Background: Previous studies of the association between intake of dairy products and colorectal cancer risk have
indicated an inverse association with milk, however, the evidence for cheese or other dairy products is inconsistent.
Methods: We conducted a systematic review and meta-analysis to clarify the shape of the dose–response
relationship between dairy products and colorectal cancer risk. We searched the PubMed database for prospective
studies published up to May 2010. Summary relative risks (RRs) were estimated using a random effects model.
Results: Nineteen cohort studies were included. The summary RR was 0.83 (95% CI [confidence interval]: 0.78–0.88,
I2 = 25%) per 400 g/day of total dairy products, 0.91 (95% CI: 0.85–0.94, I2 = 0%) per 200 g/day of milk intake and
0.96 (95% CI: 0.83–1.12, I2 = 28%) per 50 g/day of cheese. Inverse associations were observed in both men and
women but were restricted to colon cancer. There was evidence of a nonlinear association between milk and total
dairy products and colorectal cancer risk, P < 0.001, and the inverse associations appeared to be the strongest at the
higher range of intake.
Conclusion: This meta-analysis shows that milk and total dairy products, but not cheese or other dairy products, are
associated with a reduction in colorectal cancer risk.
Key words: colorectal cancer, dairy products, diet, meta-analysis
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com
product intake and colorectal cancer risk. We followed a predefined studies that did not report these, but reported the total number of cases/
protocol for the review (http://www.dietandcancerreport.org/downloads/ person-years, if dairy intake was analyzed by quantiles (and could be
SLR_Manual.pdf), which includes details of the search terms used. We approximated), e.g., the total number of person-years was divided by 5
also searched the reference lists of all the studies that were included in our when data were analyzed by quintiles in order to derive the number of
analysis as well as those listed in the published systematic reviews and person-years in each quintile. If this information was missing and the
meta-analyses [31, 32]. We followed standard criteria for conducting and results were reported by functional categories (e.g. <1, 1–3, 4–6, and ‡7
reporting meta-analyses [33]. servings per week), we used variance-weighted least squares regression to
estimate the slopes. The median or mean level of dairy product intake in
study selection each category of intake was assigned to the corresponding RR for each
We included prospective cohort, case–cohort and nested case–control study. For studies that reported dairy product intake by ranges of intake, we
studies of total dairy products or specific types of dairy products and estimated the midpoint in each category by calculating the average of the
colorectal cancer incidence. To be included in the analyses, estimates of the lower and upper bound. When the highest or the lowest category was open-
relative risk (RR) (such as hazard ratio or risk ratio) with the 95% ended, it was assumed that the open-ended interval length had the same
confidence intervals (CIs) had to be available in the publication. For the length as the adjacent interval. If the intakes were reported in densities (i.e.
dose–response analysis, a quantitative measure of intake had to be g per 1000 kcal), we recalculated the reported intakes to absolute intakes
provided. When there were several publications from the same study, we using the mean or median energy intake reported in the publication [27,
selected the publication with the largest number of cases. If all the required 29]. When studies reported the intake in servings and times per day or
information was not provided in the paper, we used the publication that week, we converted the intakes to grams of intake per day using standard
presented the results with sufficient information to be incorporated into units of 244 g (or 244 ml) for milk, 43 g for cheese (two slices) and 177 g for
the dose–response analyses. Thirty-five potentially relevant full-text total dairy products based on serving sizes reported in the ‘United States
publications [9–30, 34–46] were identified. We excluded seven publications Department of Agriculture Food and Nutrient Database for Dietary Studies’
of colorectal cancer mortality [36, 37, 40, 42–45], one publication reporting [49]. For one study that reported cheese intake in slices per week and per
on childhood dairy intake that only had information on intake by day, we used 21.5 g as a unit for each slice [26]. The dose–response results
household level [46], two publications that did not provide risk estimates in the forest plots are presented for a 400, 200 and 50 g/day increment
[38] or CIs [39] and one duplicate publication [41]. For the dose–response for total dairy, total milk and cheese, respectively. We examined a potential
analysis, we further excluded one publication because no quantities of the nonlinear dose–response relationship between total dairy and total milk
intake were provided [14], and four others because only the highest versus intakes and colorectal cancer by using fractional polynomial models [50].
the lowest level of intake was reported [11, 28, 34, 35]. We determined the best-fitting second order fractional polynomial
regression model, defined as the one with the lowest deviance. A likelihood
ratio test was used to assess the difference between the nonlinear and linear
data extraction
models to test for nonlinearity [51].
