Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a...

Intakes of vitamins A, C, and E and use of multiple vitaminsupplements and risk of colon cancer: a pooled analysis ofprospective cohort studies

Yikyung Park,Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA02115, USA

Donna Spiegelman,Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave, Boston, MA02115, USA. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

David J. Hunter,Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA02115, USA. Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave,Boston, MA 02115, USA. Channing Laboratory, Brigham and Women’s Hospital and HarvardMedical School, Boston, MA, USA

Demetrius Albanes, Leif Bergkvist,Department of Surgery and Centre for Clinical Research, Central Hospital, Västerås, Sweden

Julie E. Buring,Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave, Boston, MA02115, USA. Division of Preventive Medicine, Brigham and Women’s Hospital and HarvardMedical School, Boston, MA, USA

Jo L. Freudenheim,Department of Social and Preventive Medicine, University at Buffalo, State University of NewYork, Buffalo, NY, USA

Edward Giovannucci,Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA02115, USA. Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave,Boston, MA 02115, USA. Channing Laboratory, Brigham and Women’s Hospital and HarvardMedical School, Boston, MA, USA

R. Alexandra Goldbohm,Department of Prevention and Health, TNO Quality of Life, Leiden, The Netherlands

Lisa Harnack,Division of Epidemiology and Community Health, School of Public Health, University ofMinnesota, Minneapolis, MN, USA

Ikuko Kato,Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

Vittorio Krogh,

© Springer Science+Business Media B.V. 2010Correspondence to: Stephanie A. Smith-Warner, [email protected] Address: Y. Park, D. Albanes, A. Schatzkin, Nutritional Epidemiology Branch, Division of Cancer Epidemiology andGenetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA

NIH Public AccessAuthor ManuscriptCancer Causes Control. Author manuscript; available in PMC 2011 November 1.

Published in final edited form as:Cancer Causes Control. 2010 November ; 21(11): 1745–1757. doi:10.1007/s10552-010-9549-y.

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Nutritional Epidemiology Unit, National Cancer Institute, Milan, Italy

Michael F. Leitzmann,Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg,Germany

Paul J. Limburg,Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,USA

James R. Marshall,Department of Cancer Prevention and Population Science, Roswell Park Cancer Institute,Buffalo, NY, USA

Marjorie L. McCullough,Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA

Anthony B. Miller,Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

Thomas E. Rohan,Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx,NY, USA

Arthur Schatzkin, Roy Shore,Department of Environmental Medicine, New York University, New York, NY, USARadiationEffects Research Foundation, Hiroshima, Japan

Sabina Sieri,Nutritional Epidemiology Unit, National Cancer Institute, Milan, Italy

Meir J. Stampfer,Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA02115, USA. Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave,Boston, MA 02115, USA. Channing Laboratory, Brigham and Women’s Hospital and HarvardMedical School, Boston, MA, USA

Jarmo Virtamo,Department of Health Promotion and Chronic Disease Prevention, National Public HealthInstitute, Helsinki, Finland

Matty Weijenberg,Department of Epidemiology, School of Oncology and Developmental Biology (GROW),Maastricht University, Maastricht, The Netherlands

Walter C. Willett,Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA02115, USA. Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave,Boston, MA 02115, USA. Channing Laboratory, Brigham and Women’s Hospital and HarvardMedical School, Boston, MA, USA

Alicja Wolk,Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, KarolinskaInstitutet, Stockholm, Sweden

Shumin M. Zhang, andDepartment of Epidemiology, Harvard School of Public Health, 665 Huntington Ave, Boston, MA02115, USA. Division of Preventive Medicine, Brigham and Women’s Hospital and HarvardMedical School, Boston, MA, USA

Park et al.

Cancer Causes Control. Author manuscript; available in PMC 2011 November 1.

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Stephanie A. Smith-WarnerDepartment of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA02115, USA. Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave,Boston, MA 02115, USAStephanie A. Smith-Warner: [email protected]

AbstractObjective—To evaluate the associations between intakes of vitamins A, C, and E and risk ofcolon cancer.

Methods—Using the primary data from 13 cohort studies, we estimated study- and sex-specificrelative risks (RR) with Cox proportional hazards models and subsequently pooled RRs using arandom effects model.

Results—Among 676,141 men and women, 5,454 colon cancer cases were identified (7–20years of follow-up across studies). Vitamin A, C, and E intakes from food only were notassociated with colon cancer risk. For intakes from food and supplements (total), the pooledmultivariate RRs (95% CI) were 0.88 (0.76–1.02, >4,000 vs. ≤1,000 μg/day) for vitamin A, 0.81(0.71–0.92, >600 vs. ≤100 mg/day) for vitamin C, and 0.78 (0.66–0.92, >200 vs. ≤6 mg/day) forvitamin E. Adjustment for total folate intake attenuated these associations, but the inverseassociations with vitamins C and E remained significant. Multivitamin use was significantlyinversely associated with colon cancer risk (RR = 0.88, 95% CI: 0.81–0.96).

Conclusions—Modest inverse associations with vitamin C and E intakes may be due to highcorrelations with folate intake, which had a similar inverse association with colon cancer. Aninverse association with multivitamin use, a major source of folate and other vitamins, deservesfurther study.

KeywordsVitamin A; Vitamin C; Vitamin E; Multivitamin; Colon cancer; Cohort study; Pooled analysis

IntroductionDiet and lifestyle factors play an important role in the etiology of colon cancer, and a largeproportion of colon cancer incidence might be prevented by a healthy lifestyle [1]. Amongdietary factors, vitamins A, C, and E have been hypothesized to reduce the risk of coloncancer because of their anticarcinogenic properties: vitamin A regulates nuclear receptorsthat suppress tumor formation, induces cell apoptosis [2], and enhances immune function[3]. Vitamin C has antioxidant properties and enhances the immune system [4]. Vitamin Einhibits lipid peroxidation in cell membranes, prevents oxidative damage of DNA byscavenging free radicals, and inhibits carcinogen production [5, 6].

A limited number of observational studies have investigated the associations betweenintakes of vitamins A, C, and E and risk of colon cancer, and the results for each vitaminhave been inconsistent [7–14]. A pooled analysis of nested case–control studies from fivecohorts reported a modestly lower risk of colorectal cancer [15] comparing the highestquartile of serum alpha-tocopherol (vitamin E) concentration to the lowest. On the otherhand, a meta-analysis of seven clinical trials that tested effects of different combinations ofβ-carotene and vitamins A, C, and E on recurrence of colorectal adenomas (precursors ofcolorectal cancer) found no significant beneficial effects for supplementation with thesenutrients [16]. Two recent clinical trials of vitamin E supplementation that were not includedin the meta-analysis also found no beneficial effects of vitamin E supplementation compared

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with a placebo on colorectal cancer incidence [17, 18]. Some studies [19, 20], but not all[21], have found that use of multivitamin supplements, a good source of vitamins A, C, andE, and others, was associated with lower risk of colorectal cancer.

Whether vitamins A, C, and E provide protection from colon cancer is of considerablepublic health importance; however, this remains as an open question because of inconsistentfindings from previous studies, and randomized trials may have been of insufficient durationto reach definitive conclusions. In this analysis, we examined whether intakes of vitamins A,C, and E from foods and supplemental sources and use of multiple vitamin supplementswere associated with risk of colon cancer by reanalyzing the primary data from 13prospective cohort studies from Europe and North America.

Materials and methodsStudy population

The Pooling Project of Prospective Studies of Diet and Cancer (Pooling Project), aninternational consortium of cohort studies, was established to summarize the associationsbetween dietary factors and risks of several cancers by analyzing and combining theindividual data from each participating cohort study. The details of the Pooling Project havebeen described previously [22]. Thirteen prospective cohort studies from North America andEurope that met the following inclusion criteria for the colorectal cancer analyses wereidentified [13, 14, 23–32]: 1) at least 50 incident colorectal cancer cases; 2) assessment ofusual dietary intake; 3) a validation study of the dietary assessment method or a closelyrelated instrument; and 4) assessment of intakes of vitamins A, C, and E.

Studies including both men and women were separated into sex-specific cohorts. TheNurses’ Health Study (NHS) was treated as two separate studies, NHSa (1980–1986) andNHSb (1986–2000) to take advantage of the more detailed dietary assessment in 1986.Following survival data analysis theory, blocks of person-time in different time periods areasymptotically uncorrelated, regardless of the extent to which they are derived from thesame people [33], so pooling estimates from these two time periods is a statistically validalternative to using a single time period. Because the Alpha-Tocopherol Beta-CaroteneCancer Prevention Study and the Women’s Health Study were clinical trials of vitamin Eand beta-carotene supplementation, we included participants in the placebo group only forthese studies.

