AGA technical review: Impact of dietary fiber on colon cancer occurrence☆

Article Outline

• Abstract
• Dietary fiber: Definition, sources, and consumption
• Epidemiological evidence
  • Correlation studies
  • Case-control studies
  • Prospective studies
• Human intervention studies
• Resistant starch and short-chain fatty acids
• Biological plausibility: Potential mechanisms of action
• Conclusion
  • Summary of causal inference
  • Magnitude of CRC risk reduction
  • Dose of dietary fiber associated with decreased CRC risk
  • Duration of intervention associated with decreased CRC risk
  • Types of fiber or specific related components associated with decreased CRC risk
  • Target group(s) for fiber intervention
• Recommendations
• Acknowledgements
• References
• Copyright

Abstract 

This literature review and the recommendations therein were prepared for the American Gastroenterological Association (AGA) Clinical Practice and Practice Economics Committee. The paper was approved by the committee on September 25, 1999, and by the AGA Governing Board on November 15, 1999.

GASTROENTEROLOGY 2000;118:1235-1257

Abbreviations:  CAPP , Concerted Action Polyposis Prevention trial, CI , confidence interval, CRC , colorectal cancer, FAP , familial adenomatous polyposis, HNPCC , hereditary nonpolyposis colorectal cancer, IGF , insulin-like growth factor, OR , odds ratio, RR , relative risk, SCFA , short-chain fatty acid

Colorectal cancer (CRC) is one of the most common cancers in the developed world. In the United States, CRC is the fourth most common cancer (after lung, prostate, and breast cancers) and the second most common cause of cancer death (after lung cancer).¹ In 1998 alone, 131,600 new cases of CRC are expected to be diagnosed, and an estimated 56,500 deaths will have been caused by the disease.¹ The development of CRC is thought to be the result of an intimate and still poorly understood interplay between environmental and genetic factors. Dietary and lifestyle factors are among the most important environmental factors implicated.², ³ It has been estimated that 35% (10%-70%) of all cancers are attributable to diet and that 50%-75% of CRC in the United States may be preventable through dietary modifications.⁴ U.S. CRC mortality rates among the white population decreased by 29% from 1950 through 1990, with a more pronounced decrease in women than in men.⁵ This decrease is probably attributable to improved early detection as well as lifestyle and dietary changes.⁵

A cause-and-effect relationship between dietary or other lifestyle factors and CRC is difficult to establish. Because of inherent limitations associated with study design, epidemiological, animal, and interventional studies examining this relationship have often produced conflicting results. Therefore, the precise nature of the relationship of CRC with each nutrient or lifestyle factor and the actual magnitude of the relationship are not clear. Among dietary factors implicated in colorectal carcinogenesis, consumption of red meat, animal and saturated fat, refined carbohydrates, and alcohol, as well as total caloric (energy) intake, is believed to be positively related.², ³ On the other hand, the intake of dietary fiber, vegetables, fruits, antioxidant vitamins, calcium, and folate is negatively associated with the development of CRC.², ³ In addition, obesity, increased body mass index, and a sedentary lifestyle are associated with increased risk.², ³

There tends to be agreement among epidemiological studies regarding the risk of CRC and its relationship with overall diet and lifestyle.⁶ However, when many of the findings are examined closely and correlations between CRC and individual dietary and lifestyle factors are sought, the relationship tends to be less convincing.⁶ Therefore, these observations suggest that overall diet and lifestyle, rather than individual factors, play the more important role, thus underscoring the importance of as yet undetermined interactions among dietary components and lifestyle factors in the development of CRC. Investigators have begun to recognize the need to elucidate a unifying mechanism by which these factors modulate colorectal carcinogenesis⁷, ⁸ and to examine combinations of dietary and lifestyle modifications in the prevention of CRC (e.g., the Polyp Prevention Trial).⁹

Dietary fiber is one of several factors whose role in colorectal carcinogenesis has been extensively studied. However, the precise nature and magnitude of the relationship between fiber intake and CRC risk have not been clearly established. Dietary guidelines from the American Cancer Society and the National Cancer Institute, which encourage healthy eating habits and lifestyle modifications, recommend that individuals eat more than 5 servings of fresh vegetables and fruits and 20-30 g of fiber per day. However, the validity of these recommendations has not been scrutinized rigorously.

The objective of this technical review is a critical analysis of currently available data from epidemiological and clinical studies in humans of dietary fiber's effect on colorectal carcinogenesis. All human studies concerning CRC and its precursor, adenoma, and fiber, grains, cereals, vegetables, or fruits published in the English language from 1970 through 1999 were considered. These studies were found in the MEDLINE and CANCERLIT databases, in several extensive reviews,², ³, ¹⁰, ¹¹, ¹², ¹³, ¹⁴ and in references in the identified studies. This review emphasizes results from all the published prospective (cohort) epidemiological studies and randomized intervention studies in humans. Seminal studies of a descriptive and case-control epidemiological nature as well as previously published meta-analyses or pooled (combined) analyses of case-control studies are reviewed. Possible mechanisms by which dietary fiber may suppress colorectal carcinogenesis are also discussed.

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Dietary fiber: Definition, sources, and consumption 

Because the term dietary fiber encompasses a wide range of complex materials, it is difficult to define. There is no internationally accepted definition or method for determining the dietary fiber content of foods.¹⁵ Dietary fiber was initially defined by Burkitt and Trowell¹⁶ as the complex carbohydrate in the diet from plant sources that escapes small bowel digestion and thus reaches the colon. The U.S. Expert Panel on Dietary Fiber defined dietary fiber as the endogenous components of plant materials in the diet that are resistant to digestion by enzymes produced by humans.¹⁷ Analytically, dietary fiber is composed predominantly of nonstarch polysaccharides and nonpolysaccharides (mainly lignins).¹⁸ Nonstarch polysaccharides include cellulose and noncellulosic polysaccharides (e.g., hemicelluloses, pectins, gums, and mucilages).¹⁸ This definition excludes other substances in the plant materials such as phytates, cutins, saponins, lectins, proteins, waxes, silicon, and other organic constituents.¹⁸ Dietary fiber can be further analytically classified as soluble (some hemicelluloses, pectins, gums, and mucilages) and insoluble (most hemicelluloses, celluloses, and lignins), depending on its solubility in water and buffer solution.¹⁸ When the effect of dietary fiber on the colon is being considered, the classification of fiber as fermentable (i.e., metabolized by colonic bacteria) and nonfermentable is also useful. It became apparent in the early 1980s that some starch escapes small bowel digestion and reaches the colon. Stephen et al.¹⁹ estimated that 5%-10% of dietary starch reaches the colon and called this “resistant starch.” Dietary fiber and related compounds are summarized in Table 1.

Table 1. Dietary fiber and related compounds

Classification

Nonstarch polysaccharides:

Celluloses

Noncelluloses: hemicelluloses, pectins, gums, mucilages

Nonpolysaccharides: lignins

Classification based on solubility

Soluble (highly fermented): pectins, gums, mucilages, some hemicelluloses

Insoluble (poorly fermented): celluloses, lignins, most hemicelluloses

Minor components

Phytates, cutins, saponins, lectins, protein, waxes, silicon

Related components

Resistant starch and protein

Lignans

The development of new analytical methods²⁰, ²¹, ²² to estimate the dietary fiber content of foods allowed epidemiological studies to better define the relationship between the intake of dietary fiber and the risk of CRC. However, these assays still underestimated the actual dietary fiber content in foods. They²⁰, ²¹, ²² are based on the assumption that all starch is digested in the small bowel and that other complex carbohydrates are completely undegraded; dietary fiber is therefore considered to include all plant polysaccharides except starch and nonpolysaccharides. These assays estimated the amount of nonstarch polysaccharides in the North American diet to be in the range of 12-15 g/day.²³ Almost all of the epidemiological studies used these assays to estimate the dietary fiber intake. Currently available assays that account for resistant starch (in the range of 3-5 g/day in the North American diet²⁴) estimate the amount of polysaccharides that reach the colon to be in the region of 15-25 g/day. Even with the inclusion of resistant starch in the assessment of dietary fiber intake, currently available assays account for less than one third of total dietary fiber that reaches the colon to sustain the known rate of colonic bacterial synthesis.¹¹, ¹² Therefore, although the assays that are currently available to estimate nonstarch polysaccharides and resistant starch are very precise, they do not accurately measure dietary intake and seriously underestimate the amount of dietary fiber that reaches the colon and is available to participate in the mechanisms of CRC prevention.¹¹, ¹² Because of these difficulties, epidemiologists began to study the relationship between intake of “fiber-rich” foods (e.g., cereals, fruits, and vegetables) and the risk of CRC; most of these studies suggested a strong inverse relationship.¹¹, ¹²

Dietary fiber is found mainly in vegetables, fruits, grains, seeds, nuts, and legumes. In the Second National Health and Nutrition Examination Survey (NHANES II, 1976-1980), mean dietary fiber intake in the U.S. adult population (>19 years old) is 11.1 g/day or 13.3 g/day, depending on the methodology used.²³ On any given day, 50% of the U.S. population reports a dietary fiber intake of <10 g/day, and only  ̃10% consume >20 g/day.²³ On a per 1000-kcal basis, women consume more dietary fiber (6.5 g/1000 kcal) than men (5.5 g/1000 kcal) at every age.²³ Both men and women show the same pattern of increasing dietary fiber intake with age when fiber is examined in relation to total caloric intake.²³ A marked racial effect is evident; blacks having lower dietary fiber intake than whites in both sexes and all age groups.²³ It is uncertain at present whether mean dietary fiber intake in the U.S. adult population has significantly increased since the completion of the second NHANES. This issue is being analyzed from the recently completed NHANES III (1988-1994), which included 40,000 noninstitutionalized people aged ≥2 months and oversampled blacks, Mexican Americans, children, and elderly people.²⁵ Table 2 lists the fiber content of frequently consumed fruits and vegetables.

