ABSTRACT

Context  Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer.

Objective  To evaluate the association between dietary fiber intake and risk of colorectal cancer.

Design, Setting, and Participants  From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725 628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model.

Main Outcome Measure  Incident colorectal cancer.

Results  During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR = 0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR = 0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site = .07).

Conclusions:  In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer.

INTRODUCTION:

Dietary fiber has been hypothesized to reduce the risk of colorectal cancer. Potential mechanisms for a protective effect include dilution of fecal carcinogens and procarcinogens, reduction of transit time of feces through the bowel, production of short chain fatty acids, which promote anticarcinogenic action, and binding of carcinogenic bile acids.¹ However, the results of numerous epidemiological studies have been inconsistent. Ecological correlation studies and many case-control studies have found an inverse association between dietary fiber intake and risk of colorectal cancer.² On the other hand, most prospective cohort studies have found no association between dietary fiber intake and risk of colorectal cancer^3-7 or adenomas (precursors of colorectal cancer),⁸ and randomized clinical trials of dietary fiber supplementation have failed to show reductions in the recurrence of colorectal adenomas.^9-12 Recently, the European Prospective Investigation into Cancer and Nutrition (EPIC) study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial observed a statistically significant 25% lower risk of colorectal cancer^13-14 or adenomas,¹⁵ respectively, in the highest quintile of dietary fiber intake compared with the lowest. Because of these discordant results, the debate continues on whether dietary fiber consumption decreases colorectal cancer risk. In this study, we evaluated the association between dietary fiber intake and risk of colorectal cancer by reanalyzing the primary data from 13 prospective cohort studies.

METHODS:

Study Population

The Pooling Project of Prospective Studies of Diet and Cancer (Pooling Project) was established to summarize the association between dietary factors and risk of cancers, and the details of the Pooling Project have been described previously.¹⁶ For the colorectal cancer analyses, we identified 13 prospective cohort studies^3-6,17-25 that met the following inclusion criteria: (1) at least 50 incident colorectal cancer cases; (2) assessment of usual dietary intake; (3) completion of a validation study of the dietary assessment method or a closely related instrument; and (4) assessment of dietary fiber intake. Studies including men and women^{6, 18-19} were separated into sex-specific cohorts.

Dietary and Nondietary Assessment

Each study provided baseline intake data of foods and nutrients that were assessed by a study-specific food frequency questionnaire. We calculated energy-adjusted intakes using the residual method,²⁶ in which log_e transformed intake of each nutrient (excluding energy) was regressed against log_e transformed energy intake and then standardized to energy intakes of 2100 kcal/d for men and 1600 kcal/d for women. Pearson correlation coefficients between dietary fiber intake from the food frequency questionnaire and the reference method in the validation studies were higher than 0.50 in all studies.^27-36 Grain foods were categorized as either whole grain foods (>50% whole grain content) or refined grain foods ( 50% whole grain content).³⁷ We also received information on nondietary risk factors, which was collected by self-administered questionnaires at baseline in each study.

Case Ascertainment

Incident colorectal cancer cases were identified by each cohort through self-administered questionnaires with subsequent medical record review,^{3, 22, 25} linkage with a cancer registry,^{4, 17-21} or both.^5-6,23-24 Some studies also had an additional linkage with a death registry.^{3-6,17, 19, 21-24} The follow-up rate of these studies was generally over 90%.

Statistical Analysis

In addition to applying the exclusionary criteria used by each study, we also excluded individuals from the analyses who had a history of cancer other than nonmelanoma skin cancer at baseline and who reported implausible energy intakes (beyond 3 SDs from the study-specific log_e-transformed mean energy intake).

Data analyses comprised study- and sex-specific analyses and subsequent pooled analyses of the study-specific results. Study- and sex-specific relative risks (RRs) and 2-sided 95% confidence intervals (CIs) were estimated with the Cox proportional hazards model.³⁸ SAS statistical software (version 8, SAS Institute Inc, Cary, NC)³⁹ was used for all studies except the Canadian National Breast Screening Study and the Netherlands Cohort Study, which were analyzed as case-cohort studies⁴⁰ using Epicure software (version 2.11, HiroSoft International Corp, Seattle, Wash).⁴¹ Age at baseline (in years) and the year when the baseline questionnaire was returned were used as stratification variables, thereby creating a time metric that simultaneously accounted for age, calendar time, and time after entry into the study. Person-years of follow-up time were calculated from the date of the baseline questionnaire until the date of colorectal cancer diagnosis, death, or end of follow-up, whichever came first. The person-time experienced during the follow-up of the Nurses’ Health Study was divided into 2 asymptotically uncorrelated segments⁴² to take advantage of the more detailed dietary assessment in 1986. The RRs of colorectal cancer were estimated according to study-specific quintiles, as well as to categories defined by absolute intake cut points that were identical across studies. We performed study- and sex-specific age-adjusted and multivariate analyses. The proportion of missing values for each covariate measured in a study was generally less than 5%; an indicator variable for missing responses was created for each covariate in a study if needed. The test for trend across categories of intake was performed by assigning participants the median value of their category and entering those values as a continuous term in a regression model.

