Important: This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Prevention of colorectal cancer

EVIDENCE OF BENEFIT

Dietary Factors

The studies reviewed below include those on adenomas; special note is made if a study applies to adenomas only.

Dietary Fat and Meat Intake

Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat.[1] On average, fat comprises 40% to 45% of total caloric intake in high-incidence Western countries; in low-risk populations fat accounts for only 10% of dietary calories.[2] In laboratory studies a high fat intake increases the incidence of induced colon tumors in experimental animals.[3,4] Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake.[5,6] Although positive associations with meat consumption or with fat intake have been found frequently, the results have not always achieved statistical significance.[7] A number of prospective cohort studies have been conducted in the United States and abroad. In Japan, an increased risk of colon cancer with increased frequency of meat consumption was observed in the group with infrequent vegetable consumption among a group of 265,000 men and women.[8] In Norway, an increased risk for processed meat only was found,[9] a finding that was confirmed in the Netherlands.[10] A clearly defined gradient in risk for frequency of meat and poultry consumption was not observed in a population of Seventh Day Adventists that included a large proportion of vegetarians.[11] A prospective study among female nurses showed an increased risk of colon cancer associated with red meat consumption (beef, pork, lamb, and processed meat) and also with the intake of saturated and monounsaturated fat, predominantly derived from animals.[12] No increase in risk with meat or fat consumption was seen, however, in 2 other large prospective studies, the American Cancer Society's Cancer Prevention Study II and the Iowa Women's Health Study.[13,14] In a prospective cohort study of a low-risk population of non-Hispanic white members of the Adventist Health Study, a positive association between meat (both red and white) intake and colon cancer was observed (relative risk for greater than or equal to 1 time per week versus no meat intake = 1.85, 95% confidence interval (CI) 1.19-2.87, p for trend = 0.01).[15] It has been hypothesized that the heterocyclic amines (HCAs) formed when meat and fish are cooked at high temperatures may contribute to the increased risk of colorectal cancers associated with meat consumption that has been observed in epidemiologic studies. A population-based case-control study in Sweden, however, found no evidence of increased risk associated with total HCA intake; for colon cancer the relative risk was 0.6 (95% CI 0.4-1.0), and for rectal cancer it was 0.7 (95% CI 0.4-1.1).[16,17]

Explanations for the conflicting results regarding whether dietary fat or meat intake affects risk of colorectal cancer [10] include, (a) validity of dietary questionnaires used; (b) differences in the average age of the population studied; (c) variations in methods of meat preparation (in some instances, mutagenic and carcinogenic heterocyclic amines could have been released at high temperatures [18]) and (d) variability in the consumption of other foods, such as vegetables.[19] In addition, some epidemiological studies have reported lower incidence rates of colon cancer in populations with high intakes of both fat and fiber, compared with populations with high levels of fat but low levels of fiber consumption.[20] Although far from clear cut, the available evidence suggests colorectal cancer risk is possibly associated with some interaction of dietary fat and protein and caloric intake.

Six case-control studies and 2 cohort studies have explored potential dietary risk factors for colorectal adenomas.[21,22] Three of the 8 studies found that higher fat consumption was associated with increased risk. High fat intake has been found to increase the risk of adenoma recurrence following polypectomy.[23] In a multicenter randomized, controlled trial, a diet low in fat (20% of total calories) and high in fiber and fruits and vegetables did not reduce the risk of recurrence of colorectal adenomas.[24]

Bile Acids

A central effect of bile acids in the etiology and pathogenesis of colorectal cancer has been claimed.[25] An increased bile acid concentration in the intestinal tract accompanies a high-fat diet since bile acids are released from the gallbladder after fat ingestion. The concentration of bile acids in the colon is heavily influenced by the amount and type of fat in the diet.[26] The potential mechanism of action of bile salts in colorectal carcinogenesis is unknown, although it has been suggested that it is mediated by diacylglycerol.[27] The conversion of dietary phospholipids to diacylglycerol by intestinal bacteria is enhanced by a high-fat diet. It is proposed that diacylglycerol enters the cell directly, stimulating protein kinase C which is involved in intracellular signal transduction.