Dietary assessmentEach study assessed nutrient intakes by a self-administered food frequency questionnaire(FFQ) at baseline and provided intake data for vitamins A, C, and E from foods only(dietary intake) and from foods and supplements (total intake), if available. Information onuse of vitamin supplements (multivitamins and/or individual vitamin A, C, or Esupplements) at baseline was available in 10 studies. For the Netherlands Cohort Study andthe New York State Cohort, which collected information on the use of vitamin supplements,but did not estimate supplemental intake, we derived an estimate of total intake for eachvitamin. For the Netherlands Cohort Study, we estimated supplemental intake using themost common dose of vitamins A, C, and E in multivitamins and in individual vitamin A, C,and E supplements reported in their FFQ validation study [34]. For the New York StateCohort, we estimated supplemental intake using the dose for generic multivitamins andvitamin A, C, and E supplements used in the Nurses’ Health Study. For both studies, weassumed a frequency of one multivitamin or each individual supplement a day. Nutrientintakes from foods were energy-adjusted to 2,100 kcal/day for men and 1,600 kcal/day forwomen by the residual method [35].

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In the validation studies (Wolk and Krogh, personal communication) [34, 36–42], thePearson correlation coefficients between dietary vitamin intake estimated by the FFQ andthe reference method were generally 0.4–0.7 for each vitamin. In additional validationstudies using biomarkers, the Pearson correlation coefficients between dietary vitamin Eintake estimated by the FFQ and its plasma concentration were 0.41 in the Nurses’ HealthStudy and 0.51 in the Health Professionals Follow-up Study [43].

We also had information on nondietary risk factors, which was collected by self-administered questionnaires at baseline in each study. We reformatted these variables tocreate standardized categories for each variable across studies.

Case ascertainmentIncident colon cancer cases were identified by each cohort through either self-report on thequestionnaire with subsequent medical record review [14, 31]; linkage with a cancer registry[13, 26–28, 30, 32]; or both [23–25, 29]. Some studies also had an additional linkage with adeath registry [13, 14, 23–25, 28–30, 32]. Each colon cancer case was further classified bytumor site: tumors from the cecum to the splenic flexure were considered to be proximalcolon cancers, and tumors in the descending and sigmoid colon were defined as distal coloncancers. The follow-up rate of studies included in this report has generally been over 90%.

We excluded individuals who had a history of cancer other than nonmelanoma skin cancerat baseline and those who reported implausible energy intakes (beyond 3 standard deviationsfrom the study-specific loge-transformed mean energy intake).

Statistical analysisData analyses were conducted using a two-stage method: (1) study- and sex-specificanalyses and (2) subsequent pooled analysis of the study-specific results. Study- and sex-specific relative risks (RR) and two-sided 95% confidence intervals (CI) were estimatedwith the Cox proportional hazards model [44] using SAS PROC PHREG [45]. TheCanadian National Breast Screening Study and the Netherlands Cohort Study were analyzedas case-cohort studies [46]. Age at baseline (in years) and the year the baseline questionnairewas returned were used as stratification variables, thereby creating a time metric whichsimultaneously accounted for age, calendar time, and time since entry into the study. Person-years of follow-up time were calculated from the date of the baseline questionnaire until thedate of colon cancer diagnosis, death, loss to follow-up, if applicable, or end of follow-up,whichever came first.

Two different categorical analyses were conducted for each vitamin: RRs of colon cancerwere estimated according to study-specific quintiles of intake and in separate analysesaccording to absolute intake cutpoints, which were identical across studies. Study- and sex-specific quintiles of vitamin intake were defined using the distributions of the baselinecohort in each study except for the Canadian National Breast Screening Study and theNetherlands Cohort Study where the distributions in the subcohorts were used. We excludedthe Alpha-Tocopherol Beta-Carotene Cancer Prevention Study and the Netherlands CohortStudy from the quintile analyses of total vitamin intake because their prevalence ofmultivitamin use was much lower (≤8%) than in the other studies (>30%), which resulted intheir intake levels for the highest categories not being comparable to those in the otherstudies. However, we included the Alpha-Tocopherol Beta-Carotene Cancer PreventionStudy and the Netherlands Cohort Study in the categorical analyses in which identicalabsolute intake cutpoints were applied. The test for trend across categories of intake wasperformed by assigning participants the median value of their category and entering it as acontinuous term in a regression model.

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In multivariate analyses, we adjusted for height, body mass index, education, physicalactivity, smoking, alcohol consumption, family history of colorectal cancer, use ofnonsteroidal anti-inflammatory drugs, use of oral contraceptives and postmenopausalhormone therapy use among women, and intakes of red meat, total milk, dietary folate, andtotal energy; multivitamin use was also adjusted for in analyses of dietary vitamin intake. Insome multivariate models, further adjustment was made for intake of total folate or totalvitamin C or E (see footnotes in the tables for the covariates in the specific models and forcoding of the covariates). In the multivariate analyses, the proportion of missing values foreach covariate measured in a study was generally less than 5%; an indicator variable formissing responses was created for each covariate in a study, if needed [47, 48].

The pooled estimates and 95% CIs were calculated using a random effects model whichweighted the study-specific loge RRs by the inverse of the sum of their variance and theestimated between-studies variance; between-studies heterogeneity was tested by the Qstatistic [49, 50]. A meta-regression model was used to test for effect modification by sex,study population, smoking status, and postmenopausal hormone therapy use in womenbecause these interactions could only be assessed between studies (sex and studypopulation) or because the potential effect modifier was a nominal variable with three levels(smoking status and postmenopausal hormone therapy use in women) [47]. We examinedwhether the associations for vitamin intakes differed by body mass index and alcoholconsumption by including a cross-product term of the ordinal score of the level of eachfactor and intake of each vitamin expressed as a continuous variable in the model [50]. Wetested for differences in the results between proximal and distal colon cancers using acontrast test [51].

ResultsDuring follow-up of 209,263 men and 466,878 women (Total = 676,141) for up to seven totwenty years in thirteen cohort studies, we identified 5,454 incident colon cancer cases(1,695 cases in men and 3,759 cases in women; 2,850 proximal colon cancer cases, 2,151distal colon cancer cases, and 453 colon cancer cases with unknown site information).Median dietary intakes (intake from food only) for each vitamin showed 2–4 folddifferences across studies (Table 1). The wide range in dietary intakes across studies reflectsboth the differences in the FFQs used in the studies and the differences in true intake acrossthe populations. The prevalence of multivitamin supplement use was higher for the studiesfrom the United States (30–50%) compared with those from Europe (3–8%). The mostcommonly used individual vitamin supplements were vitamin C supplements (prevalence =6–38% across studies). In the aggregated dataset of the ten studies (n = 608,348) withinformation on use of both multivitamins and individual vitamin supplements, theprevalence of vitamin supplement use was 0.5% for vitamin A supplements only, 1% forvitamin E supplements only, 4% for vitamin C supplements only, 4% for any combinationof individual vitamin A, C, and E supplements without multivitamins, 14% formultivitamins only, and 17% for multivitamins with any combination of individual vitaminA, C, and E supplements. The prevalence of vitamin supplements use in the US-basedcohort studies included in this pooled analysis was similar to that of the US population [52].

In the age-adjusted model, dietary vitamin A intake was inversely associated with risk ofcolon cancer (pooled RR = 0.86, 95% CI: 0.79–0.94 for comparison of the highest quintileversus the lowest, p-value, test for trend = 0.01, Table 2); however, after adjusting for othercolon cancer risk factors, the association was attenuated and no longer statisticallysignificant (pooled multivariate RR = 0.92, 95% CI: 0.81–1.05 for comparison of the highestquintile vs. the lowest, p-value, test for trend = 0.17). This attenuation in the RR was largelydue to control of confounding by dietary folate intake (pooled RR from the model adjusting

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for age and dietary folate only = 0.92, 95% CI: 0.80–1.05 for comparison of the highestquintile versus the lowest). Dietary vitamin C and E intakes were not associated with risk ofcolon cancer in either the age-adjusted or multivariate models when modeled as quintiles.When more extreme categories of dietary vitamin intake were examined, we observedsimilar results. Comparing the highest versus the lowest decile of intake, the pooledmultivariate RR was 0.89 (95% CI: 0.73–1.09) for dietary vitamin A, 0.99 (95% CI: 0.84–1.18) for dietary vitamin C, and 1.01 (95% CI: 0.89–1.15) for dietary vitamin E. For eachvitamin, there was no significant between-studies heterogeneity and no effect modificationby sex in the multivariate models. When we examined the associations between dietaryintakes of vitamins A, C, and E and colon cancer risk in the studies that collectedmultivitamin and/or individual vitamin A, C or E supplement use data, we observed similarresults (data not shown). In addition, when the associations were examined in onlyindividuals who did not use multivitamins, the results for dietary intake of each vitaminwere similar to those reported in Table 2 (data not shown).

