文献：Aune D et al.Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies.BMJ 2011;343:bmj.d6617.
前向き研究25件を対象に、食物繊維および全粒穀物の摂取と大腸癌リスクの関連をシステマティックレビューとメタアナリシスで評価。総食物繊維量10g/日摂取群の要約した相対リスクは0.90、全粒穀物3杯/日増加ごとの要約した相対リスクは0.83だった。食物繊維、特に穀物の大量摂取と大腸癌リスク減少との関連が示唆された。
Research
Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies
BMJ2011;343doi: 10.1136/bmj.d6617(Published 10 November 2011)
Cite this as:BMJ2011;343:bmj.d6617
1. Dagfinn Aune, research associate1,
2. Doris S M Chan, research associate1,
3. Rosa Lau, research associate1,
4. Rui Vieira, data manager1,
5. Darren C Greenwood, senior lecturer in biostatistics2,
6. Ellen Kampman, professor of diet and cancer3,
7. Teresa Norat, principal investigator1
Author Affiliations
1. 1Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, London W2 1PG, UK
2. 2Biostatistics Unit, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds, UK
3. 3Division of Human Nutrition, Wageningen University and Research Centre, Wageningen, Netherlands
1. Correspondence to: D Aune d.aune@imperial.ac.uk
・Accepted 21 September 2011
Abstract
Objective To investigate the association between intake of dietary fibre and whole grains and risk of colorectal cancer.
Design Systematic review and meta-analysis of prospective observational studies.
Data sources PubMed and several other databases up to December 2010 and the reference lists of studies included in the analysis as well as those listed in published meta-analyses.
Study selection Prospective cohort and nested case-control studies of dietary fibre or whole grain intake and incidence of colorectal cancer.
Results 25 prospective studies were included in the analysis. The summary relative risk of developing colorectal cancer for 10 g daily of total dietary fibre (16 studies) was 0.90 (95% confidence interval 0.86 to 0.94, I2=0%), for fruit fibre (n=9) was 0.93 (0.82 to 1.05, I2=23%), for vegetable fibre (n=9) was 0.98 (0.91 to 1.06, I2=0%), for legume fibre (n=4) was 0.62 (0.27 to 1.42, I2=58%), and for cereal fibre (n=8) was 0.90 (0.83 to 0.97, I2=0%). The summary relative risk for an increment of three servings daily of whole grains (n=6) was 0.83 (0.78 to 0.89, I2=18%).
Conclusion A high intake of dietary fibre, in particular cereal fibre and whole grains, was associated with a reduced risk of colorectal cancer. Further studies should report more detailed results, including those for subtypes of fibre and be stratified by other risk factors to rule out residual confounding. Further assessment of the impact of measurement errors on the risk estimates is also warranted.
Introduction
Colorectal cancer is the third most common type of cancer, with 1.2 million new cases diagnosed in 2008 worldwide, accounting for about 9.7% of all cases of cancer.1 Evidence from ecological studies, migrant studies, and secular trend studies suggest that environmental risk factors are of major importance in the cause of colorectal cancer.2 3 4 Dietary factors have been suspected as important, but only intakes of red and processed meat and alcohol are considered to be convincing dietary risk factors for colorectal cancer.5
In the 1970s, Burkitt proposed the hypothesis that dietary fibre reduces the risk of colorectal cancer, based on the observation of low rates of such cancer among rural Africans who ate a diet with a high fibre content.6 Several plausible mechanisms have been proposed to explain the hypothesis, including increased stool bulk and dilution of carcinogens in the colonic lumen, reduced transit time, and bacterial fermentation of fibre to short chain fatty acids.7 However, although many epidemiological studies have investigated the association between fibre intake and risk of colorectal cancer, the results have not been consistent and the possibility of residual confounding by folate intake remains a controversial issue.8 Case-control studies have generally shown a protective association,9 10 whereas the results from cohort studies have been mixed.8 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 In addition, it is not clear whether only specific types or sources of fibre are associated with the risk. Although initial cohort studies generally reported no significant association between fibre intake and risk of colorectal cancer, the hypothesis regained interest when the European Prospective Investigation into Cancer and Nutrition (EPIC) study reported a linear decrease in the risk of colorectal cancer with increasing fibre intake.19 A subsequent pooled analysis of 13 North American and European cohort studies (not including the EPIC study) reported an 18% increased risk of colorectal cancer with low fibre intake (<10 g/day v 10-15 g/day), but no further reductions in risk were observed with higher intake.31 More recently, results from additional large cohort studies23 24 25 26 27 28 29 30 have been published and, together with the EPIC study, included more than 1.7 million participants and 12?000 cases and included several studies from Asian populations.23 24 26 30 With such a large number of additional studies we had sufficient statistical power to clarify the dose-response relation between fibre intake and risk of colorectal cancer. In addition we examined whether specific types of fibre are associated with risk.