Table 2. Provisional dietary fiber table

Food	Fiber (g/100 g)a	Fiber (g/serving)
Fruits
Apple (without skin)	2.1	2.9/1 medium-sized apple
Apple (with skin)	2.5	3.5/1 medium-sized apple
Apricot (fresh)	1.7	1.8/3 apricots
Apricot (dried)	8.1	10.5/1 cup
Banana	2.1	2.5/1 banana
Blueberries	2.7	3.9/1 cup
Cantaloupe	1.0	2.7/half edible portion
Cherries, sweet	1.2	1.2/15 cherries
Dates	7.6	13.5/1 cup (chopped)
Grapefruit	1.3	1.6/half edible portion
Grapes	1.3	2.6/10 grapes
Oranges	2.0	2.6/1 orange
Peach (with skin)	2.1	2.1/1 peach
Peach (without skin)	1.4	1.4/1 peach
Pear (with skin)	2.8	4.6/1 pear
Pear (without skin)	2.3	3.8/1 pear
Pineapple	1.4	2.2/1 cup (diced)
Plums, damsons	1.7	1.7/3 plums
Prunes	11.9	11.9/11 dried prunes
Raisins	8.7	2.2/packet
Raspberries	5.1	6.3/1 cup
Strawberries	2.0	3.0/1 cup
Watermelon	0.3	1.3/4 × 8-inch wedge
Juices
Apple	0.3	0.74/1 cup
Grapefruit	0.4	1.0/1 cup
Grape	0.5	1.3/1 cup
Orange	0.4	1.0/1 cup
Papaya	0.6	1.5/1 cup
Vegetables
Cooked
Asparagus, cut	1.5	1.5/7 spears
Beans, string, green	2.6	3.4/1 cup
Broccoli	2.8	5.0/1 stalk
Brussels sprouts	3.0	4.6/7-8 sprouts
Cabbage, red	2.0	2.9/1 cup (cooked)
Cabbage, white	2.0	2.9/1 cup (cooked)
Carrots	3.0	4.6/1 cup
Cauliflower	1.7	2.1/1 cup
Corn, canned	2.8	4.5/1 cup
Kale leaves	2.6	2.9/1 cup (cooked)
Parsnip	3.5	5.4/1 cup (cooked)
Peas	4.5	7.2/1 cup (cooked)
Potato (without skin)	1.0	1.4/1 boiled
Potato (with skin)	1.7	2.3/1 boiled
Spinach	2.3	4.1/1 cup (raw)
Squash, summer	1.6	3.4/1 cup (cooked,diced)
Sweet potatoes	2.4	2.7/1 baked(5 × 2 inches)
Turnip	2.2	3.4/1 cup(cooked, diced)
Zucchini	2.0	4.2/1 cup(cooked, diced)
Raw
Bean sprout, soy	2.6	2.6/1 cup
Celery, diced	1.5	3.7/1 large stalk
Cucumber	0.8	0.2/6–8 slices with skin
Lettuce, sliced	1.5	2.0/1 wedge iceberg
Mushrooms, sliced	2.5	0.8/half cup (sliced)
Onions, sliced	1.3	1.3/1 cup
Peppers, green, sliced	1.3	1.0/1 pod
Tomato	1.5	1.8/1 tomato
Spinach	4.0	8.0/1 cup (chopped)
Legumes
Baked beans, tomato sauce	7.3	18.6/1 cup
Dried peas, cooked	4.7	4.7/half cup (cooked)
Kidney beans, cooked	7.9	7.4/half cup (cooked)
Lima beans, cooked/canned	5.4	2.6/half cup (cooked)
Lentils, cooked	3.7	1.9/half cup (cooked)
Navy beans, cooked	6.3	3.1/half cup (cooked)
Breads, pastas, and flours
Bagels	1.1	1.1/half bagel
Bran muffins	6.3	6.3/muffin
Cracked wheat	4.1	4.1/slice
Crisp bread, rye	14.9
Crisp bread, wheat	12.9
French bread	2.0	0.67/slice
Italian bread	1.0	0.33/slice
Mixed grains	3.7
Oatmeal	2.2	5.3/1 cup
Pita bread (5 inches)	0.9
Pumpernickel bread	3.2	1.0/slice
Raisin bread	2.2	0.55/slice
White bread	2.2	0.55/slice
Whole-wheat bread	5.7	1.66/slice
Pasta and rice—cooked
Macaroni	0.8	1.0/1 cup (cooked)
Rice, brown	1.2	2.4/1 cup (cooked)
Rice, polished	0.3	0.6/1 cup (cooked)
Spaghetti (regular)	0.8	1.0/1 cup (cooked)
Spaghetti (whole wheat)	2.8	3.0/1cup (cooked)
Flours and grains
Bran, corn	62.2	18.7/oz
Bran, oat	27.8	8.3/oz
Bran, wheat	41.2	12.4/oz
Rolled oats	5.7	13.7/1 cup (cooked)
Rye flour (72%)	4.5	5.2/1 cup
Rye flour (100%)	12.8	15.4/1 cup
Wheat flour
Whole meal (100%)	8.9	10.6/1 cup
Brown (85%)	7.3	8.8/1 cup
White (72%)	2.9	2.9/1 cup
Nuts
Almonds	7.2	3.6/half cup (slivered)
Peanuts	8.1	11.7/1 cup
Filberts	6.0	2.8/half cup
aDietary fiber values are averages compiled from literature sources.

Adapted and reprinted with permission.²³

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Epidemiological evidence 

The “fiber hypothesis” was first introduced when Burkitt²⁶, ²⁷ recognized the rarity of CRC in most African populations and was impressed by the high fiber and low refined carbohydrate content of the diet in Africa and other underdeveloped areas of the world. Since then, this purported inverse relationship between dietary fiber intake and the risk of CRC has been investigated by 3 types of human epidemiological studies: correlation (or ecological), case-control, and prospective studies.

In nutritional epidemiological studies, dietary intake of certain nutritional factors is assessed by several methods. In the 24-hour recall method, the basis of most national surveys, subjects are asked to report their food intake during the previous day. This method has the advantage of requiring no training or literacy and minimal effort by the participant. The most serious limitation is that dietary intake is highly variable from day to day. In the diet recording (food diary) method, detailed meal-by-meal records are kept of the types and quantities of food and drink consumed during a specified period, typically 3-7 days. This method places a considerable burden on the subject, thus limiting it to literate people who are also highly motivated. The effort involved in keeping diet records may increase consciousness of food intake and encourage alteration of diet. However, the advantages of the diet recording method are that it does not depend on memory and allows direct measurement of portion sizes. Dietary records reduce the problem of day-to-day variation by taking the average of a number of days; in addition, weekday/weekend variability, which in some societies is high, can be accounted for. Short-term recall and dietary recording methods are generally expensive, may be unrepresentative of usual intake, and are inappropriate for assessment of diet history. For these reasons, many investigators now use food frequency questionnaires, which include a food list and a frequency response section for subjects to report how often each food is eaten. Diets tend to be reasonably well correlated from year to year, and subjects are usually asked to describe how frequently they ate each food in the preceding year. Food frequency questionnaires are easy for literate subjects to complete, often as self-administered forms. Processing is readily computerized and inexpensive; even prospective studies involving repeated assessment of diet among tens of thousands of subjects are feasible.

Correlation studies 

Correlation studies examine the relationship between the per capita consumption of a dietary factor and the prevalence, incidence, or mortality of CRC in the population. Correlation studies can examine this relationship among populations residing in different countries or among different groups within a country either at a given time or over a certain period (i.e., time-trend). They provide provocative initial evidence that a particular dietary factor has a role in the development of CRC and hence are considered worthy only of hypothesis formation. Of 28 published international, within-country correlation and time-trend studies of CRC and fiber, vegetables, grains, fruits, and cereals, 23 (82%) showed either a strong or a moderate protective effect of dietary fiber or “fiber-rich foods” or equivocal results that were nevertheless consistent with the fiber hypothesis.², ³, ¹⁰, ¹¹, ¹², ¹³, ¹⁴ Four studies found no evidence for a protective effect of fiber, and 1 study showed a significant excess risk of CRC associated with high intake of fiber-rich foods.², ³, ¹⁰, ¹¹, ¹², ¹³, ¹⁴ The limitations of interpretation of data generated from these correlation studies are many. The older international studies are based on intake of crude fiber, which greatly underestimates total dietary fiber levels. Furthermore, correlation studies often fail to correct for unmeasured confounding factors that may be responsible for the observed association. They also do not control for other dietary variables or for any of the other known risk factors associated with CRC. Despite these shortcomings, it is remarkable that most of these correlation studies have indicated a strong inverse relationship between dietary fiber intake and the risk of CRC.

Case-control studies 

Case-control studies compare prior consumption of a dietary factor in subjects with CRC and matched control subjects without CRC. Many of the weaknesses of correlation studies can be avoided in case-control studies. Known or suspected potential confounding factors can be controlled or eliminated in the study design or controlled in the data analysis. The most serious limitation in retrospective studies is the accuracy with which intake of dietary factors or supplementation can be established. Individuals may misreport their habitual past diets; if cases and controls differ in the accuracy of their dietary recall, the ensuing comparison will be biased. In addition, some individual aspects of diet, especially nutrient content, may not vary greatly within a population, so case-control studies may not show wide ranges of cancer risk within that population. Another common problem is that controls are often people with another disease, because hospital patients are convenient subjects to study; their disease might also be diet related. In such situations, the study results could be seriously biased and often may not show any clear difference between cases and controls. For such reasons, the results of case-control studies of diet and cancer are sometimes inconsistent. Another problem associated with case-control studies is selection bias because of the absence of patients who do not survive long enough to be enrolled in the study. Case-control studies may produce evidence that is significant in isolation. Such evidence is strengthened by corroboration in additional studies conducted in a number of centers and particularly by consistent results from populations with different patterns of diet and of cancer.

