Journal of the National Cancer Institute Advance Access originally published online on September 25, 2007
JNCI Journal of the National Cancer Institute 2007 99(19):1471-1483; doi:10.1093/jnci/djm155
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Fruits, Vegetables, and Colon Cancer Risk in a Pooled Analysis of 14 Cohort Studies
Affiliations of authors: Departments of Nutrition (AK, DJH, ELG, SASW), Biostatistics (DS), and Epidemiology (DJH, DS, JEB, ELG, SMZ, SASW), Harvard School of Public Health, Boston, MA; The Center for Health Research, Loma Linda University School of Medicine, Loma Linda, CA (WLB, GEF); Department of Epidemiology, Maastricht University, Maastricht, The Netherlands (PAvdB); Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA (EEC, MLM); Channing Laboratory (EC, CSF, ELG, DJH) and Division of Preventive Medicine (JEB, SMZ); Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, NY (JLF); Department of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY (JRM); Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA (CSF); Department of Food and Chemical Risk Analysis, TNO Quality of Life, Zeist, The Netherlands (RAG); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN (LH, DRJ); Karmanos Cancer Institute/Department of Pathology, Wayne State University School of Medicine, Detroit, MI (IK); Nutritional Epidemiology Unit, National Cancer Institute, Milan, Italy (VK, SS); Division of Nutritional Epidemiology, National Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden (SCL, AW); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (MFL, AS); Department of Public Health Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (ABM); Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland (PP, MJV); Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER); Department of Environmental Medicine, Division of Epidemiology, New York, NY (AZJ)
Correspondence to: Anita Koushik, PhD, Department of Social and Preventive Medicine, Centre de recherche du CHUM, University of Montreal, 3875 rue Saint-Urbain, Third floor, Montreal, QC H2W 1V1, Canada (e-mail: anita.koushik{at}umontreal.ca) or Stephanie Smith-Warner, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115 (e-mail: pooling{at}hsphsun2.harvard.edu).
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ABSTRACT |
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Background: Fruit and vegetable intakes have been associated with a reduced risk of colon cancer; however, in more recent studies associations have been less consistent. Statistical power to examine associations by colon site has been limited in previous studies.
Methods: Fruit and vegetable intakes in relation to colon cancer risk were examined in the Pooling Project of Prospective Studies of Diet and Cancer. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated separately in 14 studies using Cox proportional hazards model and then pooled using a random-effects model. Intakes of total fruits and vegetables, total fruits, and total vegetables were categorized according to quintiles and absolute cutpoints. Analyses were conducted for colon cancer overall and for proximal and distal colon cancer separately. All statistical tests were two-sided.
Results: Among 756217 men and women followed for up to 6 to 20 years, depending on the study, 5838 were diagnosed with colon cancer. The pooled multivariable RRs (95% CIs) of colon cancer for the highest versus lowest quintiles of intake were 0.91 (0.82 to 1.01, Ptrend = .19) for total fruits and vegetables, 0.93 (0.85 to 1.02, Ptrend = .28) for total fruits, and 0.94 (0.86 to 1.02, Ptrend = .17) for total vegetables. Similar results were observed when intakes were categorized by identical absolute cut points across studies (pooled multivariable RR = 0.90, 95% CI = 0.77 to 1.05 for 800 or more versus <200 g/day of total fruits and vegetables, Ptrend = .06). The age-standardized incidence rates of colon cancer for these two intake categories were 54 and 61 per 100000 person-years, respectively. When analyzed by colon site, the pooled multivariable RRs (95% CIs) comparing total fruit and vegetable intakes of 800 or more versus less than 200 g/day were 0.74 (0.57 to 0.95, Ptrend = .02) for distal colon cancers and 1.02 (0.82 to 1.27, Ptrend = .57) for proximal colon cancers. Similar site-specific associations were observed for total fruits and total vegetables.
Conclusion: Fruit and vegetable intakes were not strongly associated with colon cancer risk overall but may be associated with a lower risk of distal colon cancer.
