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,3
* Registre Bourguignon des Cancers Digestifs, Faculté de Médecine, Dijon Cedex, France;
Nutrition, Hormones and Cancer Unit, Institut Gustave Roussy, Villejuif, France; and
** CRLC Val d’Aurelle, Montpellier, Cedex 5, France
3To whom correspondence should be addressed. E-mail: boutron{at}igr.fr.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • colorectal neoplasms • adenomas • ß-carotene • folate • tobacco
Colorectal cancer, one of the most common cancers in the Western world, is highly influenced by environmental factors, especially diet. The majority of colorectal cancers arise from a preexisting adenoma; the primary prevention strategies are aimed primarily at reducing the risk of adenoma recurrence. However, intervention studies on adenoma recurrence have been largely disappointing, possibly because of insufficient knowledge about risk factors for adenomas. Among possible dietary interventions, antioxidants and/or vitamins have been advocated because they are biologically plausible and easy to implement. There is limited epidemiologic evidence of a protective effect of ascorbic acid, vitamin E, or ß-carotene (1). Most of the reported intervention studies using ß-carotene and/or vitamin E had inconsistent results (2,3). However, a recent intervention study demonstrated that supplemental ß-carotene could have a beneficial effect on adenoma recurrence, but only in nonsmokers who did not drink alcohol. Indeed, ß-carotene supplementation significantly increased the risk of adenoma recurrence in smokers who drank >1 alcoholic beverage/d compared with nonsupplemented subjects (4), suggesting a strong interaction between ß-carotene and smoking and drinking status. Negative effects of ß-carotene supplementation on lung cancer in smokers were demonstrated (5,6). This suggestion of a modulating effect of tobacco and/or alcohol is of interest because tobacco has been consistently associated with the risk of colorectal adenomas (7). Folate has also been studied quite extensively in relation to colorectal tumors, with a consistent protective effect in most studies (8). Vitamin D was also suggested to have a protective effect toward colorectal carcinogenesis (9). The aim of our study was to investigate whether tobacco could modulate the effect of dietary vitamins or ß-carotene on the risk of colorectal adenomas.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Polyp-free controls (182 men, 245 women) were recruited from the same endoscopy units as the adenoma groups by consulting all endoscopy lists weekly. The mean age was 60.7 ± 10.7 y in the adenoma group, whereas polyp-free controls were significantly younger (mean age 54.1 ± 14.1 y). The refusal rate was lower in the adenoma group (16.6%) than in the polyp-free group (22.0%).
Data. The diet history questionnaire was described previously (13). It is a 2-h detailed questionnaire concerning the diet during the past year, which included the pattern of meals throughout the day. A specially trained dietician, who also coded the data, administered the questionnaire at the subjects’ homes. All nutritional data were transformed into a mean daily intake of nutrients and alcohol by using a food composition table created by compilation of available food composition tables and additional information from the food industry (14). We describe here the intakes of 8 vitamins and ß-carotene. Dietary intakes were categorized into quartiles from the distribution in the control group, separately for each gender (Table 1).
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Results were of the same magnitude along the bowel in terms of the cancer site (Table 4), although more dramatic in the colon than in the rectum, mainly because there were only 103 rectal adenomas. The significantly inverse associations between risk of adenomas and intakes of vitamin C and B-6, and the borderline association with vitamin D observed for all colorectal adenomas remained for colon adenomas, but not for rectal adenomas. In addition, thiamin intake and the risk of colon adenomas were inversely associated (P = 0.03). The interaction between ß-carotene and smoking occurred mainly for colon adenomas, P for interaction = 0.03. The ORs were 2.1 (95% CI = 1.1–4.0), 2.0 (95% CI = 1.0–3.9), and 1.9 (95% CI = 0.9–4.1) for the 2nd, 3rd, and 4th quartiles of intake, respectively, in current and former smokers; in nonsmokers, the 4th quartile was associated with a reduced risk of adenomas (OR = 0.4; 95% CI = 0.2–0.9). For rectal adenomas, ß-carotene intake was associated with a tendency for reduced risk in nonsmokers (P = 0.10), and there was no association in current and former smokers (P, interaction = 0.28).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The strengths and limitations of our data set were discussed previously (12). We avoided selection biases of cases and controls, e.g., in terms of social class, diet, or family history, by recruiting them from all private and public endoscopy units in the area. This is rarely achieved in adenoma studies because they are often hospital-based, thus selecting a specific subgroup and potentially reducing the external validity of the study. External validity can also be compromised by refusal; in our study, the refusal rate was moderate, and similar in cases and controls. Cases were slightly older than controls, which could be expected because the prevalence of adenomas increases with age, but all models were adjusted for age, thus limiting this potential confounding. Another limitation of case-control studies is the retrospective assessment of risk factors. However, our study was designed with special care regarding the dietary interviews, i.e., cases were interviewed shortly after diagnosis, and the dietary interviews were designed to be specially adapted to our population, following the pattern of meals, and using a validated questionnaire (13).