Three analyses, conducted in combined analysis or meta-analysis formats, have critically evaluated the bulk of case-control studies that address the role of dietary fiber in CRC.²⁸, ²⁹, ³⁰ Trock et al.²⁸ analyzed 23 case-control studies that examined the relationship between CRC and consumption of fiber and vegetables. Fifteen (65%) of these studies demonstrated either a strong or moderate protective effect of dietary fiber and vegetables.²⁸ Six studies (26%) showed equivocally protective effects of fiber that were not statistically significant, that became nonsignificant after adjustment, or that could not be distinguished from other factors in their relation to risk.²⁸ Only 2 studies (9%) lacked support for a protective effect of fiber.²⁸ Trock et al.²⁸ performed a meta-analysis on 16 case-control studies that provided enough data in the published articles. With fiber-rich diets (i.e., combination of fiber and vegetables), a 43% reduction in CRC risk was observed (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.50-0.64) when the highest and lowest quartiles of intake were compared.²⁸ The extent of risk reduction based on vegetable consumption was 52% (OR, 0.48; 95% CI, 0.41-0.57), whereas one based on an estimate of fiber intake was 42% (OR, 0.58; 95%, 0.51-0.66).²⁸ The data did not permit discrimination between effects ascribable to the fiber and the nonfiber components of vegetables.²⁸

Howe et al.²⁹ performed a combined (or pooled) analysis of data from 13 case-control studies previously conducted in populations from North America, Europe, Asia, Australia, and South America with differing CRC rates and dietary practices. The individual data records for 5287 case subjects and 10,470 control subjects were pooled for a common analysis. This approach thus differs from the usual meta-analysis, in which estimates of risk are pooled from published summary results. Pooled analyses provide several benefits over meta-analyses of published results or narrative reviews of the literature. When the actual individual subject level data from several studies are combined, detailed analyses are possible. Because the pooled data sets constitute a large body of data, rare exposures can be studied. Furthermore, the consistency of the association across studies can be examined, confounding and interaction of several putative risk factors can be assessed, and previously unrecognized or poorly established associations may be revealed. Using the individual data records has the advantage of eliminating artifactual differences attributable to different procedures for coding and analyzing data that may have been used in the respective original analyses.

In this pooled analysis, the risk of CRC was shown to decrease incrementally as dietary fiber intake increased, with ORs of 1.0, 0.79, 0.69, 0.63, and 0.53 for each quintile of consumption from the lowest to highest (P trend < 0.0001).²⁹ Consumption of more than 31 g of fiber per day was associated with a 47% reduction in the risk of CRC compared with diets incorporating less than 10 g of fiber per day (95% CI, 0.47-0.61).²⁹ The strong inverse association observed with fiber intake was not affected by adjustment for total energy intake, age, sex, height, weight, body mass index, and other potential confounding factors, including vitamin C and β-carotene.²⁹ When the consistency of the fiber effect across the studies was examined by calculating the relative risk of developing CRC in subjects consuming 27 g fiber per day compared with those consuming less than 11 g fiber per day in individual studies, 12 of the 13 studies showed inverse associations with dietary fiber.²⁹ In 8 of these 12 studies, the decrease in risk was statistically significant.²⁹ When all of the studies were combined and adjusted for total energy intake, age, and sex, individuals who consumed 27 g fiber per day had a 50% reduction in the risk of developing CRC compared with those who consumed less than 11 g fiber per day (relative risk [RR], 0.51; 95% CI, 0.44-0.59).²⁹ Estimates of RR per 27 g fiber per day—estimated separately for cases of left-sided (RR, 0.52; 95% CI, 0.42-0.65) and right-sided (RR, 0.45; 95% CI, 0.33-0.61) colon cancer and for rectal cancer (RR, 0.43; 95% CI, 0.34-0.56), for women (RR, 0.60; 95% CI, 0.48-0.75) and men (RR, 0.44; 95% CI 0.37-0.53), and for 2 age groups (<50 years [RR, 0.66; 95% CI, 0.43-0.99] and ≥50 years [RR, 0.49; 95% CI, 0.42-0.57])—were consistent for all subgroups.²⁹

In the original pooled analysis by Howe et al.,²⁹ it was assumed that a pooled estimate could be made of the heterogeneous results for dietary fiber and CRC risk. This heterogeneity was not examined, nor was the influence of study quality considered. Therefore, Friedenreich et al.³⁰ examined the study design features and data collection methods from the 13 case-control studies that had been included in the original pooled analysis²⁹ to determine whether they influenced the results obtained from a pooled analysis.³⁰ Friedenreich et al.³⁰ assessed methods used in each study, estimated a quality score, and used a different model (a random-effects model rather than a fixed-effects model) to re-estimate the pooled OR for the association between dietary fiber and CRC for these data.³⁰ Key features of the methods used in each study and the quality score were examined in a random-effects model to determine whether the heterogeneity found between study-specific risk estimates could be explained by these variables.³⁰ The OR for dietary fiber and CRC was 0.46 (95% CI, 0.34-0.64) for the 13 case-control studies as estimated using a random-effects model,⁶⁴ which was slightly lower than the OR estimated with the fixed-effects model in the original pooled analysis (0.51).³⁰ Two factors, whether the diet questionnaire had been validated before use in the case-control study and whether qualitative data on dietary habits and cooking methods had been incorporated into the nutrient estimation, explained some of the heterogeneity in study results.³⁰ Risk estimates for dietary fiber and CRC were closer to the null (i.e., 1.0) for studies with these 2 characteristics.³⁰ These investigators performed another pooled analysis of the 13 case-control studies included in the original pooled analysis and 4 additional case-control studies either excluded from or published after the original analysis.³⁰ Subjects consuming >27 g fiber per day had a 50% reduction in the risk of developing CRC compared with those taking <11 g fiber per day (OR, 0.49; 95% CI, 0.37-0.65).³⁰

Colonic adenomas are well-established precursors of adenocarcinoma.³¹ Several case-control studies have also found an inverse relationship between dietary fiber or fiber-rich foods and the risk of colonic adenomas, thereby supporting the association observed with CRC.³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷ The magnitude of the reduction in the risk ranged from 10% to 60% in these studies.³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷ Some of these studies also showed a dose-dependent inverse association between colorectal adenoma risk and dietary intake of fiber.³⁶, ³⁷ In some studies, the protective effect associated with dietary fiber was evident only in women³⁵, ³⁶ and for large (>1 cm) adenomas.³⁴ However, these studies are limited by small sample size.

In summary, most of the published case-control studies show either a strong or a moderate protective effect of dietary fiber or fiber-rich foods or equivocal results that are nevertheless consistent with the fiber hypothesis. Three analyses of case-control studies, conducted in combined analysis or meta-analysis formats, also provide strong support for the protective effect of dietary fiber or fiber-rich foods on colorectal carcinogenesis.²⁸, ²⁹, ³⁰ The strongest argument for the fiber hypothesis that can be made from case-control studies is the remarkable consistency of the protective effect of dietary fiber among studies conducted in populations with different patterns of diet and CRC. The combined analysis and meta-analyses of case-control studies suggest, on average, a 50% reduction in the risk of developing CRC in individuals with the highest dietary fiber intake compared with those with the lowest fiber intake.²⁸, ²⁹, ³⁰ Most of the positive case-control studies and one combined analysis of case-control studies show a significant inverse dose-dependent relationship between dietary fiber intake and the risk of CRC and colorectal adenomas.²⁹, ³⁶, ³⁷ However, several shortcomings associated with case-control studies limit interpretation of the results of these studies. Some of the most serious problems are that a large proportion of the published case-controls used dietary tools, including questionnaires, that had not been validated before use and that these studies did not incorporate qualitative data on dietary habits and cooking methods into the nutrient estimation. Furthermore, because of the limitations associated with analytical methods of determining fiber content in diet, as previously described, the accuracy of estimates of dietary fiber in these studies is in question. Another problem is that potential confounders were not adequately controlled or corrected in some of these studies. Finally, it is difficult to delineate the effect associated with dietary fiber from other potential anticarcinogens present in fiber-rich foods such as vegetables, fruits, cereals, and grains in case-control studies.

Prospective studies 

Prospective (or cohort) studies assess the diets of a large group of healthy individuals and include follow-up over time, during which a number of cohort members will develop CRC. The relationship of CRC to specific characteristics of individual diets is then analyzed. Prospective studies avoid most of the methodological problems of other epidemiological studies and can control and correct confounding factors more adequately than correlation and case-control studies. They also provide the opportunity to obtain repeated assessments of diet at regular intervals, thus improving the validity of individual dietary assessment. Because of the prospective design, in which diet is assessed before the occurrence of CRC, there is little likelihood of selection or recording bias in cohort studies.

Earlier prospective studies investigated the relationship between dietary fiber intake and CRC mortality. A large cohort study from Japan was designed to investigate the relationship between diet and other lifestyle variables and major causes of deaths in 265,118 subjects, aged ≥40 years, followed up for 13 years. During the 13-year follow-up period, 39,127 people died.³⁸ Standardized mortality rates for each cause of death were calculated according to the lifestyle variables that were studied when the subjects were still healthy at the time of the initial interview.³⁸ This study observed that CRC mortality rate decreased as rice and wheat consumption increased with an RR of 0.6 in those with the highest intake (>720 cm³ of rice and wheat per day) compared with those with the lowest intake (<180 cm³/day).³⁸ A Dutch study involving 871 middle-aged men followed up for 10 years showed a 3-fold reduction in cancer mortality in men in the highest quintile of dietary fiber intake compared with men in the lowest quintile.³⁹ The 44 men who died of cancer during 10 years of follow-up ate less dietary fiber (30.9 ± 9.7 vs. 27.0 ± 6.9 g/day; P = 0.001) and polysaccharides (206.3 ± 66.1 vs. 183.2 ± 51.5 g/day; P = 0.006) than survivors.³⁹ However, the number of men who died of colon cancer in this study during 10 years of follow-up was too small to allow statistical analysis.³⁹ Another study involving 25,493 white California Seventh-Day Adventists followed up for 21 years showed no protective effect of cereal or green salad intake on CRC mortality.⁴⁰ However, in the Seventh-Day Adventist population, distribution of dietary fiber may be narrow; therefore, protective effects of fiber may not be observed. Another prospective study examined the risk of developing colonic adenomas in 163 Hawaii Japanese autopsy subjects.⁴¹ They constituted a subset of 8006 men originally examined between 1965 and 1968 and those who died between 1969 and 1984.⁴¹ No significant differences were observed between subjects with and without adenomas in intake of dietary carbohydrates.⁴¹

Data from Cancer Prevention Study II, an ongoing prospective mortality study, support the protective role of dietary fiber in colorectal carcinogenesis⁴²; 1,185,125 men and women (average age, 57 years) in the United States completed a 4-page questionnaire in 1982 on their diet, smoking history, alcohol intake, physical activity, height, weight, medication use, medical illnesses, family history of cancer, and other characteristics. The participants' vital status was determined at 2-year intervals through personal inquiries by the volunteers. Mortality follow-up was assessed through 1988. By this time, 79,820 participants (6.7%) had died (1150 of CRC); 94.2% of participants' causes of death were determined unequivocally. Dietary questions asked about the average consumption of 32 food items and 10 beverages. Multivariate analyses showed that risk of fatal colon cancer decreased with more frequent consumption of vegetables and high-fiber grains (P trend = 0.031 in men and 0.0012 in women) after adjustment of confounding factors.⁴² The RR for the highest vs. lowest quintile of vegetable and high-fiber grains was 0.76 in men (95% CI, 0.57-1.02) and 0.62 in women (95% CI, 0.45-0.86).⁴² The strengths of this study are its size and prospective design. Its limitations include its dependence on a single, brief, self-administered questionnaire, lack of information on colon subsite, and relatively short follow-up (6 years). Because of the reliance on mortality, factors that influence survival could not be clearly differentiated from those that affect incidence. In addition, the study participants were, on average, more educated and affluent than the U.S. population as a whole. Greater access to medical care and screening might have contributed to their lower mortality rates from colon cancer. Therefore, generalization of the findings of this study to groups of lower socioeconomic status is questionable.