Dietary Fiber, Vegetables, and Fruit

The evidence on whether dietary fiber exerts a protective role in reducing the incidence of colorectal cancer is mixed. Most animal and epidemiologic studies show a protective effect of dietary fiber on colon carcinogenesis.[28] The term fiber is used to describe a complex mixture of compounds including insoluble fiber (typified by wheat bran and cellulose) and soluble fiber (usually dried beans). Ingestion of fiber could modify carcinogenesis in the large bowel by a number of potential mechanisms.[29-31] These mechanisms include binding to bile acids, increasing fecal water and possibly diluting carcinogens, and decreasing transit time (not an obvious factor). Fiber may act as a substrate for bacterial fermentation with a resultant increase in bacterial mass and the production of short chain fatty acids, typified by butyrate.[31] Butyrate has been shown to have anticarcinogenic effects in vitro and is regarded as an important fuel for the colonic epithelium.[32,33] A meta-analysis of 13 case-control studies from 9 countries concluded that intake of fiber-rich foods is inversely related to cancers of both colon and rectum.[34] The analysis did not include fiber supplements. The inverse association with fiber was observed in 12 of the 13 studies and was similar in magnitude for left-sided and right-sided colon and rectal cancers, for men and for women, and for different age groups. It has been suggested that the inverse association with fiber may be reflective of some other closely associated dietary constituents, such as the anticarcinogens found in vegetables, fruits, legumes, nuts and grains.[5,34] These substances include phenolic compounds, sulfur-containing compounds and flavones.[35,36] In a prospective cohort study of a low-risk population, an inverse association was found with legume intake and the risk of colorectal cancer (relative risk for greater than 2 times per week versus 1 time per week = 0.53, 95% CI 0.33-0.86, p for trend = 0.03).[15]

Other studies have corroborated the effects of dietary fiber. One study used a supplement of 10 g/day of wheat bran, cellulose and oat bran, and found a decreased mutagenic activity of fecal contents in those receiving wheat bran and cellulose supplementation.[37] Although, no measurable inhibition was observed during oat bran supplementation. Fecal total and secondary bile acid excretion increased during oat fiber supplementation.

Despite the evidence from case-control studies of a protective effect, results from the large prospective Nurses' Health Study found no difference in risk of colorectal cancer between women in the highest compared to lowest quintile group with respect to dietary fiber, after adjusting for age, known risk factors, and total energy intake (relative risk = 0.95; 95% CI 0.73-1.25).[38]

Many epidemiologic studies have examined the relationship between fruit and vegetable intake and the incidence of colon and/or rectal cancer,[39] with considerable variation in findings. Perhaps the most definitive analysis to date is a prospective study that examined dietary intake data based on food frequency questionnaires from 88,764 women in the Nurses Health Study and 47,325 men in the Health Professionals Follow-up Study.[40] The study included a total of 1,743,645 person-years of follow-up, 937 cases of colon cancer, and 244 cases of rectal cancer. Based on analyses adjusted for numerous covariates, the authors found no association in women or men between overall fruit and vegetable consumption and risk of colon or rectal cancer. Neither were associations observed when the data were examined for subgroups of fruits or vegetables (with the exception of legumes, which were associated with an increased risk of colon cancer in women) or individual fruits or vegetables (with the exception of prunes, which were associated with an increased risk of colon cancer in men). Results did not change when data were examined by vitamin use status, smoking status, or family history of colorectal cancer, nor were elevated risks seen when individuals with very low levels of fruit and vegetable consumption were compared to those with the highest levels. For women and men combined, the covariate-adjusted relative risk of colon cancer associated with one additional serving of fruits and vegetables per day was 1.02 (95% CI 0.98-1.05); the comparable relative risk for rectal cancer was 1.02 (95% CI 0.95-1.09).

In a population-based prospective cohort study of 61,463 women in Sweden, individuals who consumed very low amounts of fruits and vegetables (less than 1.5 servings of fruit and vegetables per day) had a relative risk for developing colorectal cancer of 1.65 (95% CI 1.23 - 2.2, p trend = 0.001) as compared with those individuals who consumed greater than 2.5 servings. However, there was little evidence of a benefit for higher as compared with moderate consumption (greater than versus less than 3.5 servings). Limitations of this study are that dietary intake during the study period was not reassessed over time and the influence of physical activity could not be accurately determined. In addition, the conclusion about very low amounts of intake of fruits and vegetables is based on a retrospective subdivision of the lowest quartile of consumption and its strength has not been adjusted for other potential confounding factors.[41]

Six case-control studies and 3 cohort studies have explored potential dietary risk factors for colorectal adenomas.[21,22,38] Four of the 9 found an association of fiber, carbohydrates and/or vegetables with reduced risk. In one study, cases with moderate or severe dysplasia had a significantly lower intake of cruciferous vegetables than those with mild dysplasia. No significant effect of dietary fiber on colorectal adenoma was found in the large cohort study of U.S. nurses.[38]

Other studies in progress or nearing completion are listed in Table 1.[28] High fiber cereal supplements over a 3-year period did not result in a decrease in adenoma recurrence in a randomized, controlled trial of 1,303 individuals.[42] In a multicenter randomized, controlled trial, a diet low in fat (20% of total calories), high in fiber (18 g of dietary fiber per 1,000 kcal) and fruits and vegetables (3.5 servings per 1,000 kcal) was not associated with a reduction in risk of recurrence of colorectal adenomas.[24]

Table 1: Ongoing Phase III Trials of New Strategies to Prevent the Recurrence of Non-Familial Colorectal Adenomas [28]

Calcium

It has been hypothesized that orally ingested calcium lowers colon cancer risk by binding bile acids and fatty acids, thereby reducing exposure to toxic intraluminal compounds.[43] Indirect effects on bile acid metabolism and a direct effect on colonic epithelial cells are also possible.