Prior knowledge Fruit and vegetable intakes have been associated with a reduced risk of colon cancer; however, in more recent studies, associations have been less consistent. Study design Pooled analysis of 14 prospective studies. Contribution Increasing fruit and vegetable intakes were not associated with colon cancer risk overall, although the lowest intakes were associated with an elevation in risk. When examined by colon site, the inverse association for fruits and vegetables was limited to cancers of the distal colon, although the risk estimates for distal and proximal colon cancer were not statistically significantly different. Results for each fruit and vegetable group were generally consistent between men and women. Implications Diets plentiful in fruits and vegetables remain important given these findings and the benefits that have been observed for other health outcomes. Limitations The study was survey based, and there may have been inaccuracies in reported fruit and vegetable intake. Further, only data on diet at the beginning of each study were available for each study so it was not possible to evaluate associations between fruit and vegetable intakes during childhood, adolescence, or early adulthood and colon cancer risk.
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The risk of colon cancer in relation to fruit and vegetable consumption has been reported in more than 50 epidemiologic studies (1). In 1997, an international panel reviewed 21 case–control and four cohort studies and concluded that there was convincing evidence that vegetable consumption reduces the risk of colon and rectal cancers (2). The panel also stated that the data available for fruit consumption were limited and inconsistent. In a subsequent evaluation of 27 case–control and 13 cohort studies published through early 2003, a different panel concluded that higher vegetable intake probably reduces the risk of colorectal cancer and that higher fruit intake possibly reduces risk (3). The conclusion for vegetables was more conservative in the latter evaluation because the reported associations for vegetable consumption and colorectal cancer risk were weaker in the cohort studies than in the case–control studies, suggesting that the inverse associations in the case–control studies may have resulted from recall and/or selection biases. Similarly, a meta-analysis published in 2003 (4) reported modest inverse associations between both fruit and vegetable intakes and colorectal cancer in case–control and cohort studies combined; however, the relative risks were essentially null when restricted to the cohort studies. Heterogeneity between the results from the cohort studies was observed for fruit intake, which may have been due to the observed differences in associations between men and women (4). Also, associations for vegetable intake differed according to cancer site (colon or rectal), although there was no statistically significant heterogeneity between studies for vegetable intakes in this meta-analysis. Inconsistencies in previous studies may also reflect differences in the specific fruits and vegetables consumed or differences in the prevalence of colon cancer risk factors that may modify associations of diet and cancer. Because analyses of specific food items and of modification of associations by other factors are not routinely reported, meta-analyses of the published literature are unable to analyze these potential sources of heterogeneity. Recent evidence also indicates that proximal and distal colon cancers may have distinct etiologies (5–7). Previous cohort studies may have been insufficiently powered to examine associations according to colon site.
To better understand fruit and vegetable consumption in relation to colon cancer risk, we analyzed intakes of total and specific fruits and vegetables in a pooled analysis of 14 North American and European prospective cohort studies (8–20). All but three of these studies (11,16,18) have previously published results on fruit and vegetable intake and colorectal cancer risk. In our analysis, we have included an extended follow-up period for most of the studies. Because colon and rectal cancers may have different etiologies (21,22), we restricted our analysis to colon cancer. Using the primary data from each study, we standardized definitions of fruit and vegetable intakes and covariate categories across studies and analyzed the risks of colon cancer overall and of proximal and distal colon cancer separately. We also examined whether associations were modified by colon cancer risk factors.
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Methods |
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Study Population
The Pooling Project of Prospective Studies of Diet and Cancer (Pooling Project) is an international consortium of cohort studies and has been described previously (23). Each of the 14 studies included in these analyses met the following predefined criteria: publication of a diet and cancer association, diagnosis of at least 50 incident colorectal cancer cases, assessment of usual diet, and conduct of a validation study of the dietary assessment method or a closely related instrument. The exclusion criteria used by each study were first applied to the data from that study, after which we excluded participants with a prior cancer diagnosis (except nonmelanoma skin cancer) at baseline or who reported energy intakes beyond three standard deviations from the study-specific loge-transformed mean energy intake. Studies that enrolled both men and women were separated into sex-specific cohorts. Each of the studies included was reviewed and approved by the institutional review board of the institution at which the study was conducted.
Colon Cancer Ascertainment
Incident colon cancer case were identified by self-report with subsequent medical record review, linkage with a cancer registry, or both (23). Mortality registries served as an additional source of incident cases in some studies. Estimated ascertainment of cancer diagnoses was high in each study and exceeded 90% in most studies. (23). Only colon cancers (International Classification of Diseases, Ninth Revision [ICD-9] codes 153.0–153.4, 153.6–153.9) were analyzed for the present report. Proximal colon cancers included tumors from the cecum to the splenic flexure (ICD-9 codes 153.0, 153.1, 153.4, 153.6, 153.7); distal colon cancers included tumors in the descending (153.2) and sigmoid (153.3) colon.