Total intakes of vitamins A, C, and E (sum of intakes from food, multivitamins andindividual vitamin supplements) were associated with 24–30% lower risks of colon cancerfor comparisons of the highest quintile versus the lowest in age-adjusted models (Table 2).After adjusting for other colon cancer risk factors, the inverse associations for total intakesof vitamins A, C, and E were attenuated slightly, but remained statistically significant. Whenwe adjusted for total folate intake, the associations were further attenuated. Comparing thehighest versus the lowest quintile of intake, the pooled multivariate RR was 0.81 (95% CI:0.71–0.94, p-value, test for trend = 0.07) for total vitamin A, 0.84 (95% CI: 0.74–0.95, p-value, test for trend = 0.004) for total vitamin C, and 0.83 (95% CI: 0.73–0.94, p-value, testfor trend = 0.04) for total vitamin E. When the associations were examined by age atdiagnosis (≤65 vs. >65 years old), total vitamin A intake showed a marginally significantdifference (p-value test for difference = 0.05), but total intakes of vitamins C and E did notshow a significant difference (data not shown). In addition, the associations were notmodified by body mass index, smoking habits, alcohol consumption, or postmenopausalhormone therapy use in women (data not shown). When we examined the associations bydifferent periods of follow-up time, we observed stronger associations between total vitaminA, C, and E intake and risk of colon cancer during the first five years of follow-up thanthose observed after a 5-year lag. When follow-up time was limited to the first five years,the pooled multivariate RRs comparing the highest versus the lowest quintile of intake were0.70 (95% CI: 0.59–0.84) for total vitamin A, 0.77 (95% CI: 0.65–0.92) for total vitamin C,and 0.73 (95% CI: 0.58–0.93) for total vitamin E. After a 5-year lag, the pooled multivariateRRs for the same comparisons were 0.84 (95% CI: 0.72–0.98) for total vitamin A, 0.84(95% CI: 0.72–0.98) for total vitamin C and 0.90 (95% CI: 0.78–1.04) for total vitamin E.The associations for total vitamin A and C intake did not differ significantly (p > 0.15) byfollow-up time, but the test for total vitamin E intake was of borderline significance (p =0.05).

A major source of intake of vitamins was multivitamin supplements, many of which containfolate. Because total folate intake was also significantly inversely associated with risk ofcolon cancer in this study population (pooled multivariate RR = 0.85, 95% CI: 0.77–0.95 forcomparison of the highest quintile of total folate intake versus the lowest; [60]), weperformed categorical analyses using identical absolute intake cutpoints across studies toseparate the effect of total vitamin A, C, and E intake on risk of colon cancer from that oftotal folate intake (Table 3). We chose cutpoints to differentiate nonusers of multivitamins,users of multivitamins only, and users of individual vitamin supplements (regardless ofwhether they also used multivitamins). In these analyses, for each vitamin, the prevalence ofsupplement use in the aggregated dataset for the reference category was ≤5% formultivitamins and ≤0.1% for the corresponding individual vitamin supplements; in the

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highest category, the prevalence was >70% for multivitamins in the analysis of each vitaminand 45% for vitamin A supplements, 94% for vitamin C supplements, and 100% for vitaminE supplements in the analyses for each corresponding vitamin. In the multivariate model,which adjusted for dietary folate intake and other risk factors for colon cancer (multivariatemodel 1), we found statistically significant inverse associations between total intakes ofvitamins C and E and risk of colon cancer. The median correlation coefficient betweenintakes of each vitamin and total folate across studies was 0.56 for total vitamin C, and 0.51for total vitamin E. When we adjusted for total folate intake rather than dietary folate intakes(multivariate model 2), we observed that total intakes of vitamin C and E retainedstatistically significant inverse associations with risk of colon cancer. Total vitamin A intakewas not significantly associated with risk of colon cancer in either of the multivariatemodels. Mutual adjustment for total intakes of vitamins C and E (multivariate model 3) alsoattenuated the association for each vitamin (median correlation coefficient between intakesof vitamins C and E = 0.57). When we examined the association between supplementalintakes of vitamins A, C, and E and risk of colon cancer, we observed results similar tothose for total intakes of each vitamin (data not shown).

The joint effect of total intakes of vitamins C and E on risk of colon cancer was alsoexamined. Compared to the group with intakes of ≤200 mg/day vitamin C and ≤25 mg/dayvitamin E (low intakes for both vitamins), the group with intakes of >600 mg/day of vitaminC and >200 mg/day of vitamin E (high intakes for both vitamins) had a significantly lowerrisk of colon cancer (pooled multivariate RR = 0.84, 95% CI: 0.72–0.98). The pooledmultivariate RR was 1.09 (95% CI: 0.87–1.36) for the group with low vitamin C but highvitamin E intake (≤200 mg/day vitamin C and >200 mg/day vitamin E) and 0.88 (95% CI:0.75–1.04) for the group with high vitamin C but low vitamin E intake (>600 mg/dayvitamin C and ≤25 mg/day vitamin E).

We also examined the associations between vitamin intakes and risk of colon cancer bytumor site (Table 4). The associations with dietary vitamin A, C, and E intake did not differby tumor site in the multivariate models (p-value, test for common effects by tumor site forquintile 5 ≥ 0.45, data not shown). For total vitamin A, C, and E intakes, the associationswere slightly stronger in the distal colon than the proximal colon, but the differences werenot statistically significant (p-value, test for common effects by tumor site for the highestcategory ≥0.34).

Because multivitamin supplements were an important source of supplemental vitaminintake, we analyzed the relation of multivitamin use to risk of colon cancer (Fig. 1). Wefound that multivitamin use was associated with a significantly lower risk of colon cancer;the pooled age-adjusted RR was 0.84 (95% CI: 0.77–0.92; p-value test for between-studiesheterogeneity = 0.12) and the pooled multivariate RR was 0.88 (95% CI: 0.81–0.96; p-valuetest for between-studies heterogeneity = 0.17) comparing users versus nonusers. Theassociation was not modified by sex, age at diagnosis, or alcohol intake (data not shown).The association also did not differ significantly by tumor site (p-value, test for commoneffects by tumor site = 0.50); the pooled multivariate RRs were 0.86 (95% CI: 0.78–0.94, p-value, test for between-studies heterogeneity = 0.45) for proximal colon cancers and 0.91(95% CI: 0.80–1.02, p-value, test for between-studies heterogeneity = 0.34) for distal coloncancers comparing users versus nonusers. When we examined the association betweenmultivitamin use and risk of colon cancer by different periods of follow-up time, the pooledmultivariate RRs were 0.85 (95% CI: 0.75–0.97) when follow-up time was limited to thefirst five years and 0.91 (95% CI: 0.83–1.00) after a 5-year lag (p-value, test for differenceby follow-up period = 0.41).

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We also examined the association between use of multivitamins and individual vitaminsupplements and risk of colon cancer by mutually adjusting for combinations of vitaminsupplement use. Compared to nonusers of supplements, the pooled multivariate RRs ofcolon cancer were 0.92 (95% CI: 0.82–1.04) for users of multivitamins only; and 0.77 (95%CI: 0.70–0.85) for those who used any combination of vitamin A, C and E supplements andused multivitamins. There was no statistically significant between-studies heterogeneity forthese comparisons.

DiscussionWe found no association between dietary intakes of vitamins A, C, and E and risk of coloncancer in this pooled analysis of thirteen prospective cohort studies. However, total intakesof vitamins A, C, and E were each inversely associated with risk of colon cancer. Afteradjusting for total folate intake, the inverse association between total vitamin A intake andrisk of colon cancer in the categorical analysis was attenuated and no longer statisticallysignificant, whereas the inverse associations between total intakes of vitamins C and E andrisk of colon cancer were slightly weakened but remained statistically significant.Multivitamin use, particularly in combination with use of individual vitamin A, C and/or Esupplements, was inversely associated with risk of colon cancer.

Because multivitamin supplements containing folate were one of the main sources of totalvitamin intakes, total vitamin A, C, and E intakes were positively correlated with total folateintake. However, total vitamin A intake was more highly correlated with total folate intakethan total vitamin C and E intakes. Therefore, the different degree of attenuation in the RRsfor total intakes of vitamins A, C, and E may be due to differences in the correlationsbetween total intake of each vitamin and total folate. The inverse association observed fortotal vitamin A intake in the age-adjusted analysis may be partially due to folate and othernutrients in multivitamins.

Plausible biologic mechanisms support our results, which suggest that total vitamin C and Eintakes may be associated with a decreased risk of colon cancer independently of total folateintake. Vitamin C as an electron donor reduces reactive radicals and iron. Vitamin E (α-tocopherol), which acts as an antioxidant, breaks free radical chain reactions by transferringa phenolic hydrogen to a free radical leaving a less reactive α-tocopheroxy radical. The α-tocopheroxy radical then may react with vitamin C to regenerate α-tocopherol [53]. In thisprocess, vitamin C acts as an electron donor to spare vitamin E. Thus, vitamins C and E mayact jointly to have a beneficial effect on risk of colon cancer.