Whole grains are a major source of dietary fibre and contain germ, endosperm, and bran, in contrast with refined grains that contain only the endosperm. The germ and bran contain numerous nutrients, which are removed during the refining process. In addition, whole grains are a major source of several vitamins, minerals, and phytochemicals, which have anticancer properties and could plausibly influence the risk of colorectal cancer by several potential mechanisms.32 An earlier review and meta-analysis of case-control studies of whole grain intake and colorectal cancer and polyps reported a summary odds ratio of 0.79 for the highest versus the lowest intake.33 However, the interpretation of case-control studies is hampered by possible recall and selection biases, which make it difficult to draw firm conclusions. Over the past decade results from several cohort studies have been published on whole grain intake and risk of colorectal cancer, with mixed results.16 20 25 27 34 35 36 37 38 39 Some studies suggested no association,16 20 34 36 whereas others reported an inverse association with higher whole grain intake.25 27 35 37 38 39 To clarify the association between dietary fibre and whole grain intake and risk of colorectal cancer we carried out a systematic review and meta-analysis of published prospective studies. We also did meta-regression and sensitivity analyses to evaluate potential sources of heterogeneity in the analyses.
Methods
Several reviewers at Wageningen University carried out the literature search and extracted data up to December 2005. They searched several databases, including PubMed, Embase, CAB Abstracts, ISI Web of Science, BIOSIS, Latin American and Caribbean Center on Health Sciences Information, Cochrane library, Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, National Research Register, and In Process Medline. As all the relevant prospective studies were identified by the PubMed searches the protocol was modified and only PubMed was used for the updated searches from January 2006 to December 2010. No language restrictions were imposed. This review was done as part of the Continuous Update Project of the World Cancer Research Fund and has been published online (www.wcrf.org/PDFs/Colorectal-cancer-CUP-report-2010.pdf). A predefined protocol was used for the review (www.dietandcancerreport.org/downloads/SLR_Manual.pdf) and we followed standard criteria for meta-analyses of observational studies.40 Abstracts, grey literature, and unpublished results or information were not included. We also searched the reference lists of the studies that were included in our analysis as well as those listed in the published meta-analyses.33 41
Study selection
To be included studies had to have a prospective cohort, case-cohort, or nested case-control design and investigate the association between dietary fibre or whole grain intake and incidence of colorectal cancer. We excluded retrospective case-control studies and cross sectional studies. The publication had to include estimates of the relative risk (hazard ratio, risk ratio) with the 95% confidence intervals. For the dose-response analysis, a quantitative measure of intake and the total number of cases and person years had to be provided. When several publications were from the same study we selected the publication with the largest number of cases. We identified 40 potentially relevant full text publications.8 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 34 35 36 37 38 39 42 43 44 45 46 47 48 49 50 51 52 53 54 We excluded seven that reported mean exposure only,42 43 44 45 46 47 48 seven that were duplicate publications,19 49 50 51 52 53 54 and one that was on mortality from colorectal cancer.34 Two publications that were included in the dietary fibre analyses reported on specific whole grain foods, not overall intake, and we excluded these from the whole grain analysis.16 20 For the dose-response analysis we further excluded two publications that reported results only for the highest versus the lowest levels of intake,30 37 and two publications that did not report quantities of intake.11 15
Data extraction
From each study we extracted data on the first author’s last name, year of publication, country where the study was done, study name, follow-up period, sample size, sex, age, number of cases, method of dietary assessment (type, number of food items, and whether the assessment method had been validated), exposure (by type of outcome), quantity of intake, relative risks and 95% confidence intervals for the highest versus the lowest intake, and variables adjusted for in the analysis. Several reviewers at Wageningen University carried out the search and extracted data of articles published up to December 2005 during the systematic literature review for the World Cancer Research Fund and Association for International Cancer Research report (www.dietandcancerreport.org/downloads/SLR/Colon_and_Rectum_SLR.pdf). Two of the authors (DSMC and RL) did the search from January 2006 to December 2010. Three authors (DSMC, RL, and DA) extracted the data into a database, and two authors (TN and DA) checked these for accuracy.