Dietary Assessment
A self-administered food-frequency questionnaire was used at baseline in each of the 14 studies to assess usual consumption of specific food items (23). In most studies, the time frame for the diet assessment was the past year (23). Food intake data were converted to units of grams per day. We examined three main food groups: total fruits and vegetables (fruits, vegetables, and juices), total fruits (fruits and fruit juices), and total vegetables (vegetables and vegetable juices). Food group intakes were calculated by summing the intakes of specific foods included in that group. Potatoes and mature beans were not classified as vegetables because of their high starch and protein content (24), respectively, compared with other vegetables. The validity of total fruit and total vegetable intake estimates was evaluated only in the Netherlands Cohort Study (Spearman correlation coefficient = .60 for total fruits and 0.38 for total vegetables) (25), the Cancer Prevention Study II Nutrition Cohort (Pearson correlation coefficient = .62 for total fruits and 0.52 for total vegetables) (26), and the Health Professionals Follow-up Study (deattenuated Pearson correlation coefficient = .71 for total fruits and 0.19 for total vegetables) (27). Therefore, we were unable to correct our analyses for measurement error in dietary assessment. We also examined fruits and vegetables grouped according to botanical taxonomy to evaluate potentially rich sources of particular bioactive compounds. The botanical classifications analyzed were Compositae, Cruciferae, Cucurbitaceae, Leguminosae, Rosaceae, Rutaceae, Solanaceae, and Umbelliferae (28). Also, green leafy vegetables (e.g. lettuce, spinach) and individual fruits and vegetables for which intake was assessed in at least half of the studies were examined. The individual foods analyzed were apples, pears, apple sauce, bananas, cantaloupe, grapefruit, oranges, peaches, fruit juices, broccoli, brussels sprouts, cabbage, carrots, lettuce, peas, lima beans, string beans, spinach, tomatoes, yams, mature beans, and potatoes.
Statistical Analysis
All statistical analyses were conducted using the Statistical Analysis System (SAS) software (Cary, NC). We used a two-stage method to estimate pooled relative risks (RRs). First, study- and sex-specific RRs and 95% confidence intervals (CIs) were estimated with the Cox proportional hazards model (29) using SAS PROC PHREG (30). Person-years of follow-up were calculated from the date of the baseline questionnaire until the date of colorectal cancer diagnosis, death, or end of follow-up. The cases occurring and person-time experienced during follow-up in the Nurses' Health Study were considered to be two different cohorts (1980–1986, Nurses' Health Study [a]; 1986–2000, Nurses' Health Study [b]) so that the more detailed dietary assessment conducted in 1986 could be utilized. According to the underlying theory of survival analysis, blocks of person-time in different time periods are asymptotically uncorrelated, regardless of the extent to which they are derived from the same people (31). The Canadian National Breast Screening Study and Netherlands Cohort Study were analyzed as case–cohort studies (32). To adjust for age and calendar time, analyses were stratified on age at baseline (in years) and the year the baseline questionnaire was returned. We also conducted multivariable analyses adjusted for other colon cancer risk factors including body mass index, height, education, physical activity, family history of colorectal cancer, postmenopausal hormone use, oral contraceptive use, use of nonsteroidal anti-inflammatory drugs, multivitamin use, smoking habits, red meat intake, total milk intake, alcohol, and total energy (see fourth footnote to Table 2 for categories). In additional multivariable analyses, we simultaneously adjusted total fruits for total vegetables and adjusted for quintiles of intakes of dietary fiber, dietary folate, and vitamin C.
After estimating the study-specific relative risks, pooled relative risks were calculated by combining the study-specific loge relative risks, weighted by the inverse of their variance, using a random-effects model (33). The presence of heterogeneity between studies was tested for using the Q statistic, which follows an approximate chi-square distribution (33,34). To verify the assumption of proportional hazards, we fitted models that included an interaction term between age and fruit and vegetable intake. The study-specific parameter estimates for the interaction terms were pooled using the random-effects model, and we tested the statistical significance of the pooled interaction term. We observed no evidence of violation of the proportional hazards assumption. All statistical tests were two-sided, and a P value of .05 was considered to be statistically significant.
