Affiliations of authors: Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA (EC, GAC, EG, WCW, DJH); Harvard School of Public Health, Departments of Nutrition (SASW, SSY, WCW, KW, DJH), Epidemiology (SASW, GAC, DJH, DS, WCW), and Biostatistics (DS), 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 (PAB); Harvard Center for Cancer Prevention, Boston, MA (GAC, WCW, DJH); Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (ARF); Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo (JLF, SG); Department of Epidemiology, TNO Nutrition and Food Research Institute, Zeist, The Netherlands (RAG); Department of Public Health Sciences, Faculty of Medicine, University of Toronto, Canada (ABM); Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland (PP, MV); Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA (JDP); Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER); Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC (P. Terry); Department of Obstetrics/Gynecology, New York University School of Medicine, New York, NY (P. Toniolo); Division of Nutritional Epidemiology, National Institute of Environmental Medicine, Stockholm, Sweden (AW); Nelson Institute of Environmental Medicine and Kaplan Cancer Center, New York University School of Medicine, New York (AZJ).
Correspondence to: Eunyoung Cho, ScD, Channing Laboratory, 181 Longwood Ave., Boston, MA 02115 (e-mail: eunyoung.cho{at}channing.harvard.edu)
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ABSTRACT |
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INTRODUCTION |
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Results from epidemiologic studies of consumption of dairy foods and calcium and colorectal cancer risk have been inconclusive, with most studies reporting weak, statistically nonsignificant inverse associations (710), perhaps reflecting limited sample sizes. In this study, we examined the associations between the consumption of dairy foods and calcium and colorectal cancer risk in a pooled analysis of 10 cohort studies from North America and Europe. Most of the individual studies included in our analysis have published results of intakes of calcium (1118) and dairy foods (11,12,14,16,1820) on colorectal cancer risk. For most of these studies, follow-up was extended in the current analysis relative to the time of follow-up in the original published results.
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METHODS |
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The Pooling Project of Prospective Studies of Diet and Cancer has been described elsewhere (21,22). For the colorectal cancer analyses, we identified 10 prospective studies (1113,1618,20,23,24) that met the following predefined criteria: at least 50 people diagnosed with incident colorectal cancer; assessment of long-term dietary intake; and validation of either the dietary assessment method itself or a closely related instrument. Because most studies included only one sex, studies that included women and men were analyzed as two separate cohorts. The person-time experienced during follow-up of the Nurses Health Study (17) was divided into two segments to take advantage of the more detailed dietary assessment completed in 1986. On the basis of the underlying theory of survival data, blocks of person-time in different time periods are asymptotically uncorrelated, regardless of the extent to which they are derived from the same people (25).
Exclusion Criteria
For the primary data from each study, we applied the exclusion criteria used by that study (1113,1618,20,23,24), and then we further excluded participants if they had loge-transformed energy intakes beyond three standard deviations from the study-specific loge-transformed mean energy intake of the population. We also further excluded participants if they reported a history of cancer other than nonmelanoma skin cancer at baseline.
Case Definition
In each study, incident colorectal cancers were ascertained by self-report with subsequent medical record review (17), linkage with a cancer registry (1113,18,23,24), or both (16,20). In some studies (13,1618,23,24), additional linkage with a death registry was used.
Dietary Assessment
The baseline food frequency questionnaire for each study inquired about typical consumption of food items, generally over the past year. The number of questions on dairy foods on the food frequency questionnaires ranged from one in the New York State Cohort (24) to 20 in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (16). We examined associations between colorectal cancer risk and three groups of dairy foods (milk, cheese, and yogurt) because these groups were measured in most of the studies. Other dairy foods that were measured in at least half of the studies were examined separately.