We observed that the associations between total vitamin C and E intake and risk of coloncancer were stronger in the distal colon than in the proximal colon although the differenceswere not statistically significant. The different strength of the associations may be partiallydue to physiologic differences between the proximal and distal colon. The proximal colonplays a major role in fermentation of undigested substances such as dietary fiber, whereasthe distal colon is more involved in water absorption and electrolyte transport [54]. It hasalso been suggested that tumors in the proximal and distal colon might follow differentmolecular carcinogenic pathways [54].

Multivitamin use was associated with a significantly lower risk of colon cancer in our study.One may argue that multivitamin users may be more health conscious and have a healthierlifestyle than nonusers, which may confound the association observed between multivitaminuse and risk of colon cancer. In our analysis, we adjusted for several colon cancer riskfactors including lifestyle and other dietary factors and observed no substantial confoundingby these factors. However, in most studies included in these analyses, information on

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colorectal cancer screening practices and nonsteroidal anti-inflammatory drug use waslacking, thus incomplete adjustment for healthy behaviors which may be related tosupplement use may result in our observed associations being confounded.

In contrast to our findings, randomized clinical trials have failed to confirm beneficialeffects of antioxidant vitamins on colorectal adenomas or cancer [16, 55]. However, theresults of trials do not provide conclusive evidence against the protective effect ofantioxidant vitamins because of alternative explanations related to the trials. The duration ofthe available trials has been relatively short, mostly 4–7 years, which may not be sufficientlylong enough to observe preventive effects. In addition, some trials used small adenomas asan endpoint. If antioxidant vitamins play a role during the progression of small to advancedadenomas or the progression of advanced adenomas to invasive cancer, but not in thedevelopment of adenomas, the beneficial effects of vitamins would not be detected in thosetrials.

We observed stronger associations with vitamins and multivitamin use during the first 5years of follow-up than those observed after a 5-year lag. Because most studies did notreassess diet during the follow-up, the different strength of the associations observed duringdifferent follow-up periods may partially be due to increasing misclassification of vitaminintakes over time. In the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study trial,compared to the nonvitamin E supplementation group, the vitamin E supplementation grouphad a modestly lowered risk of colorectal cancer during the approximately 6 years of thetrial (RR = 0.78, 95% CI: 0.55–1.09). However, this suggestive inverse associationdisappeared during the post-trial follow-up period (RR = 1.02, 95% CI: 0.70–1.47, 3–6 yearsafter the end of the trial) [56]. The stronger associations observed during the first 5 years offollow-up rather than after a 5-year lag also suggest that vitamin intakes may not have long-term effects on colon cancer risk. However, other studies have reported that past, but notrecent, long-term multivitamin supplement use was associated with a lower risk of colorectalcancer [19, 20].

In our study, information on duration and past use of vitamin supplements at baseline wasnot available from most studies. This may induce misclassification of intakes of totalvitamins A, C, and E because the reference group may include former vitamin supplementusers whose usual intakes of vitamins A, C, and E may have been higher than that measuredat baseline. Also, we could not examine the effect of duration of vitamin supplement use ashas been done in some studies that found the beneficial effect of vitamin supplement use oncolon cancer among only those individuals who had used vitamin supplements for a longduration [57, 58]. Selenium, which is another nutrient important in the antioxidant systemsuggested to have a protective effect on colon cancer risk [59], was not investigated in ourstudy due to a lack of reliable food composition data for selenium.

Our study had several strengths. This study included over 5,000 colon cancer cases fromthirteen studies of diverse populations, which provided a wide range of vitamin intakes andprevalence of vitamin supplement use. Moreover, as opposed to meta-analyses of thepublished literature, we were able to examine dose–response relationships in detail byreanalyzing the primary data from each study and we were able to adjust for other coloncancer risk factors by standardizing the format of the covariates across studies. In addition,due to the large sample size, we could examine whether associations with specific vitaminintakes and vitamin supplement use were modified by various factors.

In conclusion, we found null associations for dietary vitamin A, C, and E intakes and totalvitamin A intake and inverse associations for total vitamin C and E intake and multivitaminuse. These associations were generally consistent across studies, between men and women,

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and across subsites of the colon. Separating the effect of each vitamin from the effect ofmultivitamins containing folate and other vitamins which may protect against colon cancerwas challenging. Although we made an effort to separate the effect of each vitaminindependent from that of multivitamins in the categorical analyses and in analyses ofvitamin supplement use, moderate to high correlations among these vitamins made itdifficult to separate completely the effect of each vitamin on risk of colon cancer. Asreported in our accompanying article [60], high folate intake, mostly from multivitaminsupplements, was associated with a lower risk of colon cancer. Because modest inverseassociations with vitamins C and E and multivitamin use were similar to that with folate, wecannot rule out the possibility that the apparent protective effects of total vitamin C and Eintakes and of multivitamin supplement use against colon cancer were due to their positivecorrelations with total folate intake or intakes of other vitamins present in multivitaminssuch as vitamin B6.

AcknowledgmentsFinancial support The study was funded by research grants CA55075 from the National Institutes of Health andthe National Colorectal Cancer Research Alliance of the Entertainment Industry Foundation.

References1. Platz EA, Willett WC, Colditz GA, Rimm EB, Spiegelman D, Giovannucci E. Proportion of colon

cancer risk that might be preventable in a cohort of middle-aged US men. Cancer Causes Control.2000; 11:579–588. [PubMed: 10977102]

2. Niles RM. Vitamin A and cancer. Nutrition. 2000; 16:573–576. [PubMed: 10906560]3. Semba RD. Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc.

1999; 58:719–727. [PubMed: 10604208]4. Padayatty SJ, Katz A, Wang Y, et al. Vitamin C as an antioxidant: evaluation of its role in disease

prevention. J Am Coll Nutr. 2003; 22:18–35. [PubMed: 12569111]5. Packer L. Protective role of vitamin E in biological systems. Am J Clin Nutr. 1991; 53:1050S–

1055S. [PubMed: 2012017]6. Kline K, Yu W, Sanders BG. Vitamin E: mechanisms of action as tumor cell growth inhibitors. J

Nutr. 2001; 131:161S–163S. [PubMed: 11208955]7. Potter JD, McMichael AJ. Diet and cancer of the colon and rectum: a case–control study. J Natl

Cancer Inst. 1986; 76:557–569. [PubMed: 3007842]8. Slattery ML, Edwards SL, Anderson K, Caan B. Vitamin E and colon cancer: is there an

association? Nutr Cancer. 1998; 30:201–206. [PubMed: 9631491]9. La Vecchia C, Braga C, Negri E, et al. Intake of selected micronutrients and risk of colorectal

cancer. Int J Cancer. 1997; 73:525–530. [PubMed: 9389567]10. Chiu BC, Ji BT, Dai Q, et al. Dietary factors and risk of colon cancer in Shanghai, China. Cancer

Epidemiol Biomarkers Prev. 2003; 12:201–208. [PubMed: 12646508]11. Levi F, Pasche C, Lucchini F, La Vecchia C. Selected micronutrients and colorectal cancer. A

case–control study from the canton of Vaud, Switzerland. Eur J Cancer. 2000; 36:2115–2119.[PubMed: 11044650]

12. Shibata A, Paganini-Hill A, Ross RK, Henderson BE. Intake of vegetables, fruits, beta-carotene,vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study.Br J Cancer. 1992; 66:673–679. [PubMed: 1419605]

13. Bostick RM, Potter JD, McKenzie DR, et al. Reduced risk of colon cancer with high intake ofvitamin E: the Iowa Women’s Health Study. Cancer Res. 1993; 53:4230–4237. [PubMed:8364919]

14. Wu K, Willett WC, Chan JM, et al. A prospective study on supplemental vitamin e intake and riskof colon cancer in women and men. Cancer Epidemiol Biomarkers Prev. 2002; 11:1298–1304.[PubMed: 12433706]

Park et al.


