Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
Correspondence: Volker Mai, Division of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, 10 South Pine St, MSTF-934, Baltimore, MD 21201, USA. E-mail: vmai{at}epi.umaryland.edu
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Abstract |
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Methods We studied 45 491 women in the Breast Cancer Detection Demonstration Project (BCDDP) follow-up cohort. A 62-item FFQ was administered from 1987 and 1989 to assess dietary intake. Participants received follow-up questionnaires (in 19921995 and 19951998) on which they reported incident cancers. Cases were also identified through searches of the National Death Index and state cancer registries. Cox proportional hazard regression was used to generate risk ratios and 95% CI for quintiles of total fibre intake and fibre subtypes.
Results During a mean follow-up time of 8.5 years we identified 487 colorectal cancer cases. The 10th and 90th percentiles of dietary fibre intake were 5.4 g and 18.2 g respectively. For total fibre we observed no association with colorectal cancer (fifth versus first quintile, RR = 0.94, 95% CI: 0.711.23). Analyses by subgroup of fibre and by anatomical subsite did not reveal any stronger inverse associations.
Conclusions Within a cohort of older women characterized by a relatively low fibre intake, there was little evidence that dietary fibre intake lowers the risk of colorectal cancer.
Accepted 13 September 2002
Colorectal cancer (CRC) is the second most common cancer (excluding non-melanoma skin cancer) in the US and the fourth most common cause of death from cancer worldwide. Epidemiological studies suggest that environmental factors contribute to the aetiology of colorectal cancer. Burkitt proposed an association between high fibre intake and colorectal cancer (CRC) based on the low age-adjusted rates of CRC reported in various rural regions in Africa.1 Due to the observations that rural Africans (1) eat a diet rich in fibre from unrefined grains and/or leafy vegetables and (2) defecate stools that are bulkier, softer and less odorous than the stools of Westerners, he proposed a protective effect of fibre on CRC.
Several epidemiological studies, especially ecologic and case-control studies, have shown an inverse association between dietary fibre and colorectal cancer. However, recent prospective studies like the Nurses Health Study2 and a study of a Swedish mammography-screening cohort3 reported no relation between fibre intake and colon cancer incidence. Furthermore, increased dietary fibre intake did not reduce colorectal adenoma recurrence in three recent clinical trials.46
We evaluated the association between total dietary fibre intake and incident CRC in a cohort of 45 491 women that had previously participated in the Breast Cancer Detection Demonstration Project (BCDDP). We also analysed the data for associations between source of fibre (fruits, vegetables, beans, grains) and cancer by location (colon, rectum, descending and sigmoid colon, and caecum and ascending colon).
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Subjects and Methods |
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The BCDDP follow-up study has proceeded in several phases beginning with baseline interviews between 1979 and 1981. A total of 61 429 of the invited women (96%) gave informed consent and completed the baseline questionnaire, which was updated annually for up to 6 years by telephone interviews. Participants completed additional mailed questionnaires during three separate follow-up periods: 19871989, 19921995, and 19951998. We contacted non-responders with additional mailings and phone calls. Each follow-up questionnaire updated existing data, collected information about additional presumed risk factors, and provided self-reports of any newly diagnosed cancers.
Dietary assessment
The 62-item Block/NCI food frequency questionnaire (FFQ) was included in the 19871989 questionnaire. This FFQ, which captures usual dietary intake over the previous year, has been described and evaluated elsewhere.8 Estimates of daily nutrient intake, including dietary fibre, were calculated by software specifically designed for this FFQ.9 Fibre subtypes were calculated based on the food source of the fibre and separated into fruit, vegetable, bean, and grain fibre.
Analytical cohort
We excluded women who did not complete a 19871989 questionnaire (n = 9740), and women with a CRC diagnosed before the 19871989 questionnaire (n = 479). In order to avoid inclusion of unrealistic dietary intake data we also excluded women who skipped more than 30 items on their FFQ or reported a calculated energy intake outside the range of 4003800 kcal per day (n = 5647). For this analysis we also excluded subjects who reported consuming more than 16 servings of fruit or vegetables per day (n = 72). The final analytical cohort consisted of 45 491 individuals.
The follow-up period for each subject extended from the completion date for the 19871989 questionnaire until the date of the earliest of the following events: death; colorectal cancer diagnosis; completion of 19951998 questionnaire; or study end-date. For subjects who did not complete questionnaires subsequent to the 19871989 questionnaire and who were not identified as deceased the study end-date was calculated as follows: the end-date of the follow-up period was the date of last contact during 19951998 for subjects who were contacted. For those who could not be contacted, the end-date of the follow-up period was calculated as the date their last questionnaire was completed plus the average cohort follow-up time subsequent to that questionnaire. We were able to follow-up 90.8% of the final cohort through 19951998, meaning that they either answered the 19951998 questionnaire or were identified as dead.