Studies provided data for the intake of calcium from food only (dietary calcium) and from food and supplements (total calcium), if available. Because the amount of calcium in multivitamins was not estimated in the Adventist Health Study (20) and in the New York State Cohort (24), we used the calcium values for generic multivitamins (130 mg/day) in the Nurses Health Study food frequency questionnaire database to derive total calcium intakes for these studies. The correlations for dietary calcium between intakes estimated by the food frequency questionnaire and either multiple diet records or 24-hour recalls ranged from 0.48 to 0.70 (2629) (A. Wolk and L. Sampson: personal communications). We used the regression-residual method (30) to adjust nutrient intakes for a total energy intake of 1600 kcal/day for women and 2100 kcal/day for men.
Among dietary covariates, there were no missing data for nutrients. In most studies, less than 1% of the participants in each study had missing values for intake of red meat and alcohol.
Nondietary Covariates
Each study collected baseline information on nondietary covariates by using self-administered questionnaires. Most studies assessed age, smoking habits, physical activity, education, height, weight, multivitamin use, and, among women, oral contraceptive use and postmenopausal hormone use. The proportion of missing values was generally less than 5% in each study that measured the covariate. We categorized the covariate information in a consistent manner across studies.
Statistical Analysis
Primary data for dairy food and calcium intakes were modeled as categorical variables with uniform absolute intake cut points across the studies. Intake cut points were chosen to ensure a good number of cases in each category and to minimize exclusion of individual studies from any of the intake categories. Calcium intake was also categorized by study-specific quantiles on the basis of the distributions of the subcohorts in the Canadian National Breast Screening Study (23) and The Netherlands Cohort Study (12), each of which used a casecohort design (31) and on the distributions of the whole cohort in the remaining studies. To calculate the Ptrend, we assigned participants the median value of their category of intake, and this variable was used as a continuous variable in the study-specific regression models.
Each study was analyzed with the Cox proportional hazards model. The assumptions of proportionality were satisfied. Epicure software (32) was used for the Canadian National Breast Screening Study (23) and The Netherlands Cohort Study (12), and SAS PROC PHREG (33) was used for the remaining studies. We stratified the data by age at baseline and by the year that the baseline questionnaire was returned. Person-years of follow-up were calculated from the date the questionnaire was returned until the date of colorectal cancer diagnosis, death, or end of follow-up, whichever came first. Multivariable relative risks (RRs) were adjusted for smoking (never, past smoker with <20 years duration, past smoker with 2039 years duration, past smoker with 40 years duration, current smoker of <25 cigarettes per day and <40 years duration, current smoker of
25 cigarettes per day and <40 years duration, current smoker of <25 cigarettes per day and
40 years duration, or current smoker of
25 cigarettes per day and
40 years duration), body mass index (<23, 23 to <25, 25 to <30, or
30 kg/m2 of body surface area), education (less than high school, high school graduate, or more than high school), height (<1.60, 1.60 to <1.65, 1.65 to <1.70, 1.70 to <1.75, or
1.75 m for women; <1.70, 1.70 to <1.75, 1.75 to <1.80, 1.80 to <1.85, or
1.85 m for men), physical activity (low, medium, or high), family history of colorectal cancer (no, yes), use of nonsteroidal anti-inflammatory drugs (no, yes), use of multivitamins [no, yes <6/week, yes
6/week, or yes missing dose for the Health Professionals Follow-up Study (17), Iowa Womens Health Study (11), and Nurses Health Study (17); no, yes for the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (16), The Netherlands Cohort Study (12), and New York State Cohort (24)], energy intake (continuous), alcohol intake (0, >0 to <5, 5 to <15, 15 to <30,
30 g/day), red meat (quartiles), and dietary folate (quintiles). For women, the relative risks were also adjusted for history of oral contraceptive use (no, yes) and postmenopausal hormone use (premenopausal, ever, never). If there were missing data for a measured covariate within a study, an indicator variable was created for missing responses for that covariate. Two-sided 95% confidence intervals (CIs) were calculated. A random-effects model was used to combine the study-specific loge relative risks (34); the study-specific relative risks were weighted by the inverse of their variance. Tests of heterogeneity were conducted by using the Q statistic (34,35).