NIH


NIH


NIH


15. Longnecker MP, Martin-Moreno JM, Knekt P, et al. Serum alpha-tocopherol concentration inrelation to subsequent colorectal cancer: pooled data from five cohorts. J Natl Cancer Inst. 1992;84:430–435. [PubMed: 1531683]

16. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Anti-oxidant supplements for prevention ofgastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004; 364:1219–1228.[PubMed: 15464182]

17. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovasculardisease and cancer: the Women’s Health Study: a randomized controlled trial. Jama. 2005;294:56–65. [PubMed: 15998891]

18. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascularevents and cancer: a randomized controlled trial. Jama. 2005; 293:1338–1347. [PubMed:15769967]

19. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer inwomen in the Nurses’ Health Study. Ann Intern Med. 1998; 129:517–524. [PubMed: 9758570]

20. Jacobs EJ, Connell CJ, Chao A, et al. Multivitamin use and colorectal cancer incidence in a UScohort: does timing matter? Am J Epidemiol. 2003; 158:621–628. [PubMed: 14507597]

21. Zhang SM, Moore SC, Lin J, et al. Folate, vitamin B6, multivitamin supplements, and colorectalcancer risk in women. Am J Epidemiol. 2006; 163:108–115. [PubMed: 16339055]

22. Smith-Warner SA, Spiegelman D, Ritz J, et al. Methods for pooling results of epidemiologicstudies: the pooling project of prospective studies of diet and cancer. Am J Epidemiol. 2006;163:1053–1064. [PubMed: 16624970]

23. Malila N, Virtamo J, Virtanen M, Pietinen P, Albanes D, Teppo L. Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers. Eur J ClinNutr. 2002; 56:615–621. [PubMed: 12080400]

24. Jacobs EJ, Connell CJ, Patel AV, et al. Vitamin C and vitamin E supplement use and colorectalcancer mortality in a large American Cancer Society cohort. Cancer Epidemiol Biomarkers Prev.2001; 10:17–23. [PubMed: 11205484]

25. Mai V, Flood A, Peters U, Lacey JV Jr, Schairer C, Schatzkin A. Dietary fibre and risk ofcolorectal cancer in the Breast Cancer Detection Demonstration Project (BCDDP) follow-upcohort. Int J Epidemiol. 2003; 32:234–239. [PubMed: 12714542]

26. Terry P, Jain M, Miller AB, Howe GR, Rohan TE. Dietary intake of folic acid and colorectalcancer risk in a cohort of women. Int J Cancer. 2002; 97:864–867. [PubMed: 11857369]

27. Verhoeven DTH, Assen N, Goldbohm RA, et al. Vitamins C and E, retinol, beta-carotene anddietary fibre in relation to breast cancer risk: a prospective cohort study. Br J Cancer. 1997;75:149–155. [PubMed: 9000614]

28. Bandera EV, Freudenheim JL, Marshall JR, et al. Diet and alcohol consumption and lung cancerrisk in the New York State Cohort (United States). Cancer Causes Control. 1997; 8:828–840.[PubMed: 9427425]

29. Kato I, Akhmedkhanov A, Koenig K, Toniolo PG, Shore RE, Riboli E. Prospective study of dietand female colorectal cancer: the New York University Women’s Health Study. Nutr Cancer.1997; 28:276–281. [PubMed: 9343837]

30. Terry P, Giovannucci E, Michels KB, et al. Fruit, vegetables, dietary fiber, and risk of colorectalcancer. J Natl Cancer Inst. 2001; 93:525–533. [PubMed: 11287446]

31. Higginbotham S, Zhang ZF, Lee IM, et al. Dietary glycemic load and risk of colorectal cancer inthe Women’s Health Study. J Natl Cancer Inst. 2004; 96:229–233. [PubMed: 14759990]

32. Sieri S, Krogh V, Muti P, et al. Fat and protein intake and subsequent breast cancer risk inpostmenopausal women. Nutr Cancer. 2002; 42:10–17. [PubMed: 12235640]

33. Rothman, KJ.; Greenland, S. Modern epidemiology. Lippincott Williams & Wilkins; Philadelphia:1998.

34. Goldbohm RA, van den Brandt PA, Brants HAM, et al. Validation of a dietary questionnaire usedin a large-scale prospective cohort study on diet and cancer. Eur J Clin Nutr. 1994; 48:253–265.[PubMed: 8039485]

35. Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am JEpidemiol. 1986; 124:17–27. [PubMed: 3521261]

Park et al.


NIH


NIH


NIH


36. Jain M, Howe GR, Rohan T. Dietary assessment in epidemiology: comparison of a food frequencyand a dietary history questionnaire witih a 7-day food record. Am J Epidemiol. 1996; 143:953–960. [PubMed: 8610709]

37. Pietinen P, Hartman AM, Haapa E, et al. Reproducibility and validity of dietary assessmentinstruments II. A qualitative food-frequency questionnaire. Am J Epidemiol. 1988; 128:667–676.[PubMed: 2843041]

38. Flagg EW, Coates RJ, Calle EE, Potischman N, Thun MJ. Validation of the American CancerSociety Cancer Prevention Study II Nutrition Survey Cohort food frequency questionnaire.Epidemiology. 2000; 11:462–468. [PubMed: 10874556]

39. Munger RG, Folsom AR, Kushi LH, Kaye SA, Sellers TA. Dietary assessment of older Iowawomen with a food frequency questionnaire: nutrient intake, reproducibility, and comparison with24-hour dietary recall interviews. Am J Epidemiol. 1992; 136:192–200. [PubMed: 1415141]

40. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC. Reproducibility andvalidity of an expanded self-administered semiquantitative food frequency questionnaire amongmale health professionals. Am J Epidemiol. 1992; 135:1114–1126. [PubMed: 1632423]

41. Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitativefood frequency questionnaire. Am J Epidemiol. 1985; 122:51–65. [PubMed: 4014201]

42. Willett, W. Nutritional epidemiology. Oxford University Press; New York: 1998.43. Ascherio A, Stampfer MJ, Colditz GA, Rimm EB, Litin L, Willett WC. Correlations of vitamin A

and E intakes with the plasma concentrations of carotenoids and tocopherols among Americanmen and women. J Nutr. 1992; 122:1792–1801. [PubMed: 1512628]

44. Cox DR. Regression models and life-tables. J R Stat Soc B. 1972; 34(2):187–220.45. SAS II. SAS/STAT user’s guide, version 8. SAS Institute Inc; Cary: 1999.46. Prentice RL. A case-cohort design for epidemiologic cohort studies and disease prevention trials.

Biometrika. 1986; 73:1–11.47. Miettinen, O. Theoretical epidemiology. Oxford University Press; New York: 1985.48. Huberman M, Langholz B. Application of the missing-indicator method in matched case–control

studies with incomplete data. Am J Epidemiol. 1999; 150:1340–1345. [PubMed: 10604777]49. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177–188.

[PubMed: 3802833]50. Stram DO. Meta-analysis of published data using a linear mixed-effects model. Biometrics. 1996;

52:536–544. [PubMed: 8672702]51. Anderson, T. Introduction to multivariate statistics. Wiley; New York: 1984.52. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use

by US adults: data from the National Health and Nutrition Examination Survey, 1999–2000. Am JEpidemiol. 2004; 160:339–349. [PubMed: 15286019]

53. Murray, RK.; Granner, GD.; Mayes, PA.; Rodwell, VW. Harper’s biochemistry. McGraw-Hill;New York: 2000.

54. Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer. 2002; 101:403–408. [PubMed:12216066]

55. Davies AA, Davey Smith G, Harbord R, et al. Nutritional interventions and outcome in patientswith cancer or preinvasive lesions: systematic review. J Natl Cancer Inst. 2006; 98:961–973.[PubMed: 16849679]

56. Virtamo J, Pietinen P, Huttunen JK, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. Jama. 2003;290:476–485. [PubMed: 12876090]

57. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate and colon cancer inwomen in the nurses’ health study. Ann Intern Med. 1998; 129:517–524. [PubMed: 9758570]

58. Jacobs EJ, Connell CJ, Patel AV, et al. Multivitamin use and colon cancer mortality in the CancerPrevention Study II cohort (United States). Cancer Causes Control. 2001; 12:927–934. [PubMed:11808712]

59. Dumas L. Lung cancer in women: rising epidemic, preventable disease. Nurs Clin North Am.1992; 27:859–869. [PubMed: 1448361]

Park et al.


NIH


NIH


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60. Kim, D-H.; Smith-Warner, SA.; Spiegelman, D.; Yaun, S-S.; Colditz, GA.; Freudenheim, JL.;Giovannucci, E.; Goldbohm, RA.; Graham, S.; Harnack, L.; Jacobs, EJ.; Leitzmann, M.;Mannisto, S.; Miller, AB.; Potter, JD.; Rohan, TE.; Schatzkin, A.; Speizer, FE.; Stevens, VL.;Stolzenberg-Solomon, R.; Terry, P.; Toniolo, P.; Weijenberg, MP.; Willett, WC.; Wolk, A.;Zeleniuch-Jacquotte, A.; Hunter, DJ. Pooled analyses of 13 prospective cohort studies on folateintake and colon cancer. 2010.

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Fig. 1.Study-specific and pooled multivariate RRs (adjusted for covariates listed in Table 2 legendc) of colon cancer in multivitamin users versus nonusers. The squares and horizontal linescorrespond to the study-specific multivariate RR and 95% CIs, respectively. The size of asquare reflects the study-specific weight (inverse of the variance), and the diamondrepresents the pooled multivariate RR and 95% CI. The vertical dotted line represents thepooled RR. The abbreviations of the studies are the same as in Table 1

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Park et al.