Recently, several well-designed and -conducted prospective studies have examined the relationship between dietary fiber intake and the risk of CRC and adenomas, but the findings of these studies are not consistent (Table 3).⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸ In the Nurses' Health Study,⁴³ 121,700 female registered nurses between 34 and 59 years of age in the United States completed a mailed questionnaire on known and suspected risk factors for cancer and cardiovascular disease in 1976. Every 2 years thereafter, follow-up questionnaires were sent to identify new cases of cancer and cardiovascular disease. In 1980, the questionnaire was expanded to include an assessment of diet, the Willett semiquantitative food frequency questionnaire⁴⁹; 88,751 women were available for analysis in 1986, representing 6 years of follow-up. Among these women, 150 cases of CRC were identified and confirmed. Energy-adjusted intakes of crude and total dietary fiber were both inversely associated with the risk of colon cancer, but these trends were not statistically significant.⁴³ When intake of fiber from fruit, vegetables, and cereals were analyzed individually, only fiber from fruit was associated with any appreciable reduction in risk, and the overall trend was not statistically significant.⁴³ Some limitations of this well-designed prospective study are relatively short follow-up (6 years) and uncontrolled confounding factors (e.g., family history of CRC, physical activity) that might affect the development of CRC.

Table 3. Dietary fiber intake and risk of CRC and adenoma: Summary of prospective studies

NS, not significant.

The observations from this study extended for 16 years of follow-up (1980-1996) have recently been published.⁴⁴ During the 16 years of follow-up, 787 new cases of CRC were identified and confirmed among the 88,757 eligible women. After adjustment for age, total energy intake, and most of the established risk factors for CRC in a multivariate model, total dietary fiber intake was not significantly associated with the incidence of CRC; the relative risk for the quintile group with the highest (median 24.9 g/day) compared with the lowest (median 9.8 g/day) total dietary fiber intake was 0.95 (95% CI, 0.73-1.25), and no dose-dependent inverse association was observed (P trend = 0.59).⁴⁴ No protective effect of total fiber intake was observed when events during the first 6 years of follow-up were excluded to examine the possibility that total dietary fiber influences the risk of CRC only after several years or when the analysis was limited to women who maintained a consistent level of dietary fiber intake during the study period.⁴⁴ Cereal and fruit fiber was not associated with any appreciable reduction in CRC risk, whereas greater consumption of vegetable fiber was associated with a significant increase in the risk of CRC (RR, 1.35 in the highest [median 10.0 g/day] compared with the lowest [median 2.7 g/day] quintile; 95% CI, 1.05-1.72; P trend for a dose-dependent relationship = 0.004).⁴⁴ However, this adverse effect was no longer observed when the analysis excluded women who altered their fiber intake during the follow-up period (RR, 1.22; 95% CI, 0.50-2.98; P trend for a relationship = 0.39).⁴⁴ The relationship between fiber intake and the risk of adenomas in the left side of the colon and the rectum was also investigated among 27,530 women who reported undergoing colonoscopy or sigmoidoscopy between 1980 and 1994.⁴⁴ There was no reduction in the risk of colorectal adenomas with increasing dietary intake of total, cereal, fruit, or vegetable fiber.⁴⁴

The same group of investigators also examined the relationship between dietary fiber and the risk of colon cancer in men.⁴⁵ The Health Professional Follow-up Study is a prospective study of heart disease and cancer among 51,529 U.S. male health professionals between the ages of 40 and 75 years who completed the original questionnaire in 1986. Again, dietary intake was assessed using the Willett semiquantitative food frequency questionnaire.⁴⁹ Among 47,949 men who were free of diagnosed cancer in 1986, 205 new cases of colon cancer were diagnosed and confirmed between 1986 and 1992. Analyses were performed in a similar fashion as in the Nurses' Health Study.⁴³, ⁴⁴ Age, family history of CRC, obesity, physical activity, cigarette use, alcohol consumption, and other confounding factors were adjusted for analysis. No clear association between total dietary fiber intake and risk of colon cancer was observed; the RR for the highest (median 32.8 g/day) compared with the lowest (median 14.2 g/day) quintile group with respect to total dietary fiber intake was 1.08 (95% CI, 0.68-1.70), and no dose-dependent inverse association was observed (P trend = 0.12).⁴⁵ No significant protective effect was observed for total crude, fruit, vegetable, or cereal fiber.⁴⁵

The same group of investigators also examined the relationship between dietary intake of fiber and the risk of colorectal adenoma in the same male cohort of the Health Professional Follow-up Study.⁴⁶ The analysis was done on 7284 individuals who had undergone either colonoscopy or flexible sigmoidoscopy. There were 170 cases of endoscopically diagnosed adenomas of the left colon or rectum between 1986 and 1988.⁴⁶ Again, most potential confounding factors were adjusted for analysis. Dietary fiber was inversely associated with risk of adenoma (P for trend < 0.0001); RR for men in the highest (>28.3 g/day) vs. the lowest (<16.6 g/day) quintile was 0.36 (95% CI, 0.22-0.60).⁴¹⁶ All sources of fiber (crude, vegetable, fruit, and grain) were associated with decreased risk (P < 0.02).⁴⁶ The inverse relationship with fiber persisted after adjustment for other nutrients commonly found in fruits and vegetables (β-carotene, potassium, magnesium, and vitamins C and E).⁴⁶

This study⁴⁶ was further analyzed with a longer follow-up (1986-1994), a larger cohort (16,448 men), and newly available data on dietary composition for specific fiber components and fiber water solubility.⁴⁷ Among 16,448 men who underwent endoscopy between 1986 and 1994, 690 cases of adenoma of the distal colon (n = 531) and rectum (n = 159) were identified. In the basic model, the risk of distal colon adenoma decreased with increasing intake of total dietary fiber (P trend = 0.01) and fruit fiber (P trend = 0.001) but not with fiber from cereals, wheat, vegetables, or cruciferous vegetables (basic model).⁴⁷ The RRs comparing the highest (median 32.3 g/day for total fiber and 8.4 g/day for fruit fiber) with the lowest (median 11.6 g/day for total fiber and 1.3 g/day for fruit fiber) quintile were 0.65 (95% CI, 0.46-0.91) for total fiber and 0.67 (95% CI, 0.50-0.90) for fruit fiber.⁴⁷ In the full multivariate model that controlled for all potential confounding factors, the risk of distal colon adenomas decreased with increasing intake of fruit fiber (P trend = 0.03) and the association with total fiber intake became nonsignificant (P trend = 0.10).¹¹⁷ A strongly decreasing risk of distal colon adenomas was observed for soluble fiber (P trend = 0.0003) but not for insoluble fiber (P trend = 0.34) in basic models.⁴⁷ In the full multivariate model, the strong inverse association between intake of soluble fiber and distal colon adenomas persisted (P trend = 0.007).⁴⁷ No consistent relationship between fiber and rectal adenomas was observed in this study.⁴⁷

In the earlier report of this study, increased total dietary fiber was strongly associated with a decreased risk of total colorectal adenomas (P< 0.0001), and fiber from vegetables, fruits, and grains was beneficial.⁴⁶ However, in the updated report, total dietary fiber was only modestly inversely associated with risk of total colorectal adenomas, and only fiber from fruits (not from vegetables or cereal) appeared to be protective.⁴⁷ The major difference between the earlier⁴⁶ and updated⁴⁷ reports of this prospective study is that the earlier analysis assessed fewer potential confounders, which might have led to an overestimation of the relationship between total fiber or source of fiber and adenoma risk. Another problem in the earlier report is the small number of cases arising during 2 years of follow-up, compared with 8 years in the later report.

The Iowa Women's Health Study⁴⁸ included 98,030 postmenopausal women aged 55-69 years who were asked to complete a self-administered questionnaire dealing with various health issues and diet. Nearly half of the women (41,837) returned the questionnaire. This cohort was then followed up for 4 years. Dietary intake of various factors was assessed using the Willett semiquantitative food frequency questionnaire.⁴⁹ The occurrence of CRC was documented, and the diagnosis was verified. After specific exclusion criteria were applied, 212 cases and 35,004 noncases remained for analysis. Mean dietary intake was divided into quartiles of incremental increase, and the relative risk for development of CRC was calculated for each quartile compared with the quartile with the lowest intake. A weak and statistically nonsignificant inverse association was observed between dietary fiber intake and the risk of colon cancer, particularly of the distal colon.⁴⁸ Furthermore, increased total intake of both vegetables and fruits did not reduce the relative risk of CRC; similar results were obtained when each vegetable or fruit item was independently analyzed except for garlic.⁴⁸

In summary, published large prospective studies have produced equivocal findings. Although the data from earlier prospective studies that examined the relationship between dietary fiber intake and CRC mortality were inconsistent,³⁸, ⁴⁰, ⁴¹ the most recent large prospective study (Cancer Prevention Study II),⁴² involving more than 1 million subjects, showed a significant inverse relationship with a 30% reduction of CRC mortality in subjects consuming the highest amount of dietary fiber compared with those consuming the lowest amount. This study also showed that the risk of fatal colon cancer decreased with more frequent consumption of vegetable and high-fiber grains (P trend = 0.031 in men and 0.0012 in women).⁴² More recently published prospective studies of the relationship between dietary fiber intake and the risk of CRC or adenomas have demonstrated a protective effect of dietary fiber against distal colon and rectal adenomas in men⁴⁶, ⁴⁷ but not in women (Table 3).⁴⁴ When all potential confounding factors were corrected for, however, an inverse dose-responsive association was observed only for fruit and soluble fiber.⁴⁷ In these 2 studies,⁴⁶, ⁴⁷ there was a 35%-63% reduction in the risk of developing distal colon and rectal adenomas in men with the highest dietary fiber intake compared with those with the lowest fiber intake. These studies also showed a significant inverse dose-responsive relationship (P trend < 0.001).⁴⁶, ⁴⁷ However, it appears that dietary fiber has no significant effect on CRC incidence in men⁴⁵ or women (Table 3).⁴³, ⁴⁴, ⁴⁸ It is possible that, at least in men, dietary fiber influences the early stages of colorectal carcinogenesis and not the late stages. This hypothesis is further supported by the observation that dietary fiber has a protective effect against small (<1 cm) and not large (>1 cm) adenomas.⁴⁷