We evaluated whether total calcium intake was nonlinearly associated with colorectal cancer by comparing the nonparametric regression curve using restricted cubic splines to the linear model using the likelihood ratio test and by visual inspection of the graphs (36,37). Studies were combined into a single dataset stratified by study for these analyses. Four knot positions were specified at the 5th (406 mg/day), 35th (716 mg/day), 65th (997 mg/day), and 95th percentiles (1667 mg/day) for calcium intake based on the intake distribution across all studies.
To evaluate heterogeneity, we tested for variation in relative risks by sex and vitamin D intake by using meta-regression models (38). We evaluated whether associations differed by subsite of the large bowel (proximal colon, distal colon, and rectum), using a Wald test (39,40) to test the null hypothesis of no difference among the loge rate ratios.
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RESULTS |
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Because the association between dairy foods and colorectal cancer risk may vary by cancer site, we analyzed associations for cancers of the colon (proximal and distal colon) and rectum separately (Table 3). The associations for milk consumption varied by cancer site (test for common effects by cancer site, P = .03), and the inverse association was limited to cancers of the distal colon and rectum. The associations between cheese or yogurt consumption and colorectal cancer risk were not statistically significantly different across the cancer site of the large bowel.
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Because dairy foods are a good source of vitamin D, which has been hypothesized to reduce colorectal cancer risk (41), we examined the independent effects of calcium and vitamin D intakes in the five studies with total vitamin D intake data (n = 2816 colorectal cancer cases). Spearman correlation coefficients for total calcium and total vitamin D were generally more than 0.5 across studies. In analyses in which both nutrients were included in the multivariable models, the relative risk for the highest quintile of total calcium intake compared with the lowest changed slightly but was still statistically significant (from 0.78 [95% CI = 0.69 to 0.88] to 0.83 [95% CI = 0.72 to 0.95]), and the corresponding relative risk for total vitamin D changed from 0.86 (95% CI = 0.73 to 1.01) to 0.93 (95% CI = 0.79 to 1.10) after the adjustment. Table 5 presents the results for total calcium intake by tertiles of total vitamin D intake. Although the test for heterogeneity for the highest quintile of total calcium intake across tertiles of total vitamin D intake was not statistically significant (P = .29), total calcium intake was statistically significantly inversely associated with colorectal cancer risk only within the highest tertile of total vitamin D intake. We also examined the cross-classifications of these nutrients modeled as tertiles. The relative risk was the lowest (RR = 0.74, 95% CI = 0.65 to 0.84) for persons in the highest tertiles of both total calcium and total vitamin D intake compared with the lowest tertile of intake for both nutrients.
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To calculate the population attributable risk for calcium intake for women and men separately, we combined studies of the same sex into a single dataset and used the age-adjusted relative risk and prevalence of calcium intakes of less than 1000 mg/day (76% of women and 58% of men). Assuming that the association between calcium and colorectal cancer risk is causal, if individuals who consumed less than 1000 mg/day of calcium increased their intake to 1000 mg/day or more, 15% and 10% of the colorectal cancer cases in this study population would have been avoided for women and for men, respectively.
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DISCUSSION |
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A growing body of evidence indicates that calcium prevents colorectal carcinogenesis by influencing a complex series of signaling events induced at various tiers of colonic cell organization (42). Several animal studies (3) and some (4,6,4345), but not all (4649), clinical trials have shown that consumption of calcium and dairy food reduced colonic epithelial cell proliferation. Clinical trials also have suggested that calcium intake reduced the recurrence of colorectal adenomas (5,50). However, none of these trials directly evaluated the effects of dairy foods or calcium on colorectal cancer risk.
Many epidemiologic studies have examined consumption of dairy foods and/or calcium and colorectal cancer risk, but their findings have been inconclusive. A meta-analysis of the published literature (10), which included a few of the studies in the current analyses, found an inverse association with milk intake for cohort studies (RR = 0.80 [95% CI = 0.68 to 0.95; P heterogeneity = .77] for high versus low intake) but not for casecontrol studies. The analysis found no clear association between cheese or yogurt intake and colorectal cancer, consistent with our findings. The meta-analysis did not provide data on the doseresponse relationship of dairy food intake and colorectal cancer risk because published data with different intake cut points across studies were combined. For calcium intake and colorectal cancer risk, a meta-analysis of 24 studies (eight cohort and 16 casecontrol studies) (8), which included some of the studies in the current analysis, reported an RR of 0.86 (95% CI = 0.74 to 0.98) for individuals in the highest category of calcium intake compared with individuals in the lowest category. There was significant heterogeneity across the studies, whereas we found no suggestion of heterogeneity among the cohort studies included in our analysis for calcium or any of the dairy products examined.