Statistical analysis
We used random effects models to calculate summary relative risks and 95% confidence intervals for the highest versus the lowest levels of dietary fibre and whole grain intake and for the dose-response analysis. The average of the natural logarithm of the relative risks was estimated and we weighted the relative risk from each study by the inverse of its variance. A two tailed P<0.05 was considered statistically significant. For studies that reported results separately for colon and rectal cancer or for men and women separately, we combined the estimates using a fixed effects model to obtain an overall estimate for colorectal cancer or both sexes combined.
We used a previously described method55 for the dose-response analysis and computed study specific slopes (linear trends) and 95% confidence intervals from the natural logs of the relative risks and confidence intervals across categories of dietary fibre and whole grain intake. The method requires that the distribution of cases and person years or non-cases and the relative risks with the variance estimates are known for at least three quantitative categories of use. We estimated the distribution of cases or person years in studies that did not report these but reported the total number of cases or person years if the results were analysed by quantiles (and could be approximated)?for example, the total number of person years was divided by 5 when data were analysed by quintiles to derive the number of person years in each fifth. We assigned the median or mean level of dietary fibre or whole grain intake in each category to the corresponding relative risk for each study. For studies that reported the intake by ranges of intake we estimated the midpoint in each category by calculating the average of the lower and upper bound. When the highest category was open ended we assumed the length of the open ended interval to be the same as that of the adjacent interval. When the lowest category was open ended we set the lower boundary to zero. If the intakes were reported in densities (servings per 1000 kcal) we recalculated the reported intakes to absolute intakes using the mean or median energy intake.18 21 27 28 In studies that reported the whole grain intake in grams daily we used 30 g as a serving size for recalculation of the intakes to a common scale (servings daily). The dose-response results in the forest plots are presented for a 10 g daily increment for dietary fibre and for an increment of three servings daily (90 g) for whole grains. We examined a potential non-linear dose-response relation between dietary fibre and whole grain intake and colorectal cancer by using fractional polynomial models.56 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 non-linear and linear models to test for non-linearity.57
Heterogeneity between studies was assessed by the Q test and I2 statistic.58 I2 is the amount of total variation that is explained by variation between studies. We did not use a score to assess study quality but in subgroup analyses we determined whether indicators of study quality, such as study size, number of cases, duration of follow-up, and adjustment for confounders modified the results. Heterogeneity between subgroups was evaluated by meta-regression.
Publication bias was assessed with Egger’s test59 and Begg’s test,60 with the results considered to indicate publication bias when P<0.10. In addition, we visually explored funnel plots for asymmetry. We carried out sensitivity analyses excluding one study at a time to explore whether the results were driven by one large study or by a study with an extreme result.
Results
Dietary fibre
Twenty one prospective studies8 11 12 13 14 15 16 17 18 20 21 22 23 24 25 26 27 28 29 30 36 were identified and included in the analysis of the highest versus the lowest intake of dietary fibre and risk of colorectal cancer, 18 of which8 12 13 14 16 17 18 20 21 22 23 24 25 26 27 28 29 36 were included in the dose-response analyses (table 1?, Fig 1 ). Twelve of the studies were from the United States, five from Europe, and four from Asia. Table 1 summarises the characteristics of the included studies. The ranges of intake varied: 6.3-21.4 g/day for total dietary fibre, 1.8-15.5 g/day for fruit fibre, 1.9-16.8 g/day for vegetable fibre, 3.0-16.9 g/day for cereal fibre, and 1.3-3.8 g/day for legume fibre (results not shown).
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Fig 1 Flow chart of publications included in systematic review
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Table 1
Prospective studies of dietary fibre intake and incidence of colorectal cancer
Total dietary fibre
High versus low intake
Nineteen prospective studies (18 publications) were included in the analysis of high versus low intake of total dietary fibre and risk of colorectal cancer (table 1).8 11 12 15 16 17 18 20 21 22 23 24 25 26 27 28 29 30 The summary relative risk was 0.88 (95% confidence interval 0.82 to 0.94), with no evidence of heterogeneity (I2=0%, P=0.48, see web extra figure 1a).