Tabl

e 1

Des

crip

tion

of st

udie

s in

the

anal

yses

of i

ntak

es o

f vita

min

s A, C

, and

E a

nd u

se o

f vita

min

supp

lem

ents

and

col

on c

ance

r in

the

Pool

ing

Proj

ect

Stud

yFo

llow

-up

peri

odB

asel

ine

coho

rtc (

n)C

ance

r ca

ses (

n)D

ieta

ry in

take

aT

otal

inta

keb

Prev

alen

ce o

f sup

plem

ent u

se

Vita

min

A (μ

g/da

y)V

itam

in C

(mg/

day)

Vita

min

E (m

g/da

y)V

itam

in A

(μg/

day)

Vita

min

C (m

g/da

y)V

itam

in E

(mg/

day)

Mul

tivita

min

s (%

)V

itam

in A

(%)

Vita

min

C (%

)V

itam

in E

(%)

Men

A

lpha

-Toc

ophe

rol B

eta-

Car

oten

eC

ance

r Pre

vent

ion

Stud

y (A

TBC

)d19

85–1

999

6,78

444

1,24

3 (7

12–2

,382

)e73

(43–

122)

8 (6

–15)

1,31

9 (7

30–2

,730

)76

(44–

156)

8 (6

–17)

8–

––

C

ance

r Pre

vent

ion

Stud

y II

Nut

ritio

n C

ohor

t (C

PS II

)19

92–1

999

66,0

7146

71,

325

(798

–2,1

04)

128

(58–

220)

11 (8

–14)

1,60

6 (8

70–3

,344

)16

6 (6

8–72

2)13

(8–2

51)

335

2417

H

ealth

Pro

fess

iona

ls F

ollo

w-u

pSt

udy

(HPF

S)19

86–2

000

47,7

6645

61,

555

(874

–3,0

04)

160

(82–

276)

8 (5

–11)

2,05

3 (9

72–4

,919

)23

5 (1

00–1

,165

)10

(6–4

13)

439

3821

N

ethe

rland

s Coh

ort S

tudy

(NLC

S)19

86–1

993

58,2

7939

393

7 (6

61–1

,416

)90

(53–

148)

13 (8

–22)

950

(668

–1,4

51)

94 (5

3–15

4)14

(8–2

3)3

26

2

N

ew Y

ork

Stat

e C

ohor

t (N

YSC

)19

80–1

987

30,3

6333

51,

650

(884

–3,7

14)

197

(107

–321

)7

(5–1

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167

(988

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86)

240

(121

–769

)10

(5–3

11)

387

2419

Wom

en

B

reas

t Can

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Dem

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ratio

n Pr

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t Fol

low

-up

Coh

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BC

DD

P)

1987

–199

841

,987

349

1,27

0 (7

35–2

,205

)14

8 (6

4–27

3)9

(6–1

6)1,

613

(803

–3,4

22)

194

(78–

845)

13 (7

–278

)33

320

15

C

anad

ian

Nat

iona

l Bre

ast

Scre

enin

g St

udy

(CN

BSS

)19

80–2

000

49,6

5443

11,

016

(613

–1,7

39)

131

(66–

215)

16 (1

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––

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––

C

ance

r Pre

vent

ion

Stud

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Nut

ritio

n C

ohor

t (C

PS II

)19

92–1

999

74,0

4634

91,

099

(683

–1,7

05)

128

(58–

220)

9 (6

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1,45

9 (7

62–3

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2–75

9)19

(7–2

88)

426

2823

Io

wa

Wom

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Hea

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tudy

(IW

HS)

1986

–200

134

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799

1,47

9 (7

40–2

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)13

2 (7

1–21

7)8

(6–1

1)1,

883

(820

–4,0

64)

177

(83–

672)

10 (7

–232

)33

829

15

N

ethe

rland

s Coh

ort S

tudy

(NLC

S)19

86–1

993

62,5

7335

381

4 (5

61–1

,282

)10

1 (5

9–16

1)11

(7–1

7)83

4 (5

69 –

1,32

7)10

6 (6

2–16

7)11

(7–1

8)6

47

2

N

ew Y

ork

Stat

e C

ohor

t (N

YSC

)19

80–1

987

22,5

5022

31,

586

(833

–3,5

00)

182

(99–

295)

7 (4

–10)

2,27

5 (9

87–5

,423

)23

7 (1

19–7

69)

11 (5

–312

)49

930

22

N

ew Y

ork

Uni

vers

ity W

omen

’sH

ealth

Stu

dy (N

YU

WH

S)19

85–1

998

13,2

5896

1,12

2 (6

41–2

,024

)16

4 (8

1–27

8)8

(6–1

1)2,

031

(780

–3,5

07)

249

(108

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94)

17 (7

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)50

737

27

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88,6

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120

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209)

4 (3

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7 (8

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size

s do

not r

efle

ct th

e ab

ove

excl

usio

ns

d Plac

ebo

grou

p on

ly

e Cal

orie

-adj

uste

d m

edia

n (1

0th–

90th

per

cent

ile) i

ntak

e am

ong

base

line

coho

rt or

subc

ohor

t for

the

Can

adia

n N

atio

nal B

reas

t Scr

eeni

ng S

tudy

and

the

Net

herla

nds C

ohor

t Stu

dy

f Thes

e w

omen

are

a su

bset

of t

he w

omen

incl

uded

in N

urse

s’ H

ealth

Stu

dy (a

) and

are

not

incl

uded

in th

e to

tal b

asel

ine

coho

rt si

ze


NIH


NIH


NIH


Park et al.

Tabl

e 2

Pool

ed re

lativ

e ris

ks o

f col

on c

ance

r for

qui

ntile

s of d

ieta

ry a

nd to

tal v

itam

in A

, C, a

nd E

inta

kes

Qui

ntile

1Q

uint

ile 2

Qui

ntile

3Q

uint

ile 4

Qui

ntile

5p-

valu

e, te

st fo

rtr

end

p-va

lue,

test

for

betw

een-

stud

ies h

eter

ogen

eity

a

p-va

lue,

test

for

betw

een-

stud

ies h

eter

ogen

eity

due

tose

xa

Die

tary

inta

ke

Vita

min

A

A

ge-a

djus

ted

1.00

0.98

(0.9

0–1.

06)

0.93

(0.8

5–1.

01)

0.84

(0.7

7–0.

92)

0.86

(0.7

9–0.

94)

0.01

0.48

0.68

M

ultiv

aria

teb

1.00

1.01

(0.9

2–1.

11)

1.00

(0.9

1–1.

09)

0.91

(0.8

1–1.

02)

0.92

(0.8

1–1.

05)

0.17

0.13

0.76

Vita

min

C

A

ge-a

djus

ted

1.00

0.95

(0.8

7–1.

04)

0.85

(0.7

8–0.

93)

0.90

(0.8

2–0.

98)

0.95

(0.8

7–1.

03)

0.28

0.55

0.65

M

ultiv

aria

te1.

000.

97 (0

.89–

1.07

)0.

90 (0

.81–

0.99

)0.

98 (0

.88–

1.08

)1.

06 (0

.95–

1.18

)0.

120.

680.

27

Vita

min

E

A

ge-a

djus

ted

1.00

1.01

(0.9

1–1.

12)

0.91

(0.8

2–1.

00)

0.95

(0.8

6–1.

06)

0.95

(0.8

6–1.

05)

0.35

0.14

0.81

M

ultiv

aria

te1.

001.

04 (0

.93–

1.16

)0.

94 (0

.84–

1.04

)1.

00 (0

.89–

1.13

)0.

99 (0

.89–

1.11

)0.

710.

240.

51

Tota

l int

akec

Vita

min

A

A

ge-a

djus

ted

1.00

0.84

(0.7

5–0.

95)

0.80

(0.7

3–0.

89)

0.84

(0.7

4–0.

94)

0.71

(0.6

4–0.

79)

<0.0

010.

540.

25

M

ultiv

aria

ted

1.00

0.89

(0.7

9–0.

99)

0.86

(0.7

7–0.

95)

0.90

(0.8

1–1.

01)

0.78

(0.6

9–0.

87)

0.00

10.

790.

38

Vita

min

C

A

ge-a

djus

ted

1.00

0.88

(0.7

9–0.

97)

0.91

(0.8

2–1.

00)

0.83

(0.7

4–0.

93)

0.73

(0.6

6–0.

81)

<0.0

001

0.87

0.73

M

ultiv

aria

te1.

000.

91 (0

.82–

1.01

)0.

96 (0

.86–

1.07

)0.

89 (0

.79–

0.99

)0.

80 (0

.71–

0.90

)<0

.001

0.95

0.56

Vita

min

E

A

ge-a

djus

ted

1.00

0.93

(0.8

4–1.

02)

0.88

(0.8

0–0.

97)

0.82

(0.7

4–0.

91)

0.76

(0.6

8–0.

85)

0.00

10.

320.

88

M

ultiv

aria

te1.

000.

95 (0

.86–

1.05

)0.

91 (0

.82–

1.01

)0.

88 (0

.79–

0.97

)0.

82 (0

.74–

0.91

)0.

010.

530.

85

a For q

uint

ile 5

b Adj

uste

d fo

r bod

y m

ass i

ndex

(<23

, 23–

<25,

25–

<30,

≥30

kg/

m2 )

, hei

ght (

men

: <1.

70, 1

.70–

<1.7

5, 1

.75–

<1.8

0, 1

.80–

<1.8

5, ≥

1.85

m; w

omen

: <1.

