicine and Community and Family Medicine), B. F. Cole, L. Mott, M. Grau, E. R. Greenberg (Department of Community and Family Medicine), Dartmouth Medical School, Lebanon, NH; R. Haile, Department of Preventive Medicine, University of Southern California, Los Angeles; T. R. Church, Department of Occupational and Environmental Health, University of Minnesota, Minneapolis; G. J. Beck, Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, OH.
Correspondence to: John Baron, M.D., Dartmouth Medical School, Section of Biostatistics and Epidemiology, Evergreen Center, 46 Centerra Pkwy., Ste. 300, Lebanon, NH 03766 (e-mail: john.a.baron{at}dartmouth.edu).
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ABSTRACT |
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INTRODUCTION |
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Both of the two trials reporting this adverse effect of -carotene (2,3) had recruited subjects, primarily cigarette smokers, at high risk of lung cancer. By contrast, the one large trial (1) reporting no increased risk from
-carotenethe Physicians Health Studyhad recruited healthy middle-aged physicians who had a low prevalence of smoking. The findings in these study populations suggest that cigarette smoking could play a role in possible carcinogenic effects of
-carotene supplementation. Moreover, in both the ATBC Study and the CARET (2,3), the increase in lung cancer incidence was seen only in subjects who drank alcohol (5,6), a pattern that has led to the additional hypothesis that alcohol intake may somehow modify the effect of
-carotene to increase lung cancer risk.
In these three large trials (13), -carotene did not seem to increase the incidence of cancer generally (2,68), even among subjects who drank alcohol or smoked cigarettes (7,8). However, there has been little assessment of how alcohol intake or cigarette smoking might modify the effects of
-carotene on carcinogenesis outside the lung. To provide additional insight into this issue, we report here findings from a randomized, double-blind trial of antioxidants (including
-carotene) as preventive agents for recurrence of large-bowel adenomas.
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SUBJECTS AND METHODS |
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Statistical Analysis
The analyses focused on any adenomas found during the main risk period of the trial, which was the interval beginning immediately after the year 1 colonoscopy up to and including the year 4 examination. To assess later stages of carcinogenesis, we also considered "advanced lesions"adenomas 1 cm or larger in diameter or those judged by the pathologist to be tubulovillous (25%74% villous component) or villous (75% villous component) or to contain advanced dysplasia or invasive cancer. These tumors constitute 18% of the neoplasms diagnosed in study subjects.
We categorized smoking status as current smoker versus never or former smoker at baseline and alcohol intake as nondrinker, light drinker (1 drink/day, on average), or moderate/heavy drinker (>1 drink/day, on average). In dietary analyses, we analyzed the logarithm of baseline caloric intake, the residuals of the regression of log baseline dietary
-carotene intake on log caloric intake, and the residuals of the regression of log baseline fat intake on log caloric intake.
Crude and adjusted risk ratios (RRs) were used to assess -carotene effects within strata of smoking and alcohol use. For multivariate analysis of all adenomas, we used generalized linear models (11) fit with a log link function to compute RRs. Estimates were adjusted for allocation to vitamins C and E and, in multivariate analyses, also for age, sex, study center, and length of follow-up. In some analyses, we also adjusted for dietary intake of calories, fat, and
-carotene. Interactions among cigarette smoking, alcohol intake, and
-carotene supplementation were assessed using product interaction terms and Wald tests. In an adjusted model that included
-carotene interactions with smoking and alcohol intake (any versus none) as well as the three-way interaction of these factors, the P values for the interactions were .008, .022, and .059, respectively. These terms were then included in a model that was used to estimate
-carotene effects within strata of smoking and alcohol intake, and these RRs were compared between strata using Wald tests. We assessed the effect of
-carotene on the multiplicity of adenomas by using Poisson regression (11) to compute ratios of the numbers of adenomas in the
-carotene and placebo groups; the analysis strategy, independent variables, and adjustment factors were as described above. Generalized linear model analysis was similarly used to assess the impact of smoking and alcohol intake on associations of adenoma risk with baseline serum
-carotene and baseline dietary
-carotene intake. Computations were performed using STATA version 7 (Stata Corporation, College Station, TX). All statistical tests were two-sided, with P values <.05 considered statistically significant.