Several [44-47] but not all [22,48] epidemiologic studies have observed an inverse relationship between calcium intake and cancer risk. Interpretation of these studies can be quite complex. For example, in Utah, an inverse relationship between colon cancer and calcium was observed in a study that compared members of the Church of Jesus Christ of Latter-Day Saints (Mormons) and Seventh Day Adventists with a group from the U.S. population at large. Both study groups have higher calcium intakes, mainly milk and dairy products, than the national average. Unlike the Seventh Day Adventists, however, the Mormon group had a consumption of meats and fat similar to that of the general population.

Experimental studies in rodents [49] and some but not all [50-53] human studies have described a decrease in colonic epithelial cell proliferation after the administration of calcium citrate. Human studies using labeling index are dependent on a complex methodology.[54] A randomized placebo-controlled trial tested the effect of calcium supplementation (3 g calcium carbonate daily (1200 mg elemental calcium)) on the risk of recurrent adenoma.[55] The primary endpoint was the proportion of subjects (72% of whom were male) in whom at least 1 adenoma was detected following a first and/or second follow-up endoscopy. A modest decrease in risk was found for both developing at least 1 recurrent adenoma (adjusted risk ratio = 0.81, 95% CI 0.67-0.99) and in the average number of adenomas (adjusted risk ratio = 0.76, 95% CI 0.60-0.96). The investigators found the effect of calcium was similar across age, sex, and baseline dietary intake categories of calcium, fat, or fiber. The study was limited to individuals with a recent history of colorectal adenomas and so could not determine the effect of calcium on risk of first adenoma, nor was it large enough or of sufficient duration to examine risk of invasive colorectal cancer. The results of other ongoing adenoma recurrence studies are awaited with interest (Table 1). It is important to note that the dose of calcium salt administered may be important; the usual daily doses in trials have ranged from 1,250 to 2,000 mg of calcium.

Postmenopausal Female Hormone Supplements

Several epidemiologic studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements.[56-58] For rectal cancer, most studies have observed no association or a slightly elevated risk. [59-61]

Other Factors

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Several but not all epidemiological studies have reported a reduction in colon cancer incidence associated with the use of aspirin. Several cohort studies suggest a preventive effect of aspirin. Among a group of over 600,000 adults enrolled in an American Cancer Society study, mortality in regular users of aspirin was about 40% lower for cancers of the colon and rectum.[62,63] In a study of over 11,000 men and women in Sweden with rheumatoid arthritis (and presumably ingesting NSAIDs), colon cancer incidence was 37% lower and rectal cancer was 28% lower than predicted from cancer registry data.[64] In a report from the Health Professionals Follow-up Study of 47,000 males, regular use of aspirin (at least 2 times per week) was associated with a 30% overall reduction in colorectal cancer including a 50% reduction in advanced cases.[65] A population-based retrospective cohort study of nonaspirin NSAID use among individuals aged 65 and older was also associated with lower risk, particularly with increasing durations of use.[66] In the Physicians' Health Study, 22,000 men aged 40 to 84 were randomized to placebo or aspirin (325 mg every other day) for 5 years. There was no reduction in invasive cancers or adenomas at a median follow-up of 4.5 years.[67] In a subsequent analysis over a 12-year period, both randomized and observational analyses indicated that there was no association between the use of aspirin and the incidence of colorectal cancer. The low dose of aspirin and the short treatment period may account for the null findings.[68] Several studies, conducted in a rigorous manner, have demonstrated the effectiveness of sulindac in reducing the size and number of adenomas in familial polyposis.[69,70]

The NSAID piroxicam, at a dose of 20 mg/day, reduced mean rectal prostaglandin concentration by 50% in individuals with a history of adenomas.[71] Several studies are in progress assessing the effect of aspirin or other nonsteroidals on polyp recurrence following polypectomy.[28] In several of these studies, mucosal prostaglandin concentration is being measured.