Case ascertainment
We defined cases as all invasive carcinomas of the colon or rectum. Cases were identified through self-reports from the 19931995 and 19951998 questionnaires. Pathology reports were sought from all self-reported colorectal cancers. We obtained pathology reports for 245 of 311 (79%) self-reported CRC. Due to the high confirmation rate for the subjects for which we were able to obtain both pathology and self-reports (94%), we decided to include self-reported CRC from subjects from whom we were unable to obtain medical records. Subjects whose pathology reports contradicted their self-reports were excluded as cases in the analyses unless state cancer registry data confirmed the self-report. We identified additional cases from pathology reports of other self-reported medical conditions (n = 17). We also included cases that were identified by the National Death Index (n = 107) and by state cancer registries (n = 66). The additional cases identified through state cancer registries were not previously identified from self-reports, path reports, and death certificates. Of the cohort members, 71% resided in states that had cancer registries and provided access to their files. All identified cases were verified by manually matching the identifiers from the state cancer registry file with the identifiers in the BCDDP follow-up cohort file. Our final cohort yielded 487 cases; 308 of these were verified by secondary sources.
Statistical analysis
We used Cox proportional hazards (proc PHREG in SAS version 6.12) with age as the underlying time metric (adjusted by left truncation) to generate rate ratios (RR). We also applied a spline modelling approach to examine the data on a continuous scale without linearity assumptions. The knots in the model were set as the 10th, 30th, 50th, 70th, and 90th percentiles, corresponding to the medians of the five intake quintiles.
Total dietary fibre intake was expressed in terms of grams of dietary fibre per 1000 kcals of total energy intake per day. Similarly, intakes for fibre subgroups were calculated as grams of fibre from fruits, vegetables, grains, and beans per 1000 kcals. We created specific fibre intake groups for fruit fibre, vegetable fibre, grain fibre, and bean fibre by calculating the fibre content of each food item assigned to a specific fibre intake group and multiplying this value by the amount of the food consumed.
Covariates such as usual alcohol intake, smoking history (ever/never), BMI (body mass index, weight in kg/height in m2), physical activity (average weekday activity in metabolic equivalent time), and level of education (high school graduate or less/at least some college) were ascertained from the 1987 1989 questionnaire. History of non-steroidal anti-inflammatory drug (NSAID) use was assessed with the 19931995 questionnaire and classified as yes/no with respect to ever having been a regular user, defined as taking at least one tablet weekly over a period of at least one year (excluding Tylenol).
We evaluated possible confounders by adding known risk factors individually and simultaneously to the unadjusted model. Covariates evaluated in multivariate models included NSAID-use, smoking, education, BMI, red meat intake, percentage of calories from fat, vitamin D intake, alcohol intake, and physical activity. We adjusted for energy using the nutrient density method, in which dietary fibre is expressed as grams per 1000 kcal, in all models. In addition, total energy intake was included as a covariate in some models (standard model).10 Standard multivariate models that included total energy intake showed associations similar to the ones observed in nutrient density models.
We analysed the association between fibre subgroups and CRC by modelling each subgroup in a substitution model (total dietary fibre included in the model) and an addition model (all other fibre subgroups individually included in the model). In addition models, fibre subgroups other than the one under investigation are held constant; in substitution models, an increase in the fibre intake from one subgroup is accompanied by a decrease in the combined intake from the other subgroups. We also analysed the effects of dietary fibre intake on CRC by anatomical subsite (colon, rectum, descending and sigmoid colon, and caecum and ascending colon) for cases for which this information was available. Finally, we performed analyses stratified by categories of a number of covariates, including BMI, NSAID-use, calcium intake, and fat intake.
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Results |
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The analysis of the associations between total dietary fibre intake and fibre intake from various sources with cancer of the colon, rectum, descending and sigmoid colon, and caecum and ascending colon did not show a statistically significant association between dietary fibre intake and cancer incidence for any of these subsites (data not shown).
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Discussion |
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The mean total dietary fibre intake in the highest quintile of fibre density intake was only 16.7 g/day, well below recommended minimum intake levels of 2530 g/day. The original hypothesis that increased dietary fibre intake was associated with lower CRC was based on daily intakes of approximately 70 g.1 It would be informative to investigate the effects of dietary fibre intake in populations that consume dietary fibre in amounts larger than those in typical Western cohorts.
Dietary fibre information derived from a 62-item FFQ may contain considerable errors, which would tend to attenuate true fibre-CRC associations. Because dietary habits might have changed prior to and after assessment, one-time administration of the FFQ might not accurately reflect long-term exposure. Our FFQ was designed to assess recent diet. If participation in the BCDDP programme caused study participants to alter their dietary habits, such that the FFQ responses no longer accurately reflected the fibre intake that was biologically relevant to colorectal carcinogenesis (a form of exposure misclassification), then we might have failed to observe a true association.