Dose-response analysis
Sixteen prospective studies (15 publications)8 12 16 17 18 20 21 22 23 24 25 26 27 28 29 were included in the dose-response analysis, with 14?514 cases among 1?985?552 participants. The summary relative risk was 0.90 (0.86 to 0.94) for each 10 g/day intake, with no significant heterogeneity (I2=0%, P=0.48, Fig 2 ). A statistically significant inverse association was seen for colon cancer8 12 13 14 21 23 24 26 27 28 29 36 (13 studies, summary relative risk 0.89, 0.81 to 0.97, I2=35%, P=0.11) but not for rectal cancer8 12 21 23 24 26 27 28 29 (10 studies, 0.91, 0.83 to 1.03, I2=15%, P=0.31), although evidence was lacking for heterogeneity between subsites (P=0.86, see table 3). Publication bias was not evident with either Egger’s test (P=0.62) or Begg’s test (P=0.56). In a sensitivity analysis excluding one study at a time, the summary relative risk for colorectal cancer ranged from 0.89 (0.85 to 0.93) when the National Institutes of Health-American Association for Retired Persons (NIH-AARP) Diet and Health Study was excluded to 0.91 (0.88 to 0.96) when the EPIC study was excluded. A non-linear association was not evident between intake of total dietary fibre and risk of colorectal cancer (P=0.32 for non-linearity, fig 2).
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Fig 2 Dose-response analyses between dietary fibre and risk of colorectal cancer. NHS=Nurses’ Health Study; HPFS=Health Professionals Follow-up Study
Fruit fibre
High versus low intake
Nine cohort studies (eight publications)8 17 18 21 22 26 27 28 were included in the analysis of high versus low intake of fruit fibre and risk of colorectal cancer. The summary relative risk was 0.94 (0.85 to 1.04; see also web extra figure 2a), with little evidence of heterogeneity (I2=39%, P=0.11).
Dose-response analysis
Nine cohort studies (eight publications)8 17 18 21 22 26 27 28 were included in the dose-response analysis of fruit fibre and risk of colorectal cancer, with 9930 cases among 1?514?871 participants. The summary relative risk for each 10 g/day intake was 0.93 (0.82 to 1.05, fig 3?), with little evidence of heterogeneity (I2=23%, P=0.24). Publication bias was not evident with Egger’s test (P=0.83) or Begg’s test (P=0.47). The summary relative risk ranged from 0.87 (0.78 to 0.96) when the NIH-AARP Diet and Health Study was excluded to 0.95 (0.84 to 1.07) when the Nurses’ Health Study was excluded.
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Fig 3 Risk of colorectal cancer according to fibre types. NHS=Nurses’ Health Study; HPFS=Health Professionals Follow-up Study
Vegetable fibre
High versus low intake
Nine cohort studies (eight publications)8 17 18 21 22 26 27 28 were included in the analysis of high versus low intake of vegetable fibre and risk of colorectal cancer. The summary relative risk was 0.98 (0.91 to 1.06, also see web extra figure 2b), with no evidence of heterogeneity (I2=0%, P=0.48).
Dose-response analysis
Nine cohort studies (eight publications)8 17 18 21 22 26 27 28 were included in the dose-response analysis of vegetable fibre and risk of colorectal cancer, with 9930 cases among 1?514?871 participants. The summary relative risk for each 10 g/day intake was 0.98 (0.91 to 1.06, fig 3), with no evidence of heterogeneity (I2=0%, P=0.60). Publication bias was not evident with Egger’s test (P=0.51) or Begg’s test (P=0.92). The summary relative risk ranged from 0.96 (0.89 to 1.04) when the Nurses’ Health Study was excluded to 1.02 (0.94 to 1.10) when the Multiethnic Cohort Study was excluded.
Legume fibre
High versus low intake
Four cohort studies8 18 22 27 were included in the analysis of high versus low intake of legume fibre and risk of colorectal cancer. The summary relative risk was 0.89 (0.78 to 1.02, see also web extra figure 2c), with moderate heterogeneity (I2=40.8%, P=0.17).
Dose-response analysis
Four cohort studies8 18 22 27 were included in the dose-response analysis of legume fibre intake and risk of colorectal cancer, with 5405 cases among 1?095?056 participants. The summary relative risk for each 10 g/day intake was 0.62 (0.27 to 1.42, fig 3), with moderate to high heterogeneity (I2=58%, P=0.07). The summary relative risk ranged from 0.38 (0.08 to 1.87) when excluding the NIH-AARP Diet and Health Study to 0.84 (0.65 to 1.09) when excluding the Women’s Health Study.