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RESULTS |
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In the placebo group, the association of recurrent adenoma risk with baseline serum -carotene followed patterns that were similar to those for random assignment to
-carotene supplementation, although without conventional statistical significance. Among subjects in the placebo group overall, serum
-carotene was essentially unrelated to adenoma recurrence (multivariate RR per 200 µg/L = 0.94, 95% CI = 0.79 to 1.11). For subjects in the placebo group who neither smoked nor drank alcohol, the adjusted RR was 0.72 (95% CI = 0.47 to 1.09); among those who both smoked and drank alcohol, the multivariate RR was 1.36 (95% CI = 0.67 to 2.76; P = .15 compared with that for the RR for nonsmokers/nondrinkers). Baseline dietary
-carotene intake among subjects in the placebo groupas assessed by a food-frequency questionnairedid not show substantial differences in RRs across smoking and alcohol groups (data not shown).
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DISCUSSION |
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There are substantial data indicating that -carotene supplementation may increase the risk of lung cancer. In addition to the earlier trials that reported statistically significant RRs of 1.18 (95% CI = 1.03 to 1.36) and 1.28 (95% CI = 1.04 to 1.57) (5,6), two more recent trials (13,14) have reported statistically nonsignificantly increased lung cancer relative risks of approximately 1.4 or 1.5. One of these trials (14) was conducted among patients with head and neck cancer who, similar to the subjects in the ATBC Study and the CARET (5,6), were predominantly current and former cigarette smokers. Subjects in the other investigationthe Womens Health Study (13)were female health professionals who had a relatively low prevalence of smoking.
In the ATBC Study, the RR for lung cancer among the -carotene group was 0.93 (95% CI = 0.65 to 1.33) among nondrinkers but was 1.35 (95% CI = 1.01 to 1.81) among those who reported consuming one or more drinks per day, on average (5). In the CARET, there was a similar interaction, with RRs of 1.07 (95% CI = 0.76 to 1.51) among nondrinkers and 1.99 (95% CI = 1.28 to 3.09) among
-carotene-supplemented subjects in the highest quartile of alcohol intake (6). In none of the previous trials did
-carotene supplementation seem to lead to an increased risk of colorectal cancer, even among subjects who reported drinking alcohol (5,7). In the Physicians Health Study, there were some suggestions that
-carotene supplementation could decrease colorectal cancer incidence among individuals who drink alcohol daily (7). In the ATBC Study, the effects of
-carotene supplementation on colorectal cancer risk did not seem to vary according to alcohol use (8).
The reasons for the differences between these findings regarding colorectal neoplasia and our results are not clear. Relatively few colorectal cancers were observed in those studies, so chance is clearly one possible explanation. An important additional possibility is that the interactions we found pertain to colorectal adenoma recurrence but not to the development of colorectal cancer itself. Arguing against this possibility, however, is our finding that advanced adenomas showed the same interaction pattern as all adenomas. This pattern suggests that the interactions are not limited to very early lesions.
In an earlier skin cancer prevention trial (15), we found that cigarette smoking modified the effect of -carotene (50 mg/day) supplementation on skin cancer recurrence. Among nonsmokers, the adjusted RR was 0.97 (95% CI = 0.82 to 1.15), whereas among current smokers, the adjusted RR was 1.44 (95% CI = 0.99 to 2.09; P = .04 for interaction). These findings, together with the results presented here, suggest that the tendency for cigarette smoking and alcohol use to modify the effects of
-carotene supplementation on carcinogenesis extend beyond the lung and the particular characteristics of the subjects in the ATBC Study and the CARET (5,6). Our results also suggest that these effects are not limited to a particular form of
-carotene supplementation. Although these other two trials used
-carotene beadlets (which tend to produce relatively high increases in blood levels), our studies and two more recent trials (13,14) used capsules with powdered
-carotene (which, by comparison, tend to produce smaller increases in blood levels).