Among the dairy items we examined, only milk consumption was statistically significantly associated with a lower risk of colorectal cancer, although the results for most of the other dairy foods were suggestive of inverse associations. This difference may have occurred because milk had a wider intake distribution than that of other dairy products. Another explanation: U.S.-based national surveys have reported that milk is the most important contributor to dietary calcium intake (51).
Calcium intake was inversely associated with the risk of colorectal cancer, with the inverse association being statistically significant only among those in the highest vitamin D intake category, although the difference in associations across vitamin D intake levels was not statistically significant. In addition, in a cross-classified analysis, the inverse association was strongest for the highest versus the lowest intakes of both nutrients together, possibly because vitamin D enhances calcium absorption and vitamin D itself may decrease colorectal cancer incidence (52). In our analyses, we could not distinguish clearly between the effects of milk and calcium because of their strong correlation in most studies. Calcium in milk is highly bioavailable, which may make milk appear to be associated with colorectal cancer risk independent of total calcium intake. Also, other components in milk may contribute to the inverse association. Dairy foods contain conjugated linoleic acid and lactoferrin, which inhibit colonic carcinogenesis in animal models (53,54), and the milk protein casein has antimutagenic activity on the digestive tract (55). Certain microorganisms in fermented dairy foods have also been hypothesized to reduce the risk of colorectal cancer (12). In our study, fermented food products such as yogurt or cheese, or fermented dairy fluids as a whole, were not strongly associated with colorectal cancer risk, but we had a limited ability to detect an association because the consumption of these foods was relatively low in most of the cohort studies.
Some of the etiologic factors for cancers of the proximal and distal colon may differ (56,57). Cancers of the distal colon have been hypothesized to be more related to exogenous factors such as diet than cancers of the proximal colon (56,57). We found that the inverse association between milk intake and colorectal cancer risk was limited to cancers of the distal colon and rectum, which is consistent with results of some of the previous studies (5860) but not others (61).
Our study has several strengths. By including only prospective cohort studies that used validated diet assessment instruments, we minimized the possibility of bias and misclassification. Furthermore, by examining the primary data instead of the published literature and applying uniform criteria to define the food and nutrient variables and other covariates, if available, we minimized potential sources of heterogeneity and improved comparability of the results across the studies. We were able to evaluate the associations across several populations with different dietary intake patterns and confirmed that the results were consistent across these studies. We examined calcium intake as study-specific quantiles as well as categories based on identical absolute intake cut points. Analyses using study-specific quantiles rank and classify participants using identical methods across studies and ensure that there are enough cases in each category. However, if distributions of intake across the studies are different, each quantile may not be comparable across studies. Analyses using identical absolute intake cut points take advantage of the actual range of intakes but assume that the intakes are measured comparably across studies. Despite these different analytic approaches and different sources of potential misclassification, we found that the results for these two approaches were consistent. Because information on calcium supplements was available in only four of the studies and the amount of calcium in multivitamins is usually small, we had limited ability to examine very high calcium intakes.
In summary, in this pooled analysis of 10 prospective studies, we found that increased consumption of milk and calcium were related to a lower risk of colorectal cancer. These data, in combination with the previous experimental studies documenting a salutary effect of calcium supplementation on colonic epithelial cell turnover and colorectal adenoma recurrence, support the concept that moderate milk and calcium intake reduces the risk of colorectal cancer.
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NOTES |
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We thank Mary Louie for computer support.
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Manuscript received November 21, 2003; revised April 29, 2004; accepted May 6, 2004.
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