Cereal fibre
High versus low intake
Eight cohort studies (seven publications)8 17 18 21 22 27 28 were included in the analysis of high versus low intake of cereal fibre and risk of colorectal cancer. The summary relative risk was 0.90 (0.83 to 0.96, also see web extra figure 2d), with no significant heterogeneity (I2=0%, P=0.94).
Dose-response analysis
Eight cohort studies (seven publications)8 17 18 21 22 27 28 were included in the dose-response analysis of cereal fibre and risk of colorectal cancer, with 9487 cases among 1?471?756 participants. The summary relative risk for each 10 g/day intake was 0.90 (0.83 to 0.97, fig 3), with no evidence of heterogeneity (I2=0%, P=0.78). Publication bias was not evident with Egger’s test (P=0.90) or Begg’s test (P=1.00). The summary relative risk ranged from 0.85 (0.76 to 0.95) when the Multiethnic Cohort Study was excluded to 0.93 (0.85 to 1.03) when the NIH-AARP Diet and Health Study was excluded.
Whole grains
Seven cohort studies were included in the analysis of total whole grain intake and risk of colorectal cancer (table 2?, Fig 1 ).25 27 35 36 37 38 39 Two studies were from Europe and the other five from the United States (table 2). Total whole grains included whole grain rye breads, whole grain breads, oatmeal, whole grain cereals, high fibre cereals, brown rice, and porridge. The range of whole grain intake varied from and 61-128 g/day (results not shown).
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Table 2
Prospective studies of whole grain intake and incidence of colorectal cancer
High versus low intake
Four cohort studies25 27 35 38 were included in the analysis of high versus low intake of whole grains and risk of colorectal cancer. The summary relative risk was 0.79 (0.72 to 0.86), with no evidence of heterogeneity (I2=0%, P=0.98, see web extra figure 1b). The results for colon and rectal cancer were similar: summary relative risks 0.82 (0.72 to 0.92, I2=23%, P=0.27)27 35 36 37 38 and 0.80 (0.59 to 1.07, I2=58%, P=0.10).27 35 38 The results for rectal cancer were, however, not statistically significant.
Dose-response analysis
Six studies (five publications)25 27 35 38 39 were included in the dose-response analysis, with a total of 7941 cases among 774?806 participants. The summary relative risk for colorectal cancer with an increment of three servings daily (90 g/day) of whole grains was 0.83 (0.78 to 0.89, fig 4?), with no evidence of heterogeneity (I2=18%, P=0.30). The summary relative risk for colon cancer27 35 36 38 was 0.86 (0.79 to 0.94), with no evidence of heterogeneity (I2=0%, P=0.42), and for rectal cancer27 35 38 was 0.80 (0.56 to 1.14), with substantial heterogeneity (I2=91%, P<0.001, table 4). In a sensitivity analysis excluding one study at a time, no particular study explained the results for colorectal cancer; the summary relative risk ranged from 0.82 (0.77 to 0.88) when the Swedish Mammography Study was excluded to 0.86 (0.80 to 0.92) when the NIH-AARP Diet and Health Study was excluded. Publication bias was not evident with Egger’s test (P=0.54) or Begg’s test (P=1.00), although the number of studies was low. However, the funnel plots did not suggest asymmetry. A non-linear association between whole grain intake and risk of colorectal cancer was not indicated (P=0.26, fig 4).
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Fig 4 Dose-response analyses between whole grains and risk of colorectal cancer. NHS=Nurses’ Health Study; HPFS=Health Professionals Follow-up Study
Subgroup, sensitivity, and meta-regression analyses
In subgroup analyses defined by sex, subsite, adjustment for confounders, number of cases, duration of follow-up, geographical location, and range of intake, total dietary fibre intake was inversely associated with risk of colorectal cancer in most subgroups, with no evidence of significant heterogeneity between subgroups with meta-regression analyses (table 3?). Similar results were observed for intake of cereal fibre and whole grains (table 4?). Intake of fruit fibre was not significantly associated with risk of colorectal cancer in most subgroup analyses. In the subgroups of studies that adjusted for alcohol intake and body mass index or weight, however, inverse associations were significant, with evidence of heterogeneity between subgroups (P=0.04, table 3). When stratified by the range of intake, an inverse association was observed for intake of fruit fibre in studies with a range of 10 g/day or more but not among studies with a range of 10 g/day or less (P=0.04 for heterogeneity), but evidence of a difference in the results for the other fibre types was lacking when stratified by the range of intake (tables 3 and 4). Intake of vegetable fibre consistently was not associated with risk of colorectal cancer in subgroup analyses (table 3?). Too few studies of legume fibre precluded any meaningful subgroup analyses.