The following data were extracted from each study: The first author’s last
Heterogeneity between the studies was assessed by I2, which is the
name, publication year, country where the study was conducted, the study
amount of total variation that is explained by the between-study variation
name, follow-up period, sample size, gender, age, number of cases, dietary
and the Q test [52]. Subgroup and meta-regression analyses by study
assessment method (type, number of food items and whether it had
characteristics were conducted to investigate potential sources of
been validated), type of dairy product (total dairy, milk, cheese etc.),
heterogeneity. Publication bias was assessed with funnel plots, Egger’s test
quantity of intake, RRs and 95% CIs for dairy product intake and variables
[53] and with Begg’s test [54] with the results considered to indicate
adjusted for in the analysis. The search and data extraction of articles
potential publication bias when P < 0.10. We conducted sensitivity analyses
published up to June 2006 was conducted by several reviewers at
excluding one study at a time to explore whether the results were robust.
Wageningen University during the systematic literature review for the
Stata version 10.1 software (StataCorp, College Station, TX) was used for
WCRF/AICR report (http://www.dietandcancerreport.org/downloads/SLR/
the statistical analyses.
Colon_and_Rectum_SLR.pdf). The search from June 2006 to May 2010 was
conducted by two of the authors (DSMC and RL). Data was extracted into
a database by three authors (DSMC, RL and DA). results
statistical methods Nineteen cohort studies (24 publications) [9–30, 34, 35] could
Random effects models were used to calculate summary RRs and 95% CIs be included in the analysis of the highest versus the lowest dairy
for the highest versus the lowest level of dairy product intake and for the product intake and colorectal cancer risk and 17 of these
dose–response analysis [47]. The natural logarithm of the RR from each studies (18 publications) [9, 10, 12, 13, 15–20, 22–27, 29, 30]
study was weighted by the inverse of its variance and pooled across studies. were included in the dose–response analysis (Supplemental
A two-tailed P < 0.05 was considered statistically significant. When results Table S1, available at Annals of Oncology online; Figure 1). Eight
were reported separately for men and women, but not combined, we of the studies were from Europe, nine from the United States
combined the two results first using a fixed-effects model to obtain an and two from Asia. All studies provided adjusted risk estimates.
overall estimate for both the sexes combined, before pooling with other A summary of the study characteristics of the included studies
studies. is provided in the Supplemental Table S1 (available at Annals of
For the dose–response analysis, we used the method described by Oncology online).
Greenland and Longnecker [48] to compute study-specific slopes (linear
trends) and 95% CIs from the natural logs of the RRs and CIs across
categories of dairy product intake. The method requires that the
total dairy products
distribution of cases and person-years or noncases and the RRs with the high versus low analysis. Twelve cohort studies [14, 16–19, 22,
variance estimates for at least three quantitative exposure categories are 23, 25–29] investigated the association between high versus low
known. We estimated the distribution of cases and person-years in total dairy product intake and colorectal cancer risk and
Figure 1. Flow-chart of study selection. CI, confidence interval; WCRF, World Cancer Research Fund.
included 11 579 cases among 1 170 942 participants. The cancer risk. The association appeared broadly linear above this
summary RR for all studies was 0.81 (95% CI: 0.74–0.90), with range of intake (Figure 3A).
moderate heterogeneity, I2 = 42% and Pheterogeneity = 0.06
(Figure 2A). The association was in the direction of decreased milk
risk for colon cancer [9, 17–19, 26], summary RR = 0.72 (95% high versus low analysis. Ten cohort studies [10, 11, 17, 19, 20,
CI: 0.51–1.02, I2 = 50%, Pheterogeneity = 0.09, n = 5), but not 22, 23, 26, 27, 30] were included in the analysis of high versus
statistically significant, while no association was observed for low milk intake and colorectal cancer risk, including a total of
rectal cancer [17–19, 26, 34], summary RR = 0.96 (95% CI: 5011 cases among 655 483 participants. The summary RR was
0.65–1.41, I2 = 44%, Pheterogeneity = 0.13, n = 5) (results not 0.83 (95% CI: 0.74–0.93) for colorectal cancer, with low
shown). heterogeneity, I2 = 14% and Pheterogeneity = 0.31 (Figure 4A).
