Dietary Factors Related to Colorectal Neoplasms

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COLORECTAL CANCER

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DIETARY FACTORS RELATED TO COLORECTAL NEOPLASMS Marcus

J.

Burnstein, MO, MSc, FRCSC

Colorectal cancer is a significant problem in Western societies. In the United States, 3% of the population will develop colon cancer by the age of 75 years, and another 1% to 2% will develop rectal cancer.84 Colorectal cancer is the second leading cause of death from cancer in the United States, Canada, the United Kingdom, and most other Western countries. The cure rate for this cancer has remained at 50% for several decades, and the impact of screening programs has been disappointing.47, 71 It is not surprising, therefore, that there has been tremendous interest in investigating the causative factors for colorectal cancer in the hope that this knowledge would permit cancer prevention. Unfortunately, despite the accumulation of a massive body of information, the causes are not known with certainty. Differences in the incidence of colorectal cancer between countries and changes in prevalence rates among migrants have implicated environmental factors in the etiology of the disease. Diet has emerged as one of the most plausible etiologic factors. The direct contact that takes place between dietary constituents and the organ at risk gives the dietary hypothesis an intuitive appeal. The data that incriminate dietary factors in the etiology of colorectal cancer come primarily from epidemiologic studies and animal experiments. Many of the data are contradictory. The limitations of epidemiologic methods and of animal investigations must be recognized. There are four types of epidemiologic study designs used in evaluating the relation between diet and cancer. 11, 35, 78 Correlational studies look for an association between per capita consumption of a dietary factor and the prevalence of the disease in the population. The principal weakness of this method is referred to as "ecologic fallacy" -the concept that the association observed for two factors might actually represent a link with a third, unmeasured factor. 35 Case-control studies begin with disease and search retrospectively for associations with putative risk factors. A problem with this design is that it depends on the recall From the Department of Surgery, University of Toronto; and St. Michael's Hospital, Toronto, Ontario, Canada

SURGICAL CLINICS OF NORTH AMERICA VOLUME 73· NUMBER 1 • FEBRUARY 1993

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of dietary habits extending over long periods of time. Prospective (cohort) studies assess exposure to presumed risk factors at one point in time and disease outcome at a subsequent date. This kind of study is expensive and time consuming. Randomized intervention trials are designed to modify the intake of a specific risk factor in one group and compare the subsequent disease incidence with that in a control population. Intervention trials are not only time consuming and expensive but limited by patient noncompliance and by changes in the practices of the control population over time. 78 Intervention trials designed to identify early and possibly reversible premalignant changes provide an alternative to intervention studies based on a cancer endpoint. 50 Studies of this type will have a shorter duration. Some potentially useful intermediate markers for colorectal cancer include functional changes such as colonocyte proliferation rates and histologic changes such as aberrant crypts. The limitations of animal studies include the fact that there is no model of spontaneously occurring colorectal cancer. In most studies, rodents exposed to potent chemical carcinogens are provided a diet supplemented with large doses of potential causative or protective agents. Extrapolation of the resulting data to the human situation is of questionable validity. 50 The relation between diet and colorectal cancer appears to be complex, and the available information is ambiguous. To avoid contributing to the confusion, the following review presumes that cancers of the colon and rectum have the same origin. However, it is not certain that the same etiologic factors play a role in cancers at these two anatomic sites. In fact, there is evolving support for the hypothesis that, to some extent, cancers of the proximal colon, distal colon, and rectum have differing epidemiologic and etiologic origins. 83, 85 For example, the incidence of right colon cancer does not differ greatly throughout the world, whereas the incidence of left colon cancer is markedly higher in Western societies. As members of the Japanese urban population have adopted a Western diet with a higher fat content, the incidence of carcinoma localized to the distal colon has increased sharply, but the incidence of proximal carcinoma of the colon has not changed. In North America, rectal cancer is more common in men than in women, but the incidence of distal colon cancer does not differ according to sex. Research into the relations of diet to colorectal cancer has focused primarily on the roles of fat, fiber, and micronutrients, Several excellent reviews have been published recently.35, 36, 67, 78, 84