The beneficial effect of folate on the risk of colorectal adenomas or cancer has received considerable attention and was reviewed recently (8); the effect is attributed to its role in DNA methylation (15). In our study, the protective effect of folate on the risk of adenomas was not influenced by smoking status. A reduced risk of adenomas with high intakes of vitamins B-6 and B-12 was also described by others for colorectal adenomas (15) or cancers (16) and was attributed to the fact that these vitamins are cofactors of folate metabolism (16,17).
Antioxidant vitamins may play a role in preventing colorectal cancer because several studies demonstrated a role of oxidative stress in this cancer (18). In agreement with our findings, vitamin C intake (19) or serum concentrations (20) were found to be inversely associated with the risk of colorectal adenomas in observational studies. The results of the intervention studies were less supportive (21), although to our knowledge, none investigated the effect of vitamin C separately.
We observed that vitamin D intake was slightly inversely associated with the risk of colorectal adenomas, in agreement with others (9), although a recent review of the literature regarding colorectal cancers concluded that analyses limited to dietary vitamin D tended to have mixed results (22).
Lifetime tobacco smoking has been consistently associated with an increased risk of colorectal adenomas, as reported in our study (11) as well as in most other studies as reviewed in (7). There is usually a strong dose-effect relation with the number of pack-years smoked. It was proposed that smoking influences mainly the earlier steps of the adenoma-carcinoma sequence, with tobacco acting as an initiator (23). ß-Carotene, a provitamin with strong antioxidant potential, was proposed as a chemopreventive agent against several neoplasms (24,25), because high fruit and vegetable intake is consistently associated with a reduced risk of most neoplasms (26) and there was no known toxic effect. The first adverse effects of ß-carotene supplementation were reported in subjects at high risk of lung cancer, especially heavy smokers, with an increased risk of neoplasms and death in the supplemented groups (5,6). For colorectal neoplasms, intervention studies failed to demonstrate a protective effect of ß-carotene on adenoma recurrence (2,3), and there was even a nonsignificant increase in risk in the supplemented group (3). A recent intervention trial attempted to determine whether alcohol and tobacco habits could modulate the effect of supplemental ß-carotene (4). A significantly reduced risk of adenoma recurrence was observed in subjects who neither smoked nor drank, whereas a significant opposite effect was registered in smokers who drank >1 alcoholic beverage/d. However, the Alpha-Tocopherol Beta-carotene study did not report an increased risk of colorectal neoplasms, neither adenomas (27) nor cancers (28) among smokers supplemented with ß-carotene. In the Physicians Health Study (29), the supplemented group even had a nonsignificant decreased risk of colorectal cancers.
To the best of our knowledge, our study is the first to suggest that lifetime smoking status, i.e., ever vs. never smoked, could modulate the effect of dietary (and not only supplemental) ß-carotene on the risk of colorectal adenomas. To date, it has been thought that only pharmacologic doses of ß-carotene could be deleterious in association with tobacco (30–32), doses that can, however, be reached by a dietary intake of 2 or 3 carrots/d. Our results are consistent with a recent case-control study on colorectal cancer, suggesting an interaction between smoking and dietary ß-carotene (33). We observed a more marked effect on colon adenomas than on rectal adenomas. In a small biological study, the ß-carotene concentration was found to decrease in the normal mucosa from the right to the left colon, thus suggesting a differential effect of ß-carotene along the colon, but no measurement was made on the rectum (34). In the same study, ß-carotene concentration was lower in adenomas than in adjacent or normal mucosa. The metabolism of ß-carotene could thus differ in adenomatous tissue compared with normal tissue, which is consistent with findings indicating an effect of ß-carotene on adenoma risk. In vitro models demonstrated that ß-carotene may serve as an antioxidant or as a prooxidant, depending on the redox potential of the biological environment in which it acts. Although ß-carotene exerts a growth inhibitory and proapoptotic effect on malignant colonic cell lines (35), possibly via the suppression of cyclooxygenase-2 (36), it can enhance DNA oxidative damage and interact on p53-related pathways when cells are exposed to tobacco condensate (37).
Supplement use was not investigated in our study because it was uncommon in our population at the time of the study. The prevalence of vitamin-mineral dietary supplement use represented only 
10% of the French population, all nutrients together, thus leading to a very low proportion of consumers for each specific nutrient (38). Therefore, supplement use is not likely to have strongly biased our results, other than potentially reduce the power of the study.
In conclusion, evidence is accumulating that ß-carotene has a global beneficial effect on the risk of neoplasia in nonsmokers but a potentially adverse effect on subjects ever exposed to tobacco. Although adenomas are only precursor lesions of colorectal cancer, the data presented herein strongly suggest that utmost caution should be taken when prescribing high levels of ß-carotene for subjects who ever smoked, especially through fortified foods or supplements.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by the Institut National de la Santé et de la Recherche Médicale (CRE 87–8011), the Europe Against Cancer Program, and the Regional Council of Burgundy.
Manuscript received 27 May 2005. Initial review completed 28 June 2005. Revision accepted 8 July 2005.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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