The summary RR was 0.82 (95% CI: 0.72–0.94, I2 = 0%,
dose–response analysis. Ten cohort studies [16–19, 22, 23, 25–
Pheterogeneity = 0.54, n = 7) for colon cancer [13, 17, 19, 26, 30,
27, 29] were included in the dose–response analysis of total
35] and 0.79 (95% CI: 0.60–1.06, I2 = 0%, Pheterogeneity = 0.79, n
dairy product intake and colorectal cancer risk. The summary
= 4) for rectal cancer [17, 19, 26, 30] (results not shown).
RR per 400 g increase per day (g/day) was 0.83 (95% CI: 0.78–
0.88) with little evidence of heterogeneity, I2 = 25% and dose–response analysis. Nine cohort studies [10, 17, 19, 20, 22,
Pheterogeneity = 0.22 (Figure 2B). There was a significant inverse 23, 26, 27, 30] were included in the dose–response analysis for
association for colon cancer (RR = 0.84, 95% CI: 0.72–0.97) but colorectal cancer. The summary RR for a 200 g/day increase in
not for rectal cancer (Table 1). The summary RR for colorectal the intake was 0.90 (95% CI: 0.85–0.94), with no evidence of
cancer ranged from 0.80 (95% CI: 0.77–0.84) when the Swedish heterogeneity, I2 = 0% and Pheterogeneity = 0.62 (Figure 4B). The
Mammography Cohort study was excluded to 0.85 (95% CI: inverse association was statistically significant only for colon
0.81–0.89) when the Cohort of Swedish Men was excluded. cancer (summary RR = 0.88, 95% CI: 0.79–0.97, I2 = 44%,
There was no indication of publication bias with Egger’s test Pheterogeneity = 0.11) (Table 1). In a sensitivity analysis, the
(P = 0.58) or with Begg’s test (P = 0.79). There was statistical summary RR for colorectal cancer ranged from 0.87 (95% CI:
evidence of a nonlinear association between total dairy product 0.83–0.92) when excluding the Cancer Prevention Study II
intake and colorectal cancer risk, P for nonlinearity < 0.001, Nutrition Cohort to 0.91 (95% CI: 0.86–0.96) when excluding
though the nonlinearity was observed at intakes below 100 the Cohort of Swedish men. There was no indication of
g/day, for which there was no evidence of decreased colorectal publication bias with Egger’s test (P = 0.86) or with Begg’s test
Annals of Oncology
Volume 23 | No. 1 | January 2012
Folate Yes 3 0.89 (0.80–0.99) 44.6 0.17 0.10 1 0.94 (0.83–1.05) 0.45 1 0.79 (0.61–1.02) 0.24
No 7 0.79 (0.74–0.84) 0 0.74 8 0.89 (0.84–0.94) 0 0.60 6 1.01 (0.86–1.18) 19.4 0.29
Energy intake Yes 9 0.83 (0.78–0.89) 32.9 0.16 0.99 8 0.89 (0.85–0.94) 0 0.57 0.51 6 0.94 (0.80–1.10) 28.6 0.22 0.44
No 1 0.83 (0.73–0.94 1 1.00 (0.72–1.39) 1 1.13 (0.80–1.61)
reviews
n denotes the number of studies. WHR, waist-to-hip ratio.
a
P for heterogeneity within each subgroup.
b
P for heterogeneity between subgroups with meta-regression analysis.
c
Subgroup analyses restricted to studies that reported results both for men and women.
d
Subgroup analyses restricted to studies that reported results both for colon and rectum.
A A
1.2
Relative Risk
Study (95% CI)
1
.8
B
B
1.2
Relative Risk
Study (95% CI)
1
.8
0 100 200 300 400 500 600 700 800 Park, 2007 0.91 ( 0.83, 0.99)
Total milk (g/day) Lee, 2009 0.81 ( 0.59, 1.11)
.25 .5 .75 1 2
Figure 3. Total dairy products and total milk and colorectal cancer,
nonlinear dose–response. RR, relative risk. Relative Risk
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