The strengths of recent prospective studies⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸ are numerous: the studies were conducted prospectively and involved a large number of subjects for adequate statistical power; most controlled for potential confounders⁴⁴, ⁴⁵, ⁴⁷, ⁴⁸; the largest study followed up study subjects for 14 and 16 years for colorectal adenomas and CRC, respectively⁴⁴; and the studies used the Willett semiquantitative food frequency questionnaire⁴⁹ to accurately estimate dietary fiber intake. One of the major weaknesses of these studies is that the investigators attempted to correlate dietary consumption of dietary fiber at baseline with subsequent incidence of CRC or adenomas.⁴³, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸ In other words, the dietary intake at baseline was assumed to reflect past and subsequent consumption. Whether the subjects in these studies changed their diets during the follow-up period and how this might have affected the study outcome cannot be deduced. The exception is the largest published study, with a 16-year follow-up, which showed no protective effect of dietary fiber intake even when the analysis included only those who maintained a consistent level of dietary fiber intake during the first 6 years of follow-up.⁴⁴ Except for this one study with a follow-up of 16 years,⁴⁴ these studies are limited by the relatively short follow-up (2-8 years).⁴³, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸ This issue is important because of the uncertainty regarding the biologically relevant period of exposure before the development of colorectal adenomas or CRC. Another potential shortcoming that limits the interpretation of results is imprecise estimation of dietary fiber intake. Although the Willett semiquantitative food frequency questionnaire has been shown to be reproducible and valid in these cohorts,⁵⁰, ⁵¹, ⁵² the estimates of dietary fiber intake were dependent on a self-administered questionnaire. As previously mentioned, analytical tools used to determine the fiber content of foods also are relatively imprecise and underestimate amounts of dietary fiber. Therefore, fiber values assigned to each reported food consumed have errors. These prospective studies also lack data on food preparation methods, cooking, and chewing, which can alter the physiological properties of fiber.⁵³ The 2 cohorts studied in the Nurses' Health Study and Health Professionals Follow-up Study⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷ are highly educated and affluent professionals with relatively homogeneous lifestyles and dietary habits and thus may not be representative of the general population. Therefore, the applicability of observations made in these cohorts to the general population is in question. One solution to this difficult issue is corroborative evidence from international and cross-cultural prospective studies. The other potential problem is that in the Nurses' Health Study and Health Professionals Follow-up Study cohorts,⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷ the range of dietary fiber consumed might have been narrow, and thus protective effects of fiber might have not been observed. Therefore, potential protective effects of extremely high intake of dietary fiber (>35-50 g/day) cannot be ruled out. Some studies examined the incidence of colonic adenomas only in the distal colon, and results cannot be extrapolated to the proximal colon.⁴⁴, ⁴⁶, ⁴⁷

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Human intervention studies 

In theory, randomized intervention studies in humans should provide definitive support for the purported cause-and-effect relationship between a dietary factor and CRC. However, intervention studies are often difficult to carry out because of the slowly progressive nature of neoplastic transformation and the large number of subjects necessary to achieve an adequate statistical power. However, several strategies have been developed to circumvent these problems. One is to study the modulatory effects of nutritional factors on colorectal carcinogenesis in individuals at high risk of developing CRC. The second strategy is to use so-called intermediate biomarkers of CRC rather than occurrence or recurrence of CRC as the endpoint.⁵⁴, ⁵⁵ These biomarkers include adenoma, proliferation markers, mitotic index, DNA aneuploidy aberrant crypts, mucins, and more recently alterations of several molecular biological markers.⁵⁴, ⁵⁵ However, all intermediate biomarkers have limitations, and most have not been validated conclusively in clinical studies.⁵⁴, ⁵⁵ Furthermore, except for colorectal adenomas,⁵⁶, ⁵⁷ changes in any of these intermediate biomarkers have not yet been proven to lead to a reduction in CRC occurrence and mortality.⁵⁴, ⁵⁵ Even with adenomas, it is known that few adenomatous polyps progress to cancer; the rate is estimated at approximately 2.5 polyps per 1000 per year.³¹ It has also been well established that only adenomatous polyps with certain characteristics (>1 cm, tubulovillous or villous histology, and multiple occurrence) are associated with increased risk of developing adenocarcinoma compared with adenomas without these characteristics.³¹

Several randomized or single-arm intervention studies using a high-fiber diet as a component of chemopreventive strategies against the development of CRC have been conducted or are underway (Table 4). The first such study was conducted on 58 subjects with familial adenomatous polyposis (FAP) who had undergone total colectomy and ileorectal anastomosis at least 1 year before entry into the trial.⁵⁸ These subjects were randomized to receive either a low-fiber supplement (2.2 g/day) plus placebo (control group), a low-fiber supplement (2.2 g/day) plus ascorbic acid (4 g/day) and α-tocopherol (400 mg/day), or a high-fiber supplement (22.5 g/day) plus ascorbic acid (4 g/day) and α-tocopherol (400 mg/day).⁵⁸ The fiber supplement was from a grain source. Over the course of 4 years, each participant underwent proctosigmoidoscopy every 3 months, for a total of 18 examinations. Overall consumption of fiber from supplements and dietary sources averaged 12.2 g/day in the placebo group, 11.3 g/day in the vitamin group, and 22.4 g/day in the high-fiber group.⁵⁸ When results were analyzed on an intention-to-treat basis, only a weak protective effect of fiber against polyp occurrence was observed.⁵⁸ However, when only those with good compliance were analyzed, those who had consumed 11 g of supplemental fiber in addition to their usual dietary fiber intake had a significant reduction in polyp occurrence in the rectal stump, and polyp number decreased incrementally as the amount of ingested, prescribed fiber increased.⁵⁸ The effects of vitamins C and E were not significant, although there was a trend toward protection.⁵⁸ A significant fault of this study is poor compliance with intervention modalities over the 4 years of the study. Compliance decreased by more than 50% over 4 years in some of the groups.⁵⁸ Other legitimate criticisms are uncertainty about whether the 3 groups were similar with respect to dietary intake of components other than fiber, vitamins C and E, and fat and whether any of the groups changed their dietary patterns during the study period.

Table 4. Summary of intervention studies using high fiber as a chemopreventive strategy for CRC

RCT, randomized controlled trial; NA, not available.

One study from the Arizona Cancer Center was a single-arm study that investigated the effect of supplemental wheat bran fiber on a proliferation marker ([³H]thymidine labeling index) in patients who had undergone resection for colon or rectal cancer.⁵⁹ In this study, 13.5 g of supplemental wheat bran per day significantly reduced colorectal epithelial proliferation during the 8 weeks of follow-up.⁵⁹ However, this was not a randomized placebo-controlled study and involved only 17 subjects for the analysis. Furthermore, the [³H]thymidine labeling index is not uniformly accepted as an accurate means of determining the proliferation index of the colonic epithelium.⁵⁴, ⁵⁵ Finally, changes in this index have not been proven to decrease the incidence of CRC.⁵⁴, ⁵⁵

The same investigators have recently completed a double-blind, randomized phase II study using a 2 × 2 factorial design to determine the effects of wheat bran (2.0 or 13.5 g/day) and calcium carbonate (250 or 1500 mg/day) supplementation on [³H]thymidine labeling index in rectal mucosal biopsies and fecal bile acid concentrations at 3 months and 9 months.⁶⁰, ⁶¹ Total fiber intake ranged from 14.4 to 17.5 g/day and 25.7 to 28.7 g/day in the low- and high-fiber groups, respectively.⁶⁰, ⁶¹ The results of this study, which included 100 patients who had undergone complete colonoscopy with colonic polyp removal within 24 months of study entry, showed that neither wheat bran fiber nor calcium treatment significantly decreased the labeling index.⁶⁰ With respect to fecal bile acid concentrations and excretion rates, high-dose fiber supplementation for 9 months caused a reduction in fecal concentrations of total bile acids (52% reduction; P = 0.001) and deoxycholic acid (48% reduction; P = 0.003) compared with baseline concentrations.⁶¹ High-dose calcium supplementation also had a significant but smaller effect on the mean total bile acid (35% reduction; P = 0.044) and deoxycholic fecal bile acid (36% reduction; P = 0.52) concentrations at 9 months compared with baseline.⁶¹ Presently, the same investigators have included more than 1400 patients in a randomized phase III trial of high-dose (13.5 g/day) vs. low-dose (2 g/day) wheat bran fiber in patients with resected colorectal polyps.⁶² Polyp recurrence after 3 years of daily fiber intake serves as the primary endpoint for this dietary intervention trial.⁶²

In the trial reported by the Toronto Polyp Prevention Group from Canada, 201 subjects with adenomatous colorectal polyps were randomized after polypectomy to receive intense counseling on a diet low in fat (<50 g/day or 20% of energy) and high in fiber (50 g/day), mainly from wheat bran, or to follow a normal western diet, high in fat and low in fiber.⁶³ After 12 months of counseling, fat consumption was approximately 25% of energy in the low-fat/high-fiber group and 33% in the western diet group; fiber consumption was 35 g and 16 g respectively.⁶³ After an average of 2 years of follow-up with colonoscopy, an intention-to-treat analysis showed no significant difference between dietary groups with regard to the recurrence of adenomatous polyps.⁶³ However, when only those subjects who had received substantial dietary counseling were reanalyzed, it was found that women who ate the low-fat and high-fiber diet showed a nonsignificant 50% reduction in polyp recurrence (RR, 0.5; 95% CI, 0.2-1.9) associated with a reduced concentration of fecal bile acids.⁶³ Among men, the polyp recurrence rate was increased by approximately 90% in the low-fat/high-fiber diet group compared with the controls (RR, 1.9; 95% CI, 0.8-4.4).⁶³ This also fell short of statistical significance but was associated with an increased concentration of fecal bile acids in these subjects.⁶³ The main problems with this study were (1) a high dropout rate (only 82% of 201 subjects received colonoscopic follow-up), (2) noncompliance with the low-fat/high-fiber diet, (3) small sample size, and (4) short duration of follow-up. However, this study points out that physiological differences in fecal bile acids may exist between men and women and that these may account for differences in the rates of the polyp recurrence on the low-fat/high-fiber diet.