60, 1

.60–

<1.6

5, 1

.65–

<1.7

0, 1

.70–

<1.7

5, ≥

1.75

m),

educ

atio

n (<

high

scho

ol g

radu

ate,

hig

h sc

hool

gra

duat

e, >

high

scho

ol g

radu

ate)

, phy

sica

l act

ivity

(low

, med

ium

, hig

h), f

amily

his

tory

of c

olor

ecta

l can

cer (

no, y

es),

use

of n

onst

eroi

dal a

nti-i

nfla

mm

ator

ydr

ugs (

no, y

es),

mul

tivita

min

use

(no,

yes

<6 ti

mes

/wk,

yes

≥6

times

/wee

k, y

es m

issi

ng d

ose

for B

CD

DP,

HPF

S, IW

HS,

NY

UW

HS,

NH

S a

and

b, a

nd W

HS;

no,

yes

for A

TBC

, CPS

II, N

LCS

and

NY

SC),

smok

ing

(nev

er, p

ast (

<20,

20–

<40,

≥40

yea

rs),

curr

ent (

<25

ciga

rette

s/da

y an

d<40

yea

rs,<

25 c

igar

ette

s/da

y an

d ≥

40 y

ears

, ≥25

cig

aret

tes/

day

and

<40

year

s, ≥

25 c

igar

ette

s/da

y an

d ≥

40 y

ears

), al

coho

lco

nsum

ptio

n (0

, >0–

<5, 5

–<15

, 15–

<30,

≥30

g/d

ay),

inta

kes o

f red

mea

t (qu

intil

es),

tota

l milk

(qua

rtile

s), d

ieta

ry fo

late

(qui

ntile

s) a

nd to

tal e

nerg

y (c

ontin

uous

), an

d us

e of

pos

tmen

opau

sal h

orm

one

ther

apy

(pre

men

opau

sal,

neve

r, ev

er) a

nd o

ral c

ontra

cept

ive

use

(nev

er, e

ver)

in w

omen

. Age

in y

ears

and

yea

r of q

uest

ionn

aire

retu

rn w

ere

incl

uded

as s

tratif

icat

ion

varia

bles


NIH


NIH


NIH


Park et al. c Th

e A

lpha

-Toc

ophe

rol B

eta-

Car

oten

e C

ance

r Pre

vent

ion

Stud

y an

d th

e N

ethe

rland

s Coh

ort S

tudy

wer

e ex

clud

ed fr

om th

ese

anal

yses

bec

ause

the

prev

alen

ce o

f mul

tivita

min

and

vita

min

C a

nd E

supp

lem

ent u

se in

thes

e st

udie

s was

muc

h lo

wer

than

that

in th

e ot

her s

tudi

es w

ith su

pple

men

t use

dat

a. C

onse

quen

tly, t

he to

tal i

ntak

es in

the

high

est q

uint

iles o

f the

Alp

ha-T

ocop

hero

l Bet

a-C

arot

ene

Can

cer P

reve

ntio

n St

udy

and

the

Net

herla

nds C

ohor

t Stu

dy a

re n

ot c

ompa

rabl

e to

thos

e in

the

othe

r stu

dies

d Adj

uste

d fo

r sam

e co

varia

tes i

n fo

otno

te b

exc

ept m

ultiv

itam

in u

se


NIH


NIH


NIH


Park et al.

Tabl

e 3

Pool

ed re

lativ

e ris

ks o

f col

on c

ance

r for

cat

egor

ies o

f tot

al v

itam

in A

, C, a

nd E

inta

kes

Tot

al v

itam

in A

Cat

egor

iesb

p-va

lue,

test

for

tren

dp-

valu

e, te

st fo

r be

twee

n-st

udie

she

tero

gene

itya

p-va

lue,

test

for

betw

een-

stud

ies h

eter

ogen

eity

due

tose

xa≤1

,000

(μg/

day)

>1,0

00–1

,500

>1,5

00–2

,000

>2,0

00–2

,500

>2,5

00–4

,000

>4,0

00

Cas

e (n

)1,

152

1,07

261

349

279

437

2

Age

-adj

uste

d1.

000.

89 (0

.81–

0.97

)0.

82 (0

.74–

0.92

)0.

84 (0

.74–

0.94

)0.

79 (0

.70–

0.88

)0.

78 (0

.68–

0.89

)<0

.001

0.71

0.30

Mul

tivar

iate

1c

1.00

0.92

(0.8

4–1.

01)

0.89

(0.7

9–1.

00)

0.91

(0.8

0–1.

03)

0.87

(0.7

7–0.

98)

0.88

(0.7

6–1.

02)

0.01

0.81

0.44

Mul

tivar

iate

2d

1.00

0.93

(0.8

4–1.

02)

0.90

(0.8

0–1.

02)

0.93

(0.8

1–1.

06)

0.91

(0.7

8–1.

08)

0.93

(0.7

9–1.

10)

0.21

0.51

0.94

Tot

al v

itam

in C

Cat

egor

iesb

p-va

lue,

test

for

tren

dp-

valu

e, te

st fo

r be

twee

n-st

udie

she

tero

gene

itya

p-va

lue,

test

for

betw

een-

stud

ies h

eter

ogen

eity

due

tose

xa≤1

00 (m

g/da

y)>1

00–1

50>1

50–2

00>2

00–2

50>2

50–6

00>6

00

Cas

e (n

)1,

006

934

781

497

675

602

Age

-adj

uste

d1.

000.

85 (0

.77–

0.94

)0.

93 (0

.83–

1.05

)0.

94 (0

.80–

1.11

)0.

79 (0

.70–

0.88

)0.

73 (0

.65–

0.82

)<0

.001

0.71

0.50

Mul

tivar

iate

1c

1.00

0.88

(0.7

9–0.

97)

0.98

(0.8

7–1.

10)

1.00

(0.8

6–1.

16)

0.86

(0.7

6–0.

98)

0.81

(0.7

1–0.

92)

0.00

20.

840.

65

Mul

tivar

iate

2d

1.00

0.89

(0.8

0–0.

99)

1.02

(0.8

9–1.

16)

1.02

(0.8

9–1.

18)

0.91

(0.7

9–1.

03)

0.86

(0.7

4–0.

99)

0.02

0.87

0.61

Mul

tivar

iate

3e

1.00

0.88

(0.7

9–0.

98)

0.99

(0.8

8–1.

11)

1.01

(0.8

7–1.

16)

0.90

(0.7

8–1.

03)

0.86

(0.7

4–1.

00)

0.08

0.79

0.47

Tot

al v

itam

in E

Cat

egor

iesb

p-va

lue,

test

for

tren

dp-

valu

e, te

st fo

r be

twee

n-st

udie

s het

erog

enei

tya

p-va

lue,

test

for

betw

een-

stud

ies h

eter

ogen

eity

due

to se

xa

≤6 (m

g/da

y)>6

–9>9

–25

>25–

200

>200

Cas

e (n

)56

81,

208

1,67

955

348

7

Age

-adj

uste

d1.

000.

90 (0

.79–

1.01

)0.

83 (0

.74–

0.93

)0.

84 (0

.65–

1.06

)0.

71 (0

.59–

0.83

)0.

001

0.18

0.61

Mul

tivar

iate

1c

1.00

0.94

(0.8

3–1.

06)

0.89

(0.7

9–1.

00)

0.91

(0.7

2–1.

13)

0.78

(0.6

6–0.

92)

0.01

0.27

0.89

Mul

tivar

iate

2d

1.00

0.93

(0.8

3–1.

05)

0.89

(0.7

8–1.

01)

0.93

(0.7

3–1.

19)

0.80

(0.6

5–0.

97)

0.06

0.13

0.79

Mul

tivar

iate

3f

1.00

0.94

(0.8

2–1.

07)

0.89

(0.7

9–1.

01)

0.96

(0.7

6–1.

21)

0.83

(0.7

0–0.

99)

0.16

0.31

0.83

a For t

he h

ighe

st c

ateg

ory

b For v

itam

in A

ana

lyse

s, th

e A

lpha

-Toc

ophe

rol B

eta-

Car

oten

e C

ance

r Pre

vent

ion

Stud

y an

d th

e N

ethe

rland

s Coh

ort S

tudy

wer

e ex

clud

ed fr

om th

e hi

ghes

t cat

egor

y be

caus

e th

ese

stud

ies d

id n

ot h

ave

any

case

s in

that

cat

egor

y. F

or v

itam

in C

ana

lyse

s, th

e N

ethe

rland

s Coh

ort

Stud

y w

as e

xclu

ded

from

the

high

est c

ateg

ory

beca

use

the

stud

y di

d no

t hav

e an

y ca

ses i

n th

at c

ateg

ory.