FAT Correlational studies provide substantial evidence that fat intake influences the risk of colorectal cancer. Based on a review of international data, Armstrong and Doll reported a direct correlation between the incidence of colorectal cancer and the per capita intake of fat.> However, in Western diets, the major portion of ingested fat is derived from animal meat, and it is difficult to attribute the correlation to fat alone.?O In a comparison of dietary data from 37 countries, Drasar and Irving found the incidence of colon cancer to correlate strongly with the combined intake of fat and animal protein. 17 A 180% increase in per capita fat consumption by the Japanese population from 1959 to 1985 has been accompanied by a proportional increase in the colorectal cancer mortality rate with a lag time of 15 years. 84 In the United States, Seventh Day Adventists, who eat little or no meat and consume less fat than the general population, have a lower mortality rate from colon cancer. 59

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Case-control studies likewise have provided evidence for a relation between colorectal cancer mortality rates and the consumption of fat or meat, alone or in combination, but the results are inconsistent. Some representative casecontrol studies are summarized in Table 1. The estimates of relative risk from the study by Manousos et al45 are the largest of the set, but the study population is small, and the estimates are considered statistically unreliable. 11 The small study by Pickle et al"" supports a correlation between meat consumption and colorectal cancer death. The influence of fat intake is unclear in view of the conflicting results from the two Australian studies, with Potter and McMichael 62 finding an association but Kune et al. 37 finding none. Similarly, the French studY'" does not support a relation between high fat intake and colon cancer death. Prospective studies do not support a causative relation between dietary fat consumption and the development of colorectal cancer. In a 19-year prospective study of Chicago men, dietary fat accounted for 42% of the total energy intake in patients with colon cancer and 43% in the control subjects. 21 A study of Japanese-Hawaiian men identified a reduced risk for colorectal cancer in those individuals with the highest fat intake. 75 The effect of a high-fat diet on the proliferation rates of colonic epithelial has been evaluated. 50 Corn oil boluses were administered to normal volunteers for a period of 1 week, and colonocyte proliferation rates were determined by 3H-thymidine incorporation (labeling index). A significant correlation between consumption of large boluses of fat and an increased labeling index was seen, with coincident increases in fecal bile acid concentrations. However, in a similar study in which the labeling index was determined after manipulation of dietary fat and fiber consumption, there was no significant increase in the labeling index with a greater intake of dietary fat, and there was no protective effect from fiber ingestion. 50 In rat studies, high-fat diets increase the incidence, multicentricity, and metastatic potential of carcinogen-induced colonic tumors. 55 The timing and type of dietary fat consumption, in addition to the amount of fat consumed, influence carcinogenesis. Regardless of the type of carcinogen used or its mode of action, rats on a diet providing 40% of the total calories as fat, simulating a typical Western diet, uniformly have a higher incidence of colon cancer than rats whose fat consumption is restricted to 10% of the total caloric intake. 8s Animal studies evaluating the effect of the timing of fat consumption on the development of colorectal cancer suggest that fat plays a larger role in

Table 1. RECENT CASE-CONTROL STUDIES OF DIETARY FAT AND COLON CANCER Source

Location

Cases :Controls

Sex

Factor

Max RR*

Manousos et al Pickle et al 60 Potter & McMichael 62

Greece Nebraska Australia

Kune et aP7

Australia

Macquart-Moulin et al 44

France

100:100 86:106 121 :241 99:197 380:398 327:329 399:399

M,F M,F M F M F M,F

Meat Meat Fat Fat Fat Fat Fat

2.6 1.7 1.4 1.7 1.2 0.7 0.7

45

'Max RR = relative risk for highest quantile of intake versus lowest quantile of intake. From Korn JE: Colon cancer epidemiology: Fat, fiber, and fertility. In Perspectives in Colon and Rectal Surgery, vol 3, no 2. St Louis, Quality Medical Publishing, 1990, pp 297-308; with permission.