Fruit and vegetable intakes were categorized according to study-specific quantiles and by identical absolute cut points across studies. Study-specific quantiles were chosen to maximize the contrast between the highest and lowest levels of intake and to ensure a sufficient number of participants in each category. The categories based on absolute cut points represented multiples of fruit/vegetable servings, about 100 g per serving on average (24), and were chosen to ensure that the referent category within each study was not so small as to lead to unstable relative risk estimates. To calculate the P value for the test for trend across categories of intake, participants were assigned the median value of their category, and this variable was entered as a continuous term in the regression model, the coefficient for which was evaluated by the Wald test.
To assess the presence of heterogeneity by sex, age at diagnosis, and follow-up period and to evaluate whether associations were modified by colon cancer risk factors, including smoking (never, past, current), alcohol consumption (non-drinker, <1 drink/day, 
1 drink/day), body mass index (<25 kg/m2, 25 kg/m2), red meat intake (tertiles) and postmenopausal hormone use among women (never, past, current), we used a mixed-effects meta-regression model (35). A two-sided Wald test statistic was used to test the null hypothesis that there was no modification of the fruit/vegetable–colon cancer association by levels of the potential effect modifiers. To test for differences in associations by colon site (proximal versus distal), we used the contrast test, testing the null hypothesis that there was no difference in the pooled estimates across colon sites. This test statistic has an approximate chi-square distribution.
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Results |
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Among 242362 men and 513855 women, a total of 5838 developed colon cancer (1890 men, 3948 women) during a maximum follow-up that ranged from 6 to 20 years across the 14 studies (Table 1). Of the 5838 colon cancers, 3063 occurred in the proximal colon and 2313 occurred in the distal colon (colon site information was missing for 462 subjects). Total fruit and vegetable intake was lowest in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (median = 226 g/day) and highest in Health Professionals Follow-up Study (median = 611 g/day).
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In models that were adjusted for age, colon cancer risk was lower by 8%–13% for the highest versus the lowest quintile of total fruit and vegetable, total fruit, and total vegetable intakes for men and women combined (Table 2). In the corresponding multivariable analyses, relative risks were attenuated and no longer statistically significant. The pooled multivariable RRs (95% CIs) for the highest compared with the lowest quintiles were 0.91 (0.82 to 1.01) for total fruits and vegetables, 0.93 (0.85 to 1.02) for total fruits, and 0.94 (0.86 to 1.02) for total vegetables. For these comparisons, a statistically significant lower risk of colon cancer was observed for total fruits and vegetables only in the Netherlands Cohort Study women and the Nurses' Health Study (b) (Fig. 1) and for total fruits in the Nurses' Health Study (b) (data not shown). However, there was no statistically significant heterogeneity between studies for any food group (Table 2). The magnitude of the pooled multivariable relative risks for quintile 5 was similar across the three food groups. Also, for each food group, the pooled multivariable relative risks for quintiles 2 through 5 did not differ greatly.
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The results for total fruits not including fruit juices (results not shown) were similar to the results for total fruits. Relative risks for total fruits and total vegetables did not change greatly when both were included simultaneously in the same model (results not shown). Further adjustment for dietary fiber, dietary folate, or total vitamin C intake did not appreciably change the relative risks for any of the three food groups (results not shown).
The pooled relative risks for the European studies were similar to those for the North American studies (results not shown). In addition, the pooled relative risks were not modified by sex (Table 2) or age at diagnosis. For men and women diagnosed before the age of 65 years (n = 2056 cases), the pooled multivariable RRs (95% CIs) comparing the highest with the lowest quintile of intake were 0.90 (0.77 to 1.05) for total fruits and vegetables, 0.92 (0.79 to 1.07) for total fruits and 0.93 (0.80 to 1.09) for total vegetables, whereas for men and women diagnosed at the age of 65 years or older (n = 3617cases), the corresponding RRs (95% CIs) were 0.92 (0.81 to 1.03) for total fruits and vegetables, 0.93 (0.83 to 1.04) for total fruits and 0.93 (0.83 to 1.04) for total vegetables. The Adventist Health Study and the Prospective Study on Hormones, Diet and Breast Cancer were not included in these and other stratified analyses due to the small number of colon cancer cases in each study. None of the relative risks in Table 2 were appreciably changed when these two studies were excluded.