For

vita

min

E a

naly

ses,

the

mal

e co

hort

of th

e N

ew Y

ork

Stat

e C

ohor

t was

exc

lude

d fr

om >

25 to

200

mg/

day

cate

gory

, and

the

Alp

ha-T

ocop

hero

l Bet

a-C

arot

ene

Can

cer

Prev

entio

n St

udy

and

the

Net

herla

nds C

ohor

t Stu

dy w

ere

excl

uded

from

the

high

est c

ateg

ory

beca

use

thes

e st

udie

s did

not

hav

e an

y ca

ses i

n th

at c

ateg

ory.

The

par

ticip

ants

who

wer

e no

t cas

es w

ho w

ould

hav

e be

en in

the

high

est c

ateg

ory

wer

e in

clud

ed in

the

next

hig

hest

cate

gory

c Adj

uste

d fo

r sam

e co

varia

tes l

iste

d in

Tab

le 2

foot

note

b e

xcep

t mul

tivita

min

use


NIH


NIH


NIH


Park et al. d A

djus

ted

for c

ovar

iate

s in

mul

tivar

iate

mod

el 1

exc

ept d

ieta

ry fo

late

inta

ke (q

uint

iles)

was

repl

aced

with

tota

l fol

ate

inta

ke (q

uint

iles)

e Adj

uste

d fo

r cov

aria

tes i

n m

ultiv

aria

te m

odel

1 a

nd in

take

of t

otal

vita

min

E (≤

6, >

6–9,

>9–

25, >

25–2

00, >

200

mg/

day)

f Adj

uste

d fo

r cov

aria

tes i

n m

ultiv

aria

te m

odel

1 a

nd in

take

of t

otal

vita

min

C (≤

100,

>10

0–15

0, >

150–

200,

>20

0–25

0, >

250–

600,

>60

0 m

g/da

y)


NIH


NIH


NIH


Park et al.

Tabl

e 4

Pool

ed m

ultiv

aria

te re

lativ

e ris

ksa o

f col

on c

ance

r for

cat

egor

ies o

f tot

al v

itam

in A

, C, a

nd E

inta

kes b

y tu

mor

site

Tot

al v

itam

in A

Cat

egor

iesb

p-va

lue,

test

for

tren

dp-

valu

e, te

st fo

r be

twee

n-st

udie

s het

erog

enei

tyc

p-va

lue,

test

for

betw

een-

stud

ies

hete

roge

neity

due

to se

xcp-

valu

e, te

st fo

r co

mm

onef

fect

s by

tum

or si

tec

≤1,0

00 (μ

g/da

y)>1

,000

–1,5

00>1

,500

–2,0

00>2

,000

–2,5

00>2

,500

–4,0

00>4

,000

Cas

e (n

)59

8/49

7d58

0/41

434

7/23

527

0/18

340

5/32

619

2/15

0

Prox

imal

1.00

0.96

(0.8

4–1.

09)

0.96

(0.8

2–1.

13)

0.94

(0.8

0–1.

12)

0.85

(0.7

2–0.

99)

0.87

(0.7

1–1.

07)

0.02

0.94

0.63

0.66

Dis

tal

1.00

0.84

(0.7

2–0.

97)

0.80

(0.6

7–0.

97)

0.82

(0.6

7–1.

00)

0.85

(0.6

7–1.

09)

0.83

(0.6

5–1.

05)

0.15

0.80

0.56

Tot

al v

itam

in C

Cat

egor

iesb

p-va

lue,

test

for

tren

dp-

valu

e, te

st fo

r be

twee

n-st

udie

she

tero

gene

ityc

p-va

lue,

test

for

betw

een-

stud

ies

hete

roge

neity

due

to se

xcp-

valu

e, te

st fo

r co

mm

onef

fect

s by

tum

or si

tec

≤100

(mg/

day)

>100

–150

>150

–200

>200

–250

>250

–600

>600

Cas

e (n

)53

9/41

849

3/39

139

9/30

628

2/17

635

0/26

432

9/21

9

Prox

imal

1.00

0.85

(0.7

1–1.

00)

0.94

(0.7

6–1.

16)

1.08

(0.8

2–1.

41)

0.85

(0.7

1–1.

01)

0.85

(0.7

0–1.

05)

0.09

0.31

0.74

0.34

Dis

tal

1.00

0.92

(0.7

9–1.

07)

0.98

(0.7

6–1.

25)

0.89

(0.7

1–1.

11)

0.83

(0.6

8–1.

02)

0.72

(0.5

5–0.

93)

0.01

0.19

0.97

Tot

al v

itam

in E

Cat

egor

iesb

p-va

lue,

test

for

tren

dp-

valu

e, te

st fo

r be

twee

n-st

udie

she

tero

gene

ityc

p-va

lue,

test

for

betw

een-

stud

ies

hete

roge

neity

due

to se

xcp-

valu

e, te

st fo

r co

mm

on e

ffect

s by

tum

or si

tec

≤6 (m

g/da

y)>6

–9>9

–25

>25–

200

>200

Cas

e (n

)28

7/24

165

6/45

987

2/69

030

1/21

427

6/17

0

Prox

imal

1.00

0.96

(0.8

0–1.

15)

0.83

(0.7

0–0.

97)

0.81

(0.6

3–1.

05)

0.82

(0.6

7–0.

99)

0.14

0.49

0.24

0.58

Dis

tal

1.00

0.90

(0.7

4–1.

09)

0.97

(0.8

0–1.

16)

0.99

(0.7

5–1.

32)

0.73

(0.5

8–0.

92)

0.02

0.63

0.46

a Adj

uste

d fo

r sam

e co

varia

tes l

iste

d in

Tab

le 2

foot

note

c

b The

follo

win

g st

udie

s wer

e ex

clud

ed fr

om a

cat

egor

y be

caus

e th

ese

stud

ies d

id n

ot h

ave

any

case

s in

that

cat

egor

y; th

e pa

rtici

pant

s who

wer

e no

t cas

es w

ho w

ould

hav

e be

en in

that

cat

egor

y w

ere

incl

uded

in th

e ne

xt h

ighe

st c

ateg

ory.

The

Alp

ha-T

ocop

hero

l Bet

a-C

arot

ene

Can

cer P

reve

ntio

n St

udy

was

exc

lude

d fr

om th

e hi

ghes

t cat

egor

y of

tota

l vita

min

s A a

nd E

inta

ke in

bot

h th

e pr

oxim

al a

nd th

e di

stal

col

on c

ance

r ana

lyse

s. Th

e A

lpha

-Toc

ophe

rol B

eta-

Car

oten

e C

ance

r Pre

vent

ion

Stud

y w

as a

lso

excl

uded

from

the

>250

–600

mg/

d ca

tego

ry o

fto

tal v

itam

in C

inta

ke in

the

prox

imal

col

on c

ance

r ana

lyse

s, th

e >2

5–20

0 m

g/d

cate

gory

of t

otal

vita

min

E in

take

in th

e pr

oxim

al c

olon

can

cer a

naly

ses,

and

the

>200

–250

mg/

d ca

tego

ry o

f tot

al v

itam

in C

inta

ke in

the

dist

al c

olon

can

cer a

naly

ses.

Bot

h th

e m

ale

and

the

fem

ale

coho

rts o

f the

Net

herla

nds C

ohor

t Stu

dy w

ere

excl

uded

from

the

high

est c

ateg

ory

of to

tal v

itam

ins A

, C, a

nd E

inta

ke in

bot

h th

e pr

oxim

al a

nd d

ista

l col

on c

ance

r ana

lyse

s. Th

e m

ale

coho

rt of

the

Net

herla

nds C

ohor

t Stu

dy w

as a

lso

excl

uded

from

the

>2,0

00–2

,500

and

>2,

500–

4,00

0 μg

/day

cat

egor

ies o

f tot

al v

itam

in A

inta

ke in

the

dist

al c

olon

can

cer a

naly

ses.

The

Wom

en’s

Hea

lth S

tudy

was

exc

lude

d fr

om th

e hi

ghes

t cat

egor

y of

tota

l vita

min

C in

take

in th

e pr

oxim

al c

olon

can

cer a

naly

ses a

nd o

f tot

al v

itam

in A

inta

ke in

the

dist

al c

olon

can

cer

anal

yses

. The

New

Yor

k U

nive

rsity

Wom

en’s

Hea

lth S

tudy

was

exc

lude

d fr

om th

e di

stal

col

on c

ance

r ana

lyse

s for

tota

l vita

min

C in

take

and

tota

l vita

min

E in

take

bec

ause

the

stud

y ha

d no

cas

es in

the

refe

renc

e ca

tego

ry. B

oth

the

mal

e an

d th

e fe

mal

e co

horts

of t

he N

ew Y

ork

Stat

e C

ohor

t wer

e ex

clud

ed fr

om th

e >2

5–20

0 m

g/d

cate

gory

of t

otal

vita

min

E in

take

in b

oth

the

prox

imal

and

dis

tal c

olon

can

cer a

naly

ses

c For t

he h

ighe

st c

ateg

ory

d Cas

es in

pro

xim

al/d

ista

l col

on


Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a...

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Transcript of Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a...