The potential for the use of NSAIDs as a primary prevention measure is being studied. However, there are several unresolved issues that mitigate against making general recommendations for their use. These include apaucity of knowledge about the proper dose and duration for these agents, and concern about whether the potential preventive benefits would balance such long-term risks as gastrointestinal ulceration and hemorrhagic shock for the average risk individual.[72]

Physical Activity

A sedentary lifestyle has been associated in some [73,74] but not all [75] studies with an increased risk of colorectal cancer. There are numerous observational studies that have examined the relationship between physical activity and colon cancer risk. [76] Most of these studies have shown an inverse relationship between level of physical activity and colon cancer incidence. The average relative risk reduction is reportedly 40 to 50%. However, it is not known if or to what degree the observed association is due to confounding variables, such as diet or a genetic predisposition to colon cancer. In a population-based case control study of colorectal cancer among Chinese men and women in Western North America and China, colon and rectal cancer risk was elevated among men employed in sedentary occupations in both continents.[77] Further, the association between colorectal cancer risk and saturated fat was stronger among the sedentary than among the active population. Perhaps related to physical activity, body mass was found to be correlated with rectal cancer in men in an Australian study [75] and with colorectal cancer in men in Sweden.[78]

Alcohol Consumption

There is evidence of an association of colorectal cancer with alcoholic beverage consumption. In a meta-analysis, this association was weak.[79] In another review, statistically significant elevations of risk were found in males, particularly in regard to beer consumption and rectal cancer. It is hypothesized that alcohol may act to stimulate mucosal cell proliferation, to activate intestinal procarcinogens and possibly provide a source of unabsorbed carcinogens that can reach the distal large bowel.[80] Subsequently published case-control studies suggest a modest to strong positive relationship between alcohol consumption and large bowel cancers.[81,82]

Five studies have reported a positive association between alcohol intake and colorectal adenomas.[83] A case-control study of diet, genetic factors, and the adenoma-carcinoma sequence was conducted in Burgundy.[84] It separated adenomas less than 10 mm in diameter from larger adenomas. A positive association between current alcohol intake and adenomas was found to be limited to the larger adenomas suggesting that alcohol intake could act at the promotional phase of the adenoma-carcinoma sequence.[84]

Vitamins

In a prospective cohort study of 35,215 Iowa women, an inverse association between the risk of colon cancer and vitamin E intake was found; the relative risk for the highest compared to the lowest quartile was 0.3 (95% CI 0.19-0.54).[85] In a population-based case-control study, an inverse relationship between vitamin D intake and risk of colorectal cancer was found.[86] A prospective cohort study observed that higher energy-adjusted folate intake in the form of multivitamins containing folic acid was related to a lower risk for colon cancer (relative risk = 0.69, 95% CI 0.52-0.93) for intake greater than 400 ug/day compared with intake less than or equal to 200 ug/day after controlling for age, family history of colorectal cancer, aspirin use, smoking, body mass, physical activity, and intakes of red meat, alcohol, methionine, and fiber.[87]

Cigarette Smoking

Most case-control studies of cigarette exposure and adenomas have found an elevated risk for smokers.[21] In addition, a significantly increased risk of adenoma recurrence following polypectomy has been associated with smoking in both men and women.[21] In the Nurses' Health Study, the minimum induction period for cancer appears to be at least 35 years.[88] Similarly, in the Health Professionals Follow-up Study, a history of smoking was associated with both small and large adenomas and with a long induction period of at least 35 years for colorectal cancer.[89] In the Cancer Prevention Study II (CPS II), a large nationwide cohort study, multivariate-adjusted colorectal cancer mortality rates were highest among current smokers, intermediate among former smokers, and lowest in never smokers, with increased risk observed after 20 or more years of smoking in men and women combined.[90] Based on CPS II data, it was estimated that 12% of colorectal cancer deaths in the U.S. population in 1997 were attributable to smoking. A large population-based cohort study of Swedish twins found that heavy smoking of 35 or more years duration was associated with a nearly three-fold increased risk of developing colon cancer, although sub-site analysis found a statistically significant effect only for rectal but not colon cancer.[91] Another large population-based case-control study supports the view that current tobacco use and tobacco use within the last 10 years is associated with colon cancer. A 50% increase in risk was associated with smoking more than a pack a day relative to never smoking.[92] However, a 28-year follow-up of 57,000 Finns showed no association between the development of colorectal cancer and baseline smoking status, although there was a 57% to 71% increased risk in persistent smokers.[93] No relationship was found between cigarette smoking, even smoking of long duration, and recurrence of adenomas in a population followed for 4 years after initial colonoscopy.[94]

Polyp Removal

The National Polyp Study showed a greater than 75% reduction in the subsequent incidence of colorectal cancer after colonoscopic polypectomy compared with three nonconcurrent, external control groups.[95]

Fecal Occult Blood Testing

The Minnesota randomized trial of fecal occult blood tests investigated reduction in incidence of colorectal cancer. Nearly 85% of subjects with a positive test underwent diagnostic procedures that included colonoscopy or double contrast barium enema plus flexible sigmoidoscopy. After 18 years of follow-up, the incidence of colorectal cancer was reduced by 20% in the annually screened arm and 17% in the biennially screened arm.[96]

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Date Last Modified: 01/2002

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