The pooled relative risks for colon cancer did not vary substantially according to follow-up period (P values for difference between follow-up periods were .40 for total fruits and vegetables, .88 for total fruits, and .57 for total vegetables). For colon cancer diagnoses that occurred within the first 5 years of follow-up (n = 2288 cases), the pooled multivariable RRs (95% CIs) comparing the highest with the lowest quintiles of intake were 0.97 (0.79 to 1.18) for total fruits and vegetables, 0.94 (0.77 to 1.14) for total fruits, and 0.97 (0.84 to 1.12) for total vegetables, and for colon cancer diagnoses that occurred at 5 years or later after baseline (n = 3384 cases), the RRs (95% CIs) were 0.89 (0.78 to 1.00) for total fruits and vegetables, 0.92 (0.82 to 1.04) for total fruits, and 0.92 (0.81 to 1.03) for total vegetables. When we restricted the analysis to nonusers of multivitamin supplements, which included 3314 cases (the Canadian National Breast Screening Study and Swedish Mammography Cohort were excluded from these analyses because data on multivitamin supplement use at baseline were not available for all participants), the results were similar to those seen among the whole study population (results not shown).
When fruit and vegetable intakes were categorized using identical absolute cut points (Table 3), the associations for each fruit and vegetable group were similar to those observed when intakes were categorized as quintiles. For example, for total fruits and vegetables, the pooled multivariable RR (95% CI) for intakes of 800 g/day compared with <200 g/day was 0.90 (0.77 to 1.05). There was no evidence of heterogeneity between studies and the pooled relative risks were not statistically significantly modified by sex, although the results suggested a stronger inverse association for women than men with total fruits and vegetables and total fruits. As observed in the quintile analyses, the relative risks for the highest compared with the lowest intakes were similar in magnitude across the three food groups (Table 3). The age-standardized incidence rates of colon cancer were 61 per 100000 person-years among those who consumed <200 g/day of total fruits and vegetables and 54 per 100000 person-years among those who consumed 800 g/day.
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When fruits and vegetables were grouped according to botanical definitions (28), the pooled multivariable RRs (95% CIs) for the highest versus the lowest tertiles of intake were 1.00 (0.92 to 1.09) for Compositae, 0.99 (0.93 to 1.06) for Cruciferae, 0.96 (0.89 to 1.03) for Cucurbitaceae, 0.97 (0.90 to 1.03) for Leguminosae, 0.94 (0.86 to 1.02) for Rosaceae, 0.94 (0.88 to 1.01) for Rutaceae, 1.01 (0.94 to 1.08) for Solanaceae, and 0.97 (0.90 to 1.05) for Umbelliferae. For the consumption of green leafy vegetables, the pooled multivariable RR (95% CI) was 0.97 (0.90 to 1.05) for the highest versus the lowest tertile of intake. In the analyses of individual fruits and vegetables, inverse associations were observed for intakes of bananas and spinach (Table 4). Further adjustment for total vegetables did not appreciably change the results for spinach. The association for bananas was similar but no longer statistically significant when the analysis was further adjusted for total fruits (not shown).
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In our analyses of population subgroups (i.e., by colon cancer risk factors and by colon site), the results using quintiles of total fruits and vegetables, total fruits, and total vegetables were similar to the results where categories were based on identical absolute cut points. To take advantage of the variation in intakes across the study populations, we present only the results for categories based on identical absolute cut points (Tables 5 and 6). The association between total fruits and vegetables and colon cancer risk did not vary by levels of smoking status, body mass index, and postmenopausal hormone use. However, the association between total fruit and vegetable consumption and colon cancer risk differed by intakes of alcohol (Piteraction value, test for interaction = .02) and red meat (Piteraction value, test for interaction = .01). In particular, an inverse association with total fruit and vegetable intakes was apparent among nondrinkers of alcohol and among individuals in the lowest two tertiles of red meat intake (Table 5).