The effects of -carotene on carcinogenesis are not well understood. Originally thought to be antineoplastic, partly because of its presumed antioxidant potency (4),
-carotene is an antioxidant at low oxygen pressures, but at ambient or high oxygen pressures, it can display prooxidant properties (16). This characteristic may be a result of the formation of oxidized metabolites that can enhance lipid peroxidation and increase formation of DNA adducts (1719). High oxygen tensions are not achieved in the bowel (20), but cigarette smoking seems to increase the production of oxidized
-carotene metabolites (2123). If this occurs in the colorectal mucosa, it may provide a physiologic basis for our observed interaction between smoking and
-carotene.
Other possibly procarcinogenic effects of -carotene have also been proposed. High doses of
-carotene, but not physiologic doses, may decrease tissue concentrations of retinoic acid, decrease expression of the retinoic acid receptor
, and increase AP-1 expression, all of which would be expected to enhance carcinogenesis (21,24). It is conceivable that these effects might differ between individuals who drink alcohol or smoke cigarettes and those who do not, but we are unaware of evidence supporting that possibility.
Our data suggest that ethanol intake may counter a protective effect of -carotene on neoplasia in the bowel. Unfortunately, the effects of alcohol intake on the process of carcinogenesis are not well understood. Ethanol is not carcinogenic or mutagenic in animals, but intake of alcoholic beverages in humans is clearly associated with an increased risk of cancers at several anatomic sites (2527). Several mechanisms for such a neoplastic effect have been proposed, including induction of phase I enzymes, inhibition of phase II enzymes, disturbances of retinol metabolism, interference with DNA repair, and interference with folate metabolism (25,2832). Like
-carotene, alcohol may increase expression of AP-1 and decrease expression of the retinoic acid receptor
(3338). Acetaldehyde, the major metabolite of ethanol, is a known animal carcinogen (25,29) and may increase cell proliferation in the distal large bowel (39). In rodent studies (40), acetaldehyde produced from alcohol by microbes may promote folate deficiency in the bowel mucosa, despite normal serum folate levels. However, specific interactions with
-carotene in these contexts have not been proposed.
The pharmacologic interactions between -carotene and ethanol are not entirely clear. In cross-sectional studies (41,42) and some trials of
-carotene supplementation (43,44), alcohol intake has been associated with reduced serum
-carotene levels. However, in a feeding study that carefully controlled carotenoid intake, alcohol administration was associated with increased
-carotene levels (45). At least in animal models,
-carotene may increase the liver damage caused by alcohol intake, which in turn could interfere with the conversion of
-carotene to retinol (30). Both alcohol and
-carotene induce cytochrome P450 2E1 (46,47) but, to our knowledge, there has been no investigation of whether a pharmacologic interaction occurs. The relationship of all these effects with carcinogenesis in the bowel is not clear.
There are several possible reasons for the differences between our findings for -carotene supplementation and dietary
-carotene intake. The findings for supplementation may not be pertinent for the lower intake usually obtained from diet alone. However, data from our study argue against this possibility. Indeed, we found similar patterns when we considered effects of
-carotene supplementation on adenoma recurrence and associations with serum levels in the placebo group, which reflect dietary intake. More likely, the measurement error inherent in dietary assessment and the nonrandomized assessment of
-carotene intake probably obscured the interactions.
Although our analysis has the advantage of randomized -carotene supplementation, alcohol intake and cigarette smoking were habits taken up by the subjects themselves. Consequently these exposures bring with them the limitations of most observational analyses, including the potential for measurement error and association with other unknown lifestyle factors. The effect of these possible problems on our findings is not clear.
Our findings suggest that -carotene may have antineoplastic effects in some individuals, in particular, among those who abstain from using alcohol and tobacco. Yet, in some circumstances,
-carotene seems to be proneoplastic, for example, among individuals who drink alcohol or smoke cigarettes. These results suggest that caution must be applied in choosing interventions for large-scale use in well people, particularly when the mechanisms of action and possible interactions with lifestyle factors are not well understood.
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NOTES |
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We thank the many investigators who supported the study and the patients who took part.
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Manuscript received August 27, 2002; revised March 5, 2003; accepted March 17, 2003.
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