The pooled estimates and 95% CIs were calculated using a random-effects model that weighted individual study-specific log_e RRs by the inverse of the sum of their variance. Between-studies heterogeneity was tested by the Q statistic.⁴³ Differences in results among tumor sites were tested by the Wald test statistic.⁴⁴ A meta-regression model was used to test for variation in RRs by sex, geographical location of the study, and follow-up time.⁴⁵

In addition, we evaluated whether dietary fiber intake was log-linearly associated with risk of colorectal cancer by comparing the nonparametric regression curve obtained using restricted cubic splines with the linear model using the likelihood ratio test and by visual inspection of the restricted cubic spline graphs.⁴⁶ For this analysis, all studies were combined into a single data set stratified by study, and the number and location of the knots were identified through a stepwise selection process.

The effect of misclassification of dietary fiber intake was evaluated by the method developed by Zucker and Spiegelman.⁴⁷

RESULTS:

During follow-up times of 6 to 20 years in 13 cohort studies, 7 328 414 person-years were accumulated and 8081 incident colorectal cancer cases were identified (2776 men and 5305 women; 5726 colon cancer and 2188 rectal cancer cases plus 167 site unspecified). Among the studies, median energy-adjusted dietary fiber intake ranged from 14 to 28 g/d in men and from 13 to 24 g/d in women. The major source of dietary fiber varied across studies with cereals as a major contributor to dietary fiber intake in the European studies, and fruits and vegetables as the main sources in the North American studies.

In the age-adjusted model, dietary fiber intake was significantly associated with a 16% lower risk of colorectal cancer in the highest quintile compared with the lowest (pooled age-adjusted RR = 0.84; 95% CI, 0.77-0.92) (Table 2). This association was attenuated slightly but still remained statistically significant after adjusting for nondietary risk factors, multivitamin use, and total energy intake (multivariate model I). Additional adjustment for dietary folate intake further weakened the association (multivariate model II). In the final model, which further adjusted for red meat, total milk, and alcohol intake, only a nonsignificant weak inverse association was found (pooled RR = 0.94; 95% CI, 0.86-1.03; P for trend = .75; multivariate model III). There was no statistically significant heterogeneity between studies for the highest quintile indicating that the differences in the study-specific results were compatible with random variation (Figure 1). When we combined the studies into a single data set and analyzed associations using across-study sex-specific quintiles and adjusted for the same covariates in multivariate model III, the results were similar: compared with the lowest quintile (mean intake = 11 g/d in men and 10 g/d in women), for quintile 2 (multivariate RR, 0.91; 95% CI, 0.84-0.99); for quintile 3 (multivariate RR, 0.98; 95% CI, 0.89-1.07); for quintile 4 (multivariate RR, 0.95; 95% CI, 0.86-1.04); and for quintile 5 (multivariate RR, 0.95; 95% CI, 0.86-1.06, mean intake = 31 g/d in men and 25 g/d in women). The association between dietary fiber intake and risk of colorectal cancer was not significantly modified by sex or age at diagnosis; compared with the lowest quintile the pooled multivariate RR for the highest quintile was 0.96 (95% CI, 0.82-1.13) for men; 0.93 (95% CI, 0.83-1.04) for women; (P for between-studies heterogeneity due to sex = .74); 0.96 (95% CI, 0.82-1.12) for cases diagnosed in patients younger than age 65 years (3048 cases); and 0.92 (95% CI, 0.79-1.06) for patients diagnosed at age 65 years and older (5033 cases). We also found no statistically significant differences in the association between dietary fiber intake and colorectal cancer risk by body mass index (calculated as weight in kilograms divided by the square of height in meters), smoking, alcohol consumption, and red meat intake (data not shown). In addition, the results were similar in European and North American studies: the pooled multivariate RR in the highest quintile vs the lowest was 0.99 (95% CI, 0.80-1.23) for the European studies and 0.92 (95% CI, 0.83-1.02) for the North American studies (P for difference = .45).

…….

In conclusion, we did not find support for a linear inverse association between dietary fiber intake and risk of colorectal cancer in a pooled analysis of 13 prospective cohort studies. Although high dietary fiber intake may not have a major effect on the risk of colorectal cancer, a diet high in dietary fiber from whole plant foods can be advised because this has been related to lower risks of other chronic conditions such as heart disease and diabetes

{The meta-study of 13 studies contained over 8,081 cases of colorectal cancer in a population of over 725,000 who were followed on an average of over 11 years.—jk}