In a recently reported study from Australia, 424 subjects with adenomas and a “clean” colon were randomized to diets containing <25% of energy as fat, 25 g wheat bran supplement, and/or 20 mg β-carotene per day in a 2 × 2 × 2–factorial prospective, randomized, controlled trial.⁶⁴ Endpoints were adenomas and CRCs identified by colonoscopies performed at 2 and 4 years.⁶⁴ This trial showed that neither low-fat intervention nor wheat bran supplementation alone had a significant effect on adenoma recurrence.⁶⁴ However, low-fat intervention combined with wheat bran supplementation significantly reduced the occurrence of large adenomas (>10 mm) at 2 and 4 years of follow-up (P < 0.035).⁶⁴ In this trial, β-carotene, either alone or in combination with the low-fat or high-fiber intervention, had no effect on adenoma recurrence.⁶⁴ Problems with this trial were (1) small number of subjects in each of the 8 arms of the 2 × 2 × 2–factorial design; (2) small number of subjects with large adenoma (>1 cm), which was used as the secondary endpoint of the trial, thereby increasing uncertainty of the results; and (3) differences among groups at baseline with respect to prevalence of multiple (≥2) and large (>1 cm) adenomas.

Several randomized intervention studies using a high-fiber component for the nutritional chemoprevention of CRC are currently ongoing in the United States and Europe (Table 5). The Polyp Prevention Trial is a multi-institutional intervention study recently completed in United States.⁹ The primary goal of the trial is to test the ability of a low-fat (20% fat calories), high-fiber (18 g/1000 kcal daily) diet enriched with vegetables and fruits (5-8 servings daily) to decrease the recurrence rate of adenomatous polyps in patients previously treated for colon adenomas.⁹ To date, 2079 patients have been randomized to the intervention or control arm.⁹ This trial provides 90% power to detect a reduction of 24% in the annual adenoma recurrence rate.⁹ The final colonoscopic examinations at 4 years of follow-up were completed in early 1998.⁹ The European Cancer Prevention Organization study is an ongoing study to compare 3 groups, one given ispaghula husk (a mucilaginous substance), 3.8 g/day for 3 years; one given calcium, 2 g/day; and one given placebo.⁶⁵ All subjects in this study have at least 2 adenomas or 1 adenoma that is >5 mm in diameter (i.e., subjects with a high adenoma recurrence rate).⁶⁵ The primary endpoint is recurrence of adenoma, and secondary endpoints are mucosal cell proliferation rate and fecal bile acids.⁶⁵ To date, 656 subjects have been randomized to 3 arms of the study.⁶⁵ Two randomized trials (Concerted Action Polyposis Prevention [CAPP] 1 and 2, respectively) designed to test effects of 600 mg aspirin and/or 30 g corn starch (equivalent to 13.2 g of resistant starch) in a factorial design in FAP and hereditary nonpolyposis CRC (HNPCC) gene carriers are ongoing in Europe (14 countries). The primary endpoint of CAPP 1 is incidence or progression of colonic adenomas. To date, CAPP 1 has recruited 150 gene carriers (target n = 468) from FAP registries in 14 European countries.⁶⁶ The primary endpoint of CAPP 2 is the incidence of colorectal adenoma. The secondary endpoints include the incidence of extracolonic malignancies, crypt cell proliferation, apoptosis, and genotype. CAPP 2 has just begun recruitment (target n = 1200).

Table 5. Summary of ongoing randomized, double-blind, placebo-controlled intervention studies using high-fiber diets

In summary, 6 intervention studies in humans have been completed and published (Table 4).⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶³, ⁶⁴ Most of these studies included a small number of subjects (range 17-424) and a follow-up period of 8 weeks to 4 years.⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶³, ⁶⁴ One study⁵⁹ was uncontrolled, and 5 were randomized and placebo controlled.⁵⁸, ⁶⁰, ⁶¹, ⁶³, ⁶⁴ Except for 1 study⁵⁸ that recruited patients with FAP, the participants of most studies were individuals with sporadic colon adenomas.⁵⁹, ⁶⁰, ⁶¹, ⁶³, ⁶⁴ Three studies⁵⁸, ⁶³, ⁶⁴ used adenoma recurrence or regression as the endpoint of the trial, and the other 3 used less well-established intermediate biomarkers of CRC (labeling index⁵⁹, ⁶⁰ and fecal bile acids⁶¹). All studies⁵⁸, ⁶⁰, ⁶¹, ⁶³, ⁶⁴ except one⁵⁹ used dietary fiber supplements in conjunction with other dietary factors (vitamins, calcium, low fat). Four studies showed a moderate protective effect of dietary fiber supplements: decreased labeling index in 1 study,⁵⁹ decreased fecal bile acids in 1 study,⁶¹ and decreased adenoma recurrence in 2 studies.⁵⁸, ⁶⁴ The other 2 showed no effect on labeling index⁶⁰ or adenoma recurrence.⁶³ The strongest evidence to date to support the fiber hypothesis is the Australian Polyp Prevention Project, which showed that a diet high in fiber and low in fat prevents recurrence of large adenomas (>10 mm).⁶⁴

The major weaknesses of these intervention studies are short follow-up, small numbers of subjects, poor compliance with dietary interventions, high dropout rates, and use of less well-established intermediate biomarkers with uncertain functional ramifications in some studies. Another problem is that these studies attempted to intervene in incompletely understood biological pathways in special populations of adults at high risk of developing CRC (e.g., those with FAP or previous colonic adenomas) who therefore may be at a late, although preclinical, stage of colorectal carcinogenesis or have precancerous lesions. Other limitations are associated with intervention trials in humans. Blind or double-blind trials are usually impossible with foods or dietary macronutrients, which are recognizable. In nonblind studies of foods, subjects in the control group may adopt the dietary behavior of the treatment group if they think the treatment diet is beneficial. Such trends may obscure a real benefit of treatment. In addition, the time between a change in the level of a dietary factor and any expected change in the incidence of cancer is usually uncertain. Trials should therefore be of a long duration. Finally, people who agree to participate in trials tend to be relatively health conscious and highly motivated; people who are at high potential risk on the basis of dietary intake, and thus susceptible to intervention, are likely to be underrepresented. Hence, the validity of generalizing the results is limited. Therefore, results of intervention studies should be interpreted with caution. They are not an epidemiological “gold standard.” Controlled trials in which intervention shows beneficial effects are good evidence that the agents used are protective. However, studies in which intervention shows no effect, or even a detrimental effect, do not show that the agents used are irrelevant or harmful in the context of whole diets or among normal, healthy populations. The results of intervention studies should not be treated as a refutation of evidence from other types of epidemiological study, especially when such other evidence is backed by data from animal studies and identification of plausible biological pathways.

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Resistant starch and short-chain fatty acids 

Resistant starch is defined as that portion of ingested starch that escapes digestion in the small intestine.¹⁹, ²² More recently, it has been suggested that resistant starch be defined as “the sum of starch and starch-degradation products that, on average, reach the human large intestine.”⁶⁷ Similar to nonstarch polysaccharides, resistant starch has been shown to increase stool bulk, decrease fecal pH, alter the colonic microflora, decrease secondary bile acid concentrations and cytotoxicity of fecal water, decrease colonic mucosal proliferation, increase colonic fermentation, and contribute to short-chain fatty acid (SCFA) synthesis, especially butyrate.⁶⁸, ⁶⁹, ⁷⁰ A recently published international correlation study supports the protective role of resistant starch in the development of CRC.⁷¹ In this study, intakes of starch, nonstarch polysaccharides, protein, and fat were compared with CRC incidence in 12 populations worldwide. After fat and protein intakes were controlled for, there was a strong inverse association between starch consumption and CRC (correlation coefficient, r = −0.70); no significant association with nonstarch polysaccharides was observed (r = −0.29).⁷¹ When nonstarch polysaccharides were combined with resistant starch to give an estimate of fermentable carbohydrate, the inverse association became significant with r = −0.52.⁷¹ Resistant starch was observed to either be protective,⁷² have no effect,⁷³ or enhance tumorigenesis⁷⁴ in chemical rodent models of CRC. In another study using a knockout murine model of the adenomatous polyposis coli gene (Apc^1638N),⁷⁵ resistant starch was shown to significantly increase small bowel tumors.⁷⁶ Two randomized, double-blind, placebo-controlled intervention studies designed to test the effect of resistant starch on CRC in both FAP and HNPCC gene carriers are ongoing in Europe (CAPP 1 and 2; Table 5).

Fermentation of dietary fiber and resistant starch by colonic bacteria generates SCFAs. The principal SCFAs are acetate, propionate, and butyrate, which account for 90%-95% of SCFAs in the colon. SCFAs are an important energy source for the colonocytes. Butyrate is the preferred SCFA to meet colonic energy requirements. SCFAs, especially butyrate, have been shown to have anticarcinogenic properties, as discussed in the next section.⁷⁷, ⁷⁸ Butyrate has been shown to either suppress⁷⁹, ⁸⁰, ⁸¹ or have no effect on⁸² the development of CRC in animal models. There is a paucity of data from human epidemiological and intervention studies concerning the effects of SCFA on colorectal carcinogenesis.