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Table 3
Subgroup analyses of fibre intake and risk of colorectal cancer, dose-response analysis
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Table 4
Subgroup analyses of cereal fibre and whole grain intake and risk of colorectal cancer, dose-response analysis
In addition, the effect on the results of excluding studies from the dose-response analysis was explored. When the analysis of high versus low intake was restricted to the studies that were included in the dose-response analysis of total dietary fibre, the summary relative risk was 0.86 (0.80 to 0.92, I2=0%, P=0.46 for heterogeneity), similar to the original analysis including all studies.
The influence on the results of the method used to estimate total fibre intake was assessed. For the eight studies17 21 22 24 26 27 28 using the Association of Official Analytical Chemists method, the summary relative risk was 0.91 (0.85 to 0.97, I2=13.3%, P=0.33 for heterogeneity), for the four studies8 16 21 using the Englyst method it was 0.91 (0.81 to 1.02, I2=37.0%, P=0.19 for heterogeneity), and for the six studies12 18 20 23 25 29 with an unknown method it was 0.93 (0.86 to 1.00, I2=0%, P=0.89 for heterogeneity). In this sensitivity analysis no heterogeneity was found between subgroups (P=0.39 for heterogeneity). In addition, in one study the results did not differ materially between the two methods.21
Discussion
Our meta-analysis supports an inverse association between intake of dietary fibre, cereal fibre, and whole grains and risk of colorectal cancer, but we found no significant evidence for an association with intake of fibre from fruit, vegetables, or legumes.
Comparison with other studies
Our results for total dietary fibre are consistent with a previous meta-analysis of case-control studies, which found an inverse association between fibre intake and risk of colorectal cancer. Our results, based on prospective studies, are not, however, as strong as the previous results from case-control studies.9 The size of the summary estimates from our analyses is more in line with those of a pooled analysis of cohort studies,31 which found an 18% increased risk among people with a low intake of dietary fibre (<10 g/day). In that analysis, however, no further reduction in risk occurred with higher intake of fibre, whereas we observed a linear inverse association with increasing intake, such as shown in the EPIC study.8 Several differences between our analysis and the pooled analysis could explain the differences between the results. For example, although some overlap occurs between the studies included in the two analyses, some differences also exist. Our dose-response analysis included results from seven16 17 18 21 22 25 of the 13 studies in the Pooling Project of Prospective Studies of Diet and Cancer, but included nine additional studies8 12 20 23 24 26 27 28 29 not included in the pooled analysis, some of which were large. Thus our analysis included more than 14?000 cases among 1.9 million participants compared with 8000 cases among 700?000 participants in the pooled analysis. It is therefore possible that these additional studies contributed to a better assessment of the dose-response relation between fibre intake and risk of colorectal cancer. In line with the pooled analysis we found no evidence for an association between fruit or vegetable fibre and risk of colorectal cancer. However, in a previous meta-analysis of prospective studies we showed a reduction in risk with high intake of fruit and vegetables,61 suggesting the potential role of components other than fibre in fruits and vegetables in explaining this result. In addition, we cannot exclude the possibility that the range of fruit fibre intake was too low to detect an inverse association in the overall analysis, although no difference in the summary estimates was observed for the other fibre types when stratified by the range of intake. Inverse associations were evident between intakes of cereal fibre and whole grain and risk of colorectal cancer in our analysis, and the results for whole grain intake are consistent with a previous meta-analysis of case-control studies, which reported a 20% reduction in risk with high whole grain intake.33 The pooled analysis found a marginally significant inverse association between whole grain intake and colorectal cancer: pooled relative risk 0.92 (95% confidence interval 0.84 to 1.00).31 In contrast to our results, the Women’s Health Initiative Trial did not find a reduction in risk of colorectal cancer among participants who were randomised to an intervention with increased intakes of fruits, vegetables, grains, and fibre and reductions in fat intake.62 However, fibre intake increased by only 2.5 g/day from baseline to the three year follow-up, from 15.4 to 17.9 g/day, whereas the intake in the comparison group did not materially change (from 15.4 to 14.8 g/day). Thus the changes in fibre intake in that trial may have been too small to significantly reduce the risk of colorectal cancer. Given that our results show a 10% reduction in risk of colorectal cancer for each 10 g intake of fibre daily, only a 2-3% reduction in risk would be expected with such a small increase in fibre intake.