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Intakes of total fruits and vegetables, total fruits, and total vegetables were not associated with proximal colon cancers but were associated with statistically significant reductions in the risk of distal colon cancer for the highest versus the lowest intakes (Table 6), although the differences in associations by colon site were not statistically significant (P value, test for common effects by tumor site in the highest category > .14 for all women and men combined; Table 6). For total fruits and vegetables, the pooled multivariable RR (95% CI) comparing intakes of
800 versus <200 g/day were 0.74 (0.57 ot 0.95) for distal colon cancer and 1.02 (0.82 to 1.27) for proximal colon cancer. The suggestive differences in risk estimates for the three food groups by colon site were generally consistent among men and women (Table 6) and also when fruit and vegetable intakes were categorized by quintiles. The pooled multivariable RRs (95% CIs) comparing the highest with the lowest quintile of total fruit and vegetable intake were 0.81 (0.69 to 0.95) for distal colon cancer and 0.98 (0.86 to 1.11) for proximal colon cancer (P value, test for common effects by tumor site in the highest quintile = .20). Because of the observed lower risk of distal colon cancer with fruit and vegetable intakes, we reexamined the association between distal colon cancer risk and intakes of botanically defined food groups and green leafy vegetables and observed no statistically significant associations, with the exception of Umbelliferae (pooled multivariable RR = 0.88, 95% CI = 0.79 to 0.99, for the highest versus the lowest tertile of intake). Intakes of bananas and spinach were not statistically significantly associated with distal colon cancer risk (results not shown). |
Discussion |
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TopAbstractContext and CaveatsMethodsResultsDiscussionFundingReferencesNotes |
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In this pooled analysis of data from 14 prospective cohort studies, increasing fruit and vegetable intakes were not associated with colon cancer risk overall, though the lowest intakes were associated with an elevation in risk. This pattern of association was consistent whether examined by study-specific quintiles or categories based on identical absolute intakes across studies. An inverse association was more apparent among nondrinkers of alcohol and among low consumers of red meat. Green leafy vegetables, botanically defined fruit and vegetable groups, and most specific fruits and vegetables, except bananas and spinach, were not associated with colon cancer risk. When examined by colon site, the inverse association for fruits and vegetables was limited to cancers of the distal colon, although the risk estimates for distal and proximal colon cancer were not statistically significantly different. Results for each fruit and vegetable group were generally consistent between men and women.
The relationship between fruit and vegetable intakes and the risk of colon cancer has been examined in many previous studies (1,3). For total vegetables, 75% of the results reported in 22 case–control studies suggested that colon cancer risk was reduced by at least 20% for those in the highest compared with the lowest intake category, with 33% of the estimates indicating that the reduction in risk exceeded 50%. For total fruits, the results have been less consistent among 19 case–control studies; 48% of the risk estimates suggested at least a 20% reduction in risk and only 11% showed more than a 50% lower risk for the highest versus the lowest intakes. Among five prospective cohort studies that were not included in this pooled analysis because they did not meet our inclusion criteria (36–40), only three studies have reported associations for total fruits and/or total vegetables (38–40), among which inverse associations with colon cancer risk were suggested for total vegetable intake in one study (39) and for total fruit intake (among women only) in another study (38).
Analyzing specific foods and food groups may identify particular components of fruits and vegetables that are associated with risk, and these associations could be diluted in an analysis of total fruits and vegetables. Associations for cruciferous and green vegetable intakes and the risk of colon cancer have been reported in more than 15 studies each, with most studies suggesting inverse associations (1). Other specific food groups for which associations with colon cancer risk have been reported with less frequency are legumes, allium vegetables, and citrus fruits, and the reported associations for these groups have been inconsistent across studies. Few studies have reported associations for individual fruits and vegetables. Spinach intake (41–43) has been consistently associated with a reduced risk of colon cancer and a lower risk with banana consumption has been observed in some (42,44) but not all (43,45) studies. To our knowledge, separate evaluation of distal and proximal colon cancers has been conducted in relatively few studies (41,46–50).
The suggestive reductions in colon cancer risk observed in our multivariable analyses, ranging from 6%–9% for the highest versus the lowest quintiles of total fruit and vegetable, total fruit, and total vegetable intakes, are much weaker than those observed in most previous studies, particularly for total vegetables. Differential misclassification of fruit and vegetable intakes or differential participation rates between cases and controls may have led to biased relative risk estimates in the case–control studies. Also, in light of the stronger inverse associations that we observed for distal versus proximal colon cancers, the differences between our results and previous case–control studies may reflect differences in the distribution of colon cancers by site. In our pooled analysis that included studies with follow-up periods up to 2003, more proximal compared with distal colon cancers occurred. This site distribution is consistent with the trend over the past several decades of an increasing incidence of proximal colon cancers with a corresponding decrease in distal colon cancers (6,51). In contrast, most previous case–control studies were conducted in earlier time periods, and among the studies that provided colon site distributions (41,42,44,46–48,50,52,53), colon cancers were more frequent in the distal compared with the proximal colon, except among women only in one study (50).