We note, however, that other cohort studies based on the administration of larger FFQ at multiple times also show null results for fibre and CRC.2,3 Moreover, some of these studies do observe protective associations between fibre intake and other chronic diseases1113 (though we cannot rule out the possibility that these modest inverse associations are the attenuated products of even more substantial inverse relations). Our observational results, like those of other recent cohort studies, are consistent with the results of recent polyp trials in which increased dietary fibre intake (as supplement or food) did not reduce colorectal adenoma recurrence.46 However, because there are potential limitations to both the observational studies (dietary measurement error, for example) and the trials (short follow-up in only those with previous adenomas), it would be premature to consider the issue resolved.
The average follow-up time of 8.5 years and the mean age of 62 years at the time of administration of the FFQ prohibit demonstrating the importance of diet early in life on carcinogenesis at advanced age. This is a limitation of most current prospective studies. Following many thousands of young people over several decades is a potentialthough dauntingapproach to this problem. Unfortunately the ability of FFQ to accurately assess early life diet is problematic.14
Difficulties with assessing dietary fibre intake are compounded by problems with defining substances that should be included as dietary fibre and measuring them accurately in foods. Various heterogeneous complex materials are included in any dietary fibre definition. Recently a panel convened by the Food and Nutrition Board at the Institute of Medicine suggested new definitions as follows: 1. Dietary fibre consists of non-digestible carbohydrates and lignin that are intrinsic and intact in plants, 2. Added fibre consists of isolated, non-digestible carbohydrates that have beneficial physiological effects in humans, and 3. Total fibre is the sum of Dietary fibre and Added fibre.15 If incorporated into food ingredient databases, these proposed definitions might be useful in quantifying dietary fibre in epidemiological studies, food labelling, and intake recommendations.
Many potential mechanisms have been proposed to explain the health-mediating effect of increased dietary fibre intake.16,17 For instance, fermentable fibre can be metabolized by the bacterial flora to short chain fatty acids. Butyrate has been especially shown to influence colorectal carcinogenesis. Furthermore, specific fermentable fibre has the potential to select for a beneficial composition of the flora by selectively enhancing the growth of bacterial groups that are associated with improved health including decreased CRC risk (such as certain Lactic acid bacteria and Bifidobacteria).18 Fermentation rates and bacterial growth are highest in the proximal colon and thus any beneficial effect of fermentable fibre might be limited to that anatomical site. Insoluble fibre might lower cancer risk by accelerating the fecal transit time, which in turn results in decreased exposure of the distal colon epithelium to fecal carcinogens. These few examples illustrate that most of the proposed beneficial effects of fibre are likely to be specific to the anatomical subsite and dependent on specific kinds of dietary fibre. However, our analyses did not reveal any fibre subgroup to be associated with colorectal cancer, nor was fibre associated with specific anatomical subsites. Due to the limited intake range of fibre subgroups in this cohort and the low number of cases for subsites, these analyses had little power to detect small associations. The dietary intake data from the 62-item FFQ did not allow us to separate fibre into soluble and insoluble fibre and thus we could not explore their specific associations with CRC. It would be important in subsequent epidemiological studies to collect data that allow for stratification by physiological property of the dietary fibre and by anatomical subsite (distal and proximal colon, rectum).
Some of the strengths of this study include the large sample size, large number of CRC cases, and the high follow-up proportion. We decided to include CRC cases that were identified through state cancer registries, even though 29% of the cohort members resided in states that did not have or did not give us access to their cancer registries. When we excluded cases that were identified through the state cancer registries only, the association between dietary fibre and CRC in the states that had cancer registries was very similar to the association observed in the entire cohort, indicating limited potential for bias due to the inclusion of the state cancer registries identified cases. Similarly, exclusion of the 66 cases that were identified by self-reports only had minimal impact on the observed risk.
Early stages of CRC could influence the diet of affected subjects leading to a misclassification of their true long-term dietary exposure and a weakening of observed associations. The consistency of the results after exclusion of cases diagnosed during the first 2 years of follow-up suggests this as an unlikely problem in our study.
In summary, our study provides little evidence that dietary fibre reduces risk of CRC, though error in fibre assessment and limited intake range (for all and specific subgroups of fibre) may account for the null findings. We note that even if fibre intake should prove unrelated to colorectal carcinogenesis, there is evidence that increased fibre consumption is inversely related to the incidence of cardiovascular and other chronic diseases.
KEY MESSAGES
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Acknowledgments |
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References |
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