Limitations of the study
Our meta-analysis has limitations that affect the interpretation of the results. It is possible that the weak inverse associations between dietary fibre or whole grain intake and risk of colorectal cancer could result from unmeasured or residual confounding by other dietary or lifestyle factors. Higher intakes of dietary fibre and whole grain are typically associated with other health behaviours, such as higher intakes of calcium and folate; higher levels of physical activity; lower prevalence of smoking, overweight, or obesity; and lower intakes of alcohol and red and processed meat.22 27 63 Many but not all of the studies adjusted for potential confounding factors, although not all potential confounders were adjusted for in every study. In analyses stratified by adjustment for confounding factors, however, we found that the association between dietary fibre, cereal fibre, and whole grains persisted in most subgroups, with adjustment for potential confounding factors. In addition, in meta-regression analyses evidence that the results for these exposures differed significantly whether confounders had been adjusted for or not was lacking. Only in the analysis of fruit fibre was heterogeneity evident between studies that did or did not adjust for body mass index or weight and alcohol intake, with significant inverse associations among the studies with such adjustments. None of the included studies reported results stratified by alcohol, smoking, body mass index, or meat intake. Any further studies should report analyses stratified by other risk factors to better be able to rule out residual confounding.
Although publication bias can be a problem in meta-analyses of published literature we found no evidence of such bias in this analysis. In addition, the few studies that were excluded from the dose-response analysis of dietary fibre are unlikely to have altered the results because the results from the analyses of high versus low intake were similar when we repeated the analyses with the same dataset as in the dose-response analysis.
Accurate assessment of dietary fibre intake and other food constituents is a challenge. The definition of dietary fibre may differ between studies and may contribute to heterogeneity in the results. Some studies used the Englyst definition of fibre, which distinguishes non-starch polysaccharides from starch, whereas other studies calculated fibre intake using the Association of Official Analytical Chemists method, which includes some starch as dietary fibre. The summary relative risks were generally similar, however, no matter which method was used, and there was no evidence of heterogeneity between subgroups when stratified by the method used to calculate fibre intake.
Most studies carried out to date have used food frequency questionnaires to assess dietary intake. Concern is, however, increasing that measurement errors associated with the use of food frequency questionnaires may obscure associations between dietary intake and risk of chronic disease.64 Few studies have reported results corrected for measurement errors. In the EPIC study the relative risk of colorectal cancer was 0.75 (95% confidence interval 0.59 to 0.95) for the highest compared with lowest fifths of fibre intake, and after calibration with more detailed data the relative risk was 0.58 (0.41 to 0.85).19 In the Pooling Project of Prospective Studies the adjusted relative risk for less than 10 g/day compared with 10 g/day or more was 1.22 (1.10 to 1.35), but this increased to 2.16 (1.12 to 4.16) after correction for measurement error.31 In a pooled analysis of seven UK based cohort studies, a stronger association was observed when food diaries were used to assess dietary fibre intake; an odds ratio of 0.66 (95% confidence interval 0.45 to 0.96) for the highest versus lowest fifths of fibre density compared with 0.88 (0.57 to 1.36) when food frequency questionnaires were used to measure dietary intake.65 The latter was of similar size to our summary estimate for the highest versus lowest intake (summary relative risk 0.88, 95% confidence interval 0.82 to 0.94). The results using food diaries were further strengthened when corrected for measurement errors: odds ratio 0.68 (95% confidence interval 0.48 to 0.96) for a 0.7 g/MJ increase in fibre intake (uncorrected odds ratio 0.83, 95% confidence interval 0.70 to 0.97).65 The results from these studies suggest that our results for dietary fibre and risk of colorectal cancer are likely to be conservative estimates of the true underlying risk and that any further studies should incorporate correction for measurement error in the analyses.
Strengths of the study
Our meta-analysis also has several strengths. Because we based our analysis on prospective studies, our findings are unlikely to be explained by recall bias and selection bias. Our meta-analysis included a large number of studies and more than 14?500 cases, and almost two million participants in the dietary fibre analysis. Thus we had adequate statistical power to clarify the shape of the dose-response relation between dietary fibre intake and risk of colorectal cancer and to detect moderate reductions in risk. We also carried out sensitivity analyses to investigate whether any particular study explained the results, but the findings were generally robust. We quantified the association between intake of dietary fibre and whole grain and risk of colorectal cancer by carrying out linear and non-linear dose-response analyses.