Research in embryology, physiology, and epidemiology supports the notion that cancers of the proximal and distal colon may have different etiologies (5–7). Recent evidence shows that two distinct kinds of genetic instability contribute to carcinogenesis in the colon; chromosomal instability occurs more often in distal colon cancers, whereas microsatellite instability predominates in proximal colon cancers (6,7). Diet has been hypothesized to have more of a role in distal versus proximal colon cancers (54).
Fruits and vegetables are rich in many nutrients and bioactive compounds, such as vitamins, carotenoids, folate, and fiber, that may have cancer-preventive properties (55). Nutrients that detoxify or deactivate carcinogens may act to prevent chromosomal instability whereas nutrients that function to regulate cell cycle progression and apoptosis may prevent the growth of chromosomally unstable cells. Other than bananas and spinach, we did not identify any specific food or food group that was more strongly associated with colon cancer risk that would suggest a role for a particular class of bioactive compounds. Rather, our results for total fruits and total vegetables separately did not greatly differ from one another, suggesting that potential synergy between the numerous bioactive compounds in fruits and vegetables could contribute to this modest inverse association (56).
In each of the analyses where an inverse association was suggested, the observed relative risks for the highest versus the lowest intakes were generally modest. Thus, although we adjusted for several covariates, we cannot rule out uncontrolled confounding by an unknown and unmeasured factor or residual confounding due to measurement error in the covariates. Also, our results, particularly for distal colon cancer, may reflect uncontrolled confounding by prior colorectal cancer screening, if individuals with the highest fruit and vegetable intakes compared with the lowest intakes were more likely to have been screened for colorectal cancer and had their screen-detected adenomatous polyps (precursor lesions to colon cancer) removed. Data on screening practices were not available in most studies. On the other hand, we also cannot rule out measurement error in the assessment of fruit and vegetable consumption. Thus, the observed relative risks may represent attenuated estimates. For instance, we used only baseline dietary information, which may be subject to greater misclassification than dietary information from multiple questionnaires throughout follow-up. Also, we were unable to correct for measurement error because most studies did not evaluate the validity of total fruit and total vegetable intakes. Furthermore, if fruit and vegetable intakes during childhood, adolescence, or early adulthood are more important determinants of colon cancer risk, than intakes in later adulthood then our analysis of adult diet may not have captured the relevant exposure period.
In our analysis, in which multiple studies were combined, exposure misclassification could also arise depending on whether fruit and vegetable intakes were modeled as study-specific quantiles or as categories in which cut points were defined by identical absolute intakes across studies. With the study-specific quantile approach, true differences in intakes across studies are not accounted for, and this may result in exposure misclassification when pooling the results. On the other hand, misclassification could also occur in the analyses of absolute intake categories because varying intakes across studies may be due to differences in questionnaire design. However, our results for colon cancer overall, and for proximal and distal colon cancers separately, were consistent regardless of how intakes were analyzed.
This study had several strengths, including the fact that we prospectively examined 14 cohorts from North America and Europe with a wide range of fruit and vegetable intakes. By conducting a pooled analysis, we were able to define fruit and vegetable intakes, and other covariates, in a standardized manner across studies, thus minimizing heterogeneity between studies due to differences in exposure and covariate definitions. We examined several specific foods and food groups that have not been consistently reported in previous studies. By including more than 5800 colon cancer cases in our analysis, we were able to conduct analyses by sex and according to colon site with greater statistical power than would be possible for any individual cohort. This large sample size further allowed us to evaluate whether associations were modified by other colon cancer risk factors.
In summary, the consumption of fruits and vegetables was not strongly associated with the risk of colon cancer overall but was inversely associated with the risk of distal colon cancer. Diets plentiful in fruits and vegetables remain important given these findings and the benefits that have been observed for other health outcomes, including cardiovascular disease (57) and some other cancers (3).
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Funding |
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Canadian Institutes of Health Research (to A. K.); a Cancer Prevention Research Fellowship from the Cancer Research Foundation of America/American Society of Preventive Oncology (to S. A. S. W.); National Institutes of Health (CA55075); The National Colorectal Cancer Research Alliance of the Entertainment Industry Foundation.
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NOTES |
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The authors are grateful to Shiaw-Shyuan Yaun, Christine Rivera, and Ruifeng Li, at the Harvard School of Public Health, for their assistance with data management and statistical analyses. The sponsors had no role in the design, data collection, data analysis, interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication.
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REFERENCES |
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Manuscript received February 21, 2007; revised July 9, 2007; accepted August 7, 2007.
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