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Biological plausibility: Potential mechanisms of action 

Several potential mechanisms by which dietary fiber can protect against the development of CRC have been proposed and investigated (Table 6).¹⁸, ⁸³, ⁸⁴ Burkitt's initial hypothesis was that dietary fiber increases stool bulk, thus diluting potential carcinogens and decreasing transit time, which would permit less contact time between potential carcinogens in the lumen and the gut mucosa.²⁶ Additional mechanisms also have been proposed (Table 6).¹⁸, ⁸³, ⁸⁴

Table 6. Possible mechanisms of action of dietary fiber

Increased stool bulk

Dilution of potential carcinogens

Decrease in transit time (less contact time for carcinogens)

Binding with potential carcinogens

Binding with bile acids

Decrease in fecal bile acid concentrations

Prevention of conversion of primary to secondary bile acids

Lowers fecal pH

Reduced solubility of free bile acids

Inhibition of 7α-dehydroxylase, which converts primary to secondary bile acids

Inhibition of bacterial degradation of normal fecal constituents to potential carcinogens

Alters colonic microflora

Inhibition of microbial enzymes involved in carcinogen activation

Changes in bacterial species

Stimulation of bacterial growth, which increases fecal bulk

Fermentation by fecal flora to SCFAs

Inhibition of growth of tumor cell lines

Induction of differentiation

Induction of apoptosis

Modulation of gene expression

Prevention of insulin resistance and hyperinsulinemia

It has been demonstrated that carcinogens can bind to dietary fiber, but the extent of binding depends on the carcinogen and dietary fiber.⁸⁵, ⁸⁶, ⁸⁷ Dietary fiber has also been shown to bind with bile acids, thus reducing fecal bile acid concentration.⁸⁸, ⁸⁹ If the dietary fibers to which the bile acids or bile salts are bound are undegraded in the colon, deconjugation of bile salts and conversion of primary to secondary bile acids by bacterial enzymes may be prevented. The bound bile acids or bile salts may pass out of the alimentary tract in the feces. The possible putative interaction of secondary bile acids and colonic mucosal cells will thus be decreased.

Dietary fiber decreases fecal pH, resulting in reduced solubility of free bile acids; theoretically, this should decrease the potential tumor promoter activity of secondary bile acids.⁹⁰ Furthermore, the activity of the colonic bacterial enzyme 7α-dehydroxylase, which converts primary bile acids to secondary bile acids, is inhibited at a pH of <6-6.5.⁹¹, ⁹² Acidification of colonic contents also increases the availability of calcium for binding to free bile and fatty acids, thereby inhibiting their effects on the colonic mucosa.⁹³ A number of epidemiological studies have shown that human populations with lower fecal pH have lower rates of colon cancer.⁹⁰, ⁹⁴ However, direct experimental acidification of the colon contents in animal models have not always led to a reduction in tumorigenesis.⁹⁵ Theoretically, fecal acidification can also inhibit bacterial degradation of normal fecal constituents to potential carcinogens.¹⁸

Another potential mechanism of dietary fiber relates to alterations in colonic microflora, which can exert marked effects on the colonic environment. These may be characterized by changes in bacterial species, functional changes, or production of microbial enzymes considered to be important in carcinogen activation (e.g., α-glucuronidase, α-glucosidase, azoreductase, and nitroreductase).⁹⁶ Although dietary fibers clearly modulate colonic bacterial enzyme activity,¹³ the relationship between colonic bacterial enzyme activity and development of human CRC has not been elucidated clearly. Dietary fibers that are extensively degraded in the colon have been shown to increase fecal bulk by a stimulation of bacterial growth.⁹⁷ Bacteria, rather than undegraded dietary fiber, are the major water-holding component of feces.⁹⁷ Increased fecal bulk and reduced transit time resulting from increased bacterial growth would reduce the possibility of effective interactions of carcinogens with the colonic mucosa. Dietary fiber also can decrease numbers of anaerobes, resulting in a decrease in secondary bile acids.¹³

SCFAs, especially butyrate, produced by fermentation of dietary fiber and resistant starch by colonic bacteria appear to be an important factor in colorectal carcinogenesis.⁷⁷, ⁷⁸ Although butyrate serves as the primary energy source for normal colonic epithelium and stimulates growth of colonic mucosa, in colonic tumor cell lines it inhibits growth⁹⁸, ⁹⁹ and induces differentiation¹⁰⁰ and apoptosis.¹⁰¹ At the molecular level, butyrate has been shown to inhibit histone deacetylase, resulting in hyperacetylation of histones and increased accessibility of DNA to factors controlling gene expression.¹⁰², ¹⁰³ Butyrate also has been shown to alter the binding of regulatory transacting proteins to specific DNA sequences that control the expression of the gene.¹⁰⁴

A unifying hypothesis that may explain how diet and lifestyle factors modulate colorectal carcinogenesis has recently been put forward by McKeown-Eyssen⁷ and Giovannucci.⁸ This hypothesis suggests that the putative dietary and lifestyle factors associated with CRC risk cause insulin resistance and hyperinsulinemia and that hyperinsulinemia may in turn stimulate the growth of colorectal tumors.⁷, ⁸ Although it remains unproven whether insulin stimulates the growth of colon tumors in humans, several lines of evidence support its role. Insulin is an important growth factor for colonic mucosal cells and is a mitogen of colonic carcinoma cells in vitro.¹⁰⁵, ¹⁰⁶ Colonic cancer tissue has both insulin and insulin-like growth factor (IGF) 1 receptors¹⁰⁷, ¹⁰⁸; insulin has been shown to exert its mitogenic effect partly through IGF-1 receptors.¹⁰⁹ Insulin receptors can be bound by IGF-1,¹¹⁰ and a binding protein from IGF-1 inhibits the growth of colon cancer cells in vitro.¹¹¹ Another indirect line of evidence comes from the observation that subjects with acromegaly, characterized by chronic growth hormone and IGF-1 hypersecretion, have an increased risk of developing CRC.¹¹² It has been proposed that stimulation of IGF-1 receptors by IGF-1 or IGF-2 promotes colorectal carcinogenesis in subjects with acromegaly.¹¹² Although epidemiological studies that have examined the relationship between diabetes mellitus and CRC risk have not consistently supported this hypothesis,¹¹³ 2 recently published large prospective studies indicate a modest increase in CRC risk in subjects with diabetes compared with nondiabetic control subjects.¹¹⁴, ¹¹⁵ In a population-based cohort study from Sweden (n = 153,852), subjects with diabetes mellitus were found to have on average a 40% greater risk of developing colon cancer and a 60% greater risk of dying of colon cancer than the general population.¹¹⁴ The first Cancer Prevention Study of the American Cancer Society with more than 1 million participants showed that diabetic men had a statistically significant 30% increase in risk of developing CRC compared with nondiabetic men during 13 years of follow-up.¹¹⁵ Two recently published animal studies have demonstrated that exogenously injected insulin promotes the development of colorectal tumors¹¹⁶ and the growth of aberrant crypt foci,¹¹⁷ a putative precursor of colon cancer, thereby providing support for the causal hypothesis linking insulin resistance and CRC. Because dietary fiber, especially soluble fiber, affects glycemia and insulinemia,¹¹⁸ the insulin hypothesis could be a mechanism by which dietary fiber can modulate colorectal carcinogenesis. As such, this hypothesis merits further consideration.

Epidemiological and experimental evidence indicating a causal association between dietary fiber and CRC is strengthened when a biological pathway or mechanism by which colorectal carcinogenesis may be modified is identified and when this mechanism is biologically plausible. However, it can be argued that epidemiological data, strong and consistent, are an inadequate basis for any definite judgment of causality unless supported by mechanistic evidence.¹¹⁹ Although investigations to elucidate potential anticarcinogenic mechanisms of dietary fiber have focused on physical properties of dietary fiber, more recent work has expanded into physiological functions and molecular mechanisms of dietary fiber. A better mechanistic understanding of how dietary fiber can modulate colorectal carcinogenesis can lead to a more rational strategy using dietary fiber supplementation to prevent CRC in humans.

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Conclusion 

Summary of causal inference 

Although valuable information can be obtained from nutritional epidemiological studies examining the effect of diet on cancer, several shortcomings limit interpretation of the results of these studies (Table 7).¹²⁰

Table 7. Summary of causal inference

The strongest evidence that supports the fiber hypothesis is the remarkable consistency of the protective effect of dietary fiber among correlation and case-control studies conducted in populations with different patterns of diet and CRC. Three combined analyses or meta-analyses of case-control studies also provide strong support for the dose-dependent protective effect of dietary fiber or fiber-rich foods against colorectal carcinogenesis.²⁸, ²⁹, ³⁰ These studies suggest on average a 50% reduction in the risk of developing CRC in subjects with the highest dietary fiber intake compared with those with the lowest intake.²⁸, ²⁹, ³⁰ However, large prospective studies conducted in specific populations in the United States do not support the protective effect of dietary fiber on the development of CRC.⁴³, ⁴⁴, ⁴⁵, ⁴⁸ On the other hand, these prospective studies suggest a modest dose-dependent protective effect of dietary fiber on distal colonic and rectal adenomas in men only.⁴⁶, ⁴⁷ Although these prospective studies provided the least biased approach, the findings need to be corroborated by evidence from similar international and cross-cultural prospective studies.

It is difficult to delineate the effect associated with dietary fiber from other potential anticarcinogens present in the fiber-rich foods such as vegetables, fruits, cereals, and grains in epidemiological studies. However, most of the recently published prospective studies have adjusted for potential confounding factors, including intake of vegetables, fruits, cereals, and grains as well as antioxidant vitamins and folate.⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸ Some human intervention studies have attempted to test the effect of dietary fiber supplementation on colorectal carcinogenesis while keeping the intake of vegetables, fruits, cereals, and grains constant during the study period.⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³, ⁶⁴ It is possible that undetermined interactions among anticarcinogens present in fiber-rich foods and fiber are responsible for the observed protective effect of dietary fiber on the development of CRC.

Of the published randomized, double-blind, placebo-controlled studies in humans that have used adenoma recurrence or regression as the endpoint of the trial,⁵⁸, ⁶³, ⁶⁴ probably the best intermediate biomarker of CRC available to date,³¹ 2 have shown significant protective effects of wheat fiber supplementation⁵⁸, ⁶⁴; the other showed no effect.⁶³ In the largest intervention trial published to date (the Australian Polyp Prevention Project, n = 424),⁶⁴ a diet high in fiber and low in fat was shown to prevent recurrence of large adenomas (>10 mm), probably a more relevant biomarker than smaller adenomas (<10 mm). Five ongoing large, randomized, double-blind, placebo-controlled studies in the United States and Europe will certainly provide more insight into the effects of dietary fiber on colorectal carcinogenesis (Table 5).