Mechanisms
A protective effect of dietary fibre and whole grain consumption on risk of colorectal cancer is biologically plausible. Whole grain foods are important sources of dietary fibre and may decrease the risk of colorectal cancer by increasing stool bulk, diluting faecal carcinogens, and decreasing transit time, thus reducing the contact between carcinogens and the lining of the colorectum.7 In addition, bacterial fermentation of fibre results in the production of short chain fatty acids, which may have protective effects against colorectal cancer.66 Other components of whole grains may also protect against colorectal cancer, including antioxidants, vitamins, trace minerals, phytate, phenolic acids, lignans, and phytoestrogens.66 67 68 Whole grains have a high content of folate and magnesium, which have been associated with a reduced risk of colorectal cancer.69 70 71 Higher intakes of dietary fibre and whole grain also protect against weight gain72 73 and type 2 diabetes,74 75 and it is possible that part of the potential effect of fibre intake is mediated through improved weight control and reduced insulin resistance, although these may not be the main mechanisms. However, the results persisted in studies that adjusted for both folate and body mass index, suggesting an association independent of folate and body mass index.
Conclusions and policy implications
Our results indicate a 10% reduction in risk of colorectal cancer for each 10 g/day intake of total dietary fibre and cereal fibre and a about a 20% reduction for each three servings (90 g/day) of whole grain daily, and further reductions with higher intake. These findings thus have important public health implications. Our results provide further support for public health recommendations to increase the intake of dietary fibre in the prevention of colorectal cancer. However, they suggest a particular benefit of increasing cereal fibre and whole grain intake. Increasing the intake of dietary fibre and whole grains is also likely to reduce the risk of cardiovascular disease,76 77 78 type 2 diabetes,74 75 overweight and obesity,72 73 and possibly overall mortality,76 78 thus there are several health benefits by increasing fibre intake and replacing refined grains with whole grains.
In summary, our meta-analysis suggests that a high intake of dietary fibre, particularly from cereal and whole grains, is associated with a reduced risk of colorectal cancer. Further studies should report more detailed results, including those for subtypes of fibre, stratify the results by subsites within the colorectum, and stratify the results by other risk factors to be able to rule out residual confounding. Further assessment of the impact of measurement errors on the risk estimates is also warranted.
What is already known on this topic
・Colorectal cancer is the third most common cancer worldwide, with 1.2 million new cases annually
・Intake of dietary fibre and whole grains has been established as protective against cardiovascular disease, but the association with colorectal cancer is not convincing
・It is unclear whether only specific types of fibre or sources of fibre are associated with the risk of colorectal cancer
What this study adds
・Intakes of dietary fibre, cereal fibre, and whole grains are associated with linear decreases in the risk of colorectal cancer
・Evidence of an association between intake of fruit, vegetable, or legume fibre and risk of colorectal cancer was lacking
・Intake of dietary fibre, particularly cereal fibre and whole grains, was associated with a small reduction in the risk of colorectal cancer
Notes
Cite this as: BMJ 2011;343:d6617
Footnotes
・We thank the systematic literature review team at Wageningen University for their contributions to the colorectal cancer database.
・Contributors: The systematic literature review team at Wageningen University carried out the search, and selected and extracted data up to the end of December 2005. RV developed and managed the database for the Continuous Update Project. RL and DSMC did the updated literature search. RL, DSMC, and DA did the updated data extraction. DA and DSMC selected the studies and carried out the statistical analyses. DCG was statistical adviser and contributed to the statistical analyses. All authors revised the manuscript. EK was principal investigator of the Systematic Literature Reviews at Wageningen University. TN is principal investigator of the Continuous Update Project and wrote the protocol and implemented the study. DA wrote the first draft of the original manuscript. All authors had full access to all of the data in the study and prepared the manuscript. DA is guarantor. The sponsor of this study had no role in the decisions about the design and conduct of the study; collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript. The views expressed in this review are the opinions of the authors. They may not represent the views of the World Cancer Research Fund International/American Institute for Cancer Research and may differ from those in future updates of the evidence related to food, nutrition, physical activity, and cancer risk.
・Funding: This work was funded by the World Cancer Research Fund (grant No 2007/SP01) as part of the Continuous Update Project.
・Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.
・Ethical approval: Not required.
・Data sharing: No additional data available.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.
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