The fiber hypothesis is consistent with epidemiological observations that suggest significantly lower CRC prevalence, incidence, and mortality in countries or populations with high intake of fiber-rich foods, including vegetables, fruits, cereals, and grains.², ³, ¹¹, ¹², ¹²¹ The protective effect of dietary fiber on the development of CRC is also analogous to similar observations in breast cancer,¹², ¹²² endometrial cancer,¹²³, ¹²⁴ ovarian cancer,¹²⁵ and prostate cancer,¹²⁶ albeit to a lesser degree. More importantly, several biologically plausible mechanisms exist for dietary fiber that corroborate epidemiological and other evidence (Table 6). However, in vivo verification of some of these mechanisms is still needed.

Magnitude of CRC risk reduction 

The extent to which CRC mortality rates in the United States might be reduced by practicable dietary means has been estimated at 50%-75%.⁴ More recently, the World Cancer Research Fund panel has judged that diets high in vegetables, and therefore high in fiber, and low in meat; avoidance of alcohol; and regular physical activity may reduce the incidence of CRC by 66%-75%.¹¹⁹ With respect to the extent of CRC risk reduction associated with dietary fiber or fiber-rich foods, 3 combined analyses or meta-analyses of case-control studies suggest a 50% reduction in the risk of developing CRC in subjects with the highest dietary fiber intake compared with those with the lowest intake.²⁸, ²⁹, ³⁰ A large, ongoing prospective mortality study (Cancer Prevention Study II of the American Cancer Society) with more than 1 million participants suggests a 30% reduction in CRC mortality among individuals consuming the highest amount of vegetables and high-fiber grains compared with those consuming the lowest amount.⁴² Two large prospective studies suggest a 35%-63% reduction in the risk of developing distal colon and rectal adenomas in men consuming the highest amount of dietary fiber compared with those consuming the lowest amount.⁴⁶, ⁴⁷ Although it is difficult to estimate accurately the magnitude of CRC risk reduction attributable solely to dietary fiber or fiber-rich foods, there appears to be a significant degree of reduction.

Dose of dietary fiber associated with decreased CRC risk 

The threshold level above which dietary intake of fiber is associated with a significant degree of CRC risk reduction is not well established in epidemiological and intervention studies. Case-control and prospective studies have arbitrarily defined increasing quartiles or quintiles of dietary fiber intake, which are different from study to study and from population to population. In some populations, the difference between extreme quartiles or quintiles is quite small. In some studies, the amount of dietary intake of fiber associated with each quartile or quintile is not stated. Two combined analyses of case-control studies showed a 50% reduction in CRC risk in individuals consuming 27 g/day compared with those consuming less than 11 g/day of fiber.²⁹, ³⁰

The extreme quartiles or quintiles of dietary fiber intake in the Nurses Health Study⁴⁴ and Iowa Women Health Study,⁴⁸ which did not show any significant reduction in CRC risk , were >24.9 and <9.8 g/day and >24.7 and <14.5 g/day, respectively (Table 3). The Health Professionals Follow-up Study, which demonstrated a significantly reduced risk of distal colon adenomas⁴⁶, ⁴⁷ but not CRC,⁴⁵ generally compared those with dietary intake of fiber of 28.3-32.8 g/day with those with dietary intake of fiber of 11.6-16.6 g/day. Most of the positive case-control and prospective studies also showed significant dose-dependent inverse associations between dietary intake of fiber and CRC or adenoma risk.²⁹, ³⁰, ⁴⁶, ⁴⁷

Amounts of fiber supplement or total fiber intake chosen for intervention studies vary. Of the 2 published intervention studies that used adenoma recurrence as the endpoint of trial in subjects with sporadic colon adenomas, the Australian Polyp Prevention Project used 25 g wheat bran supplement daily in addition to usual dietary intake of fiber (the total intake of fiber was not stated in the report).⁶⁴ In contrast, the Toronto Polyp Prevention Study used 50 g of total fiber intake daily in the high-fiber group compared with the low fiber group, but total fiber intake was 35 g/day in the high-fiber group and 16 g/day in the low-fiber group.⁶³ The Phase III Arizona Cancer Center Polyp Prevention Study will determine the rate of adenoma recurrence in subjects receiving 13.5 g wheat bran supplement daily in addition to their usual daily intake of dietary fiber compared with those receiving 2.5 g wheat bran supplement daily.⁶² The Polyp Prevention Trial will determine the rate of adenoma recurrence in subjects consuming 18 g fiber/1000 kcal daily compared with those consuming usual amounts of dietary fiber.⁹

It appears that most case-control, prospective, and intervention studies have assessed the effect of total fiber intake 3-3.5 times the mean dietary fiber intake in the U.S. adult population (11.1 g/day).²³ The Toronto Polyp Prevention Study, which attempted to determine the effect of 50 g total fiber intake daily, showed only a nonsignificant 50% reduction in adenoma recurrence in women.⁶³ However, individuals assigned to the high-fiber intake in this trial consumed, on average, only 35 g/day of dietary fiber instead of 50 g/day.

Duration of intervention associated with decreased CRC risk 

There is often a latency period between exposure to a factor that modifies cancer risk and induction of the tumor itself. A further delay occurs before development of the tumor reaches the stage at which it can be diagnosed; this delay varies with different factors and different sites. Migrant studies suggest a delay between exposure of migrants to urban-industrial diets and emergence of CRC of 10-20 years.¹¹⁹ It follows that appropriate diets may have their full impact in preventing cancer only decades after they are widely adopted. These delays must be considered in setting realistic targets for CRC prevention with dietary fiber. Therefore, because CRC is strongly age related²¹ and its incidence rates increase markedly with age beginning around the sixth decade of life,¹¹⁹ fiber intervention should begin at least 10-20 years before the peak age for CRC incidence. Prospective and intervention studies, except one,⁴⁴ have not had a long enough follow-up to observe any beneficial effects associated with fiber intervention.

Types of fiber or specific related components associated with decreased CRC risk 

With respect to the exact types and sources of fiber associated with the decreased risk of CRC, animal studies suggest that insoluble and less fermentable fibers and wheat bran are most effective.¹³ Information on this issue is lacking in epidemiological and intervention studies in humans. Although an early analysis from the Health Professionals Follow-up Study suggested that all sources of fiber (crude, vegetables, fruits, and grains) were associated with decreased risk of adenoma in men,⁴⁶ a more recent analysis of this cohort suggests that only total dietary fiber, fruit fiber, and soluble fiber are significantly associated with decreased risk of colonic adenomas.⁴⁷ Most intervention studies have used either wheat bran fiber supplement⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³, ⁶⁴ or all sources of fiber.⁹ Two published intervention studies have used adenoma recurrence as the endpoint of the trial and wheat bran supplement; results of the Australian Polyp Prevention Project⁶⁴ were positive, and results of the Toronto Polyp Prevention Study⁶³ were negative.

Although the role of resistant starch in colorectal carcinogenesis has recently received much attention, convincing epidemiological evidence is lacking except for one international correlation study that showed a strong inverse association between starch and resistant starch consumption and CRC risk.⁷¹ Similarly, 4 published animal studies to date⁷², ⁷³, ⁷⁴, ⁷⁶ have produced conflicting results, with 2 studies⁷⁴, ⁷⁶ showing enhanced tumorigenesis associated with resistant starch. In contrast to resistant starch, most of the published animal studies using butyrate demonstrated protective effects of this SCFA on colorectal carcinogenesis.⁷⁹, ⁸¹ Because several biologically plausible mechanisms exist for butyrate, this SCFA warrants further consideration in intervention trials.

Target group(s) for fiber intervention 

Studies that address target groups for intervention are lacking in the literature. Intervention studies have focused on individuals at high risk of developing CRC or adenomas, including those with previous adenomas, CRC, and FAP and gene carriers of FAP or HNPCC. Whether increasing dietary intake of fiber will reduce the CRC risk in the general population must be deduced from epidemiological and intervention studies using high-risk individuals and intermediate biomarkers because of the cost and duration of the studies. At present, it appears that individuals at high risk of developing CRC and adenomas will benefit the most from fiber intervention. As previously discussed, the NHANES II study identified a marked racial effect, with blacks of both sexes and in all age groups having lower dietary fiber intake than whites.²³ Unlike the white population in the United States, blacks have not had substantial improvement in CRC incidence and mortality.⁷

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Recommendations 

Given a lack of complete scientific evidence, it is difficult to advise patients with absolute confidence. Nevertheless, the guidelines in this review represent reasonable conclusions based on currently available data. Therefore, it is reasonable to recommend total fiber intake of at least 30-35 g/day. Dietary fiber should be from all sources, including 5-7 servings of vegetables and fruits daily and generous portions of whole-grain cereals as recommended by the World Health Organization and the National Cancer Institute. Because of uncertainty about the types and sources of fiber that are most effective in the prevention of CRC and as yet undetermined potential interactions between fiber and other anticarcinogens present in fiber-rich foods, it is prudent to recommend a high intake of dietary fiber from all sources, including vegetables, fruits, cereals, grains, and legumes. It is clear that as yet undetermined interactions among dietary components and other lifestyle factors play a more important role in colorectal carcinogenesis than individual dietary and lifestyle factors. The dietary guidelines from the American Cancer Society and the National Cancer Institute encourage healthy eating habits and lifestyle modifications. All of the factors in these guidelines have been considered to play an important role in colorectal carcinogenesis as well.², ³ The guidelines can be used in conjunction with the dietary fiber recommendations. The guidelines are (1) eat each of the 5 food groups daily (meat, dairy products, grains, fruits and vegetables); (2) reduce total fat intake to less than 25%-30% of total calories and saturated fat to less than 10% of total calories; (3) eat 5 or more servings of fresh vegetables and fruits daily (raw better than cooked; include deep yellow vegetables and dark green cruciferous vegetables); (4) eat red meat infrequently (substitute chicken or fish without skin); (5) eat more fiber-rich foods such as whole-grain cereals, fruits, and vegetables (daily total of 20-30 g fiber); (6) avoid obesity; (7) eat salt-cured, smoked, and nitrite-cure foods in moderation; (8) keep alcohol consumption moderate; (9) participate in daily physical activity; and (10) do not smoke. Increasing total fiber intake to >30 g/day from the standard 10-g North American diet can not only protect against CRC but also potentially decrease cholesterol levels,¹²⁷ improve insulin resistance,¹²⁸ reduce blood pressure,¹²⁹, ¹³⁰ and prevent heart disease.¹³¹

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Acknowledgements 

The Clinical Practice and Practice Economics Committee acknowledges the following individuals, whose critiques of this review paper provided valuable guidance to the authors: Graeme P. Young, M.D., Joel Mason, M.D., and James J. Cerda, M.D.

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