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cancer promotion than in its initiation. 64 Rodent studies have also shown that diets containing linoleic acid, a prostaglandin precursor, are effective in promoting colon tumorigenesis, and that inhibitors of prostaglandin synthesis can counteract the effect of dietary fat. 12 Fish oils can inhibit the formation of prostaglandins derived from linoleic acid l2 and are protective against colon carcinogenesis in rodent models. 8s This line of investigation is particularly interesting in light of a recently published prospective study involving more than 600,000 adults, which reported that regular aspirin use at low doses may reduce the risk of fatal colon cancer.?7 In this study, no association was found between the use of another prostaglandin inhibitor, acetaminophen, and the risk for colon cancer. The most plausible mechanism by which dietary fat might promote colorectal cancer is through changes in fecal bile acid concentration. Experimentally, secondary bile acids are colon tumor promoters. 87 The fecal concentration of these bile acids is increased in individuals receiving high-fat diets.?8 This change is likely mediated by alterations in colonic flora.?8 Higher fecal concentrations of secondary bile acids have been reported in patients residing in regions with a higher incidence of colon cancer.66 Patients with colon cancer have higher fecal concentrations of bile acids than do control subjects. 34 Rats pretreated with 1,2-dimethylhydrazine, a potent carcinogen, have enhanced tumor formation after maneuvers that increase the concentration of fecal bile acids, such as provision of high-fat diets, direct infusion of bile acids into the intestine, or cholecystectomy.3s It is likely that other mechanisms also are important. Bruce has pointed out that attention must be given to the vascular exposure of the colonic epithelial cells.? Factors associated with increased dietary fat consumption promote the development of breast and pancreatic cancer, and whatever factors are responsible for malignant transformation of cells in these organs probably affect colonocytes as well. Cholesterol

In view of the association between dietary fat consumption and colon cancer and the correlation between serum cholesterol concentration and fat intake, some attention has been given to the possible relation between serum cholesterol and the risk for colon cancer. 35 In four of the five prospective studies designed to investigate coronary artery disease, an association has been noted between low serum cholesterol and an increased risk for colon cancer. The threshold for this effect has been identified at very low concentrations of cholesterol. It has been speculated that individuals with hypocholesterolemia, while following a typical Western high-fat, low-fiber diet, metabolize bile acids and cholesterol in a way that enhances the production of secondary bile acids and promotes colorectal cancer. 35

FIBER

The influence of dietary fiber has been studied intensively since Burkitt and associates popularized the theory that the higher incidence of colon cancer in affluent Western societies is attributable to depletion of fiber from the diet." The term "dietary fiber" refers to that part of ingested plant material that is resistant to human digestive enzymes.?O Dietary fibers have been classified as

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water insoluble (celluloses, hemicelluloses, and lignins) and water soluble (pectins, gums, and mucilages).7s Greenwald et al reviewed the evidence supporting an inverse association between fiber intake and colon cancer risk. 25 Forty studies were analyzed in terms of the epidemiologic criteria for causality (Table 2). The evaluation clearly suggests a relation between colorectal cancer and reduced fiber intake. However, some comparative studies of dietary fiber intake in populations with differing incidences of colorectal cancer indicate that other environmental factors must also be at work. 36 Minowa et al49 examined dietary fiber intake in Japan and found it to be similar to that in Britain. Fiber intake alone could not account for the disparate incidences of colorectal cancer in these two countries. The reduced intake of crude cereal fiber by the Japanese population coincided with a very low incidence of colon cancer. 20 During that period, the staple carbohydrate was polished rice, from which the bran fiber had been removed. Walker et al found that fiber intake by South African blacks, coloreds, Indians, and whites is similar, although the prevalence of colon cancer in these groups is very different. so Currently available data on the US population indicate that regional differences in the intake of crude cereal fiber cannot explain differences in colon cancer mortality rates. According to the second National Health and Nutrition Examination Survey, high-fiber cereal grains and bread are consumed by only 12% of the white population of the South, where death rates from colon cancer are lowest, compared with 19% in the Northeast, where the rates are highest. 20 The case-control studies evaluating dietary fiber consumption and the risk for colorectal cancer, as is the case with similar studies evaluating the influence of dietary fat consumption, have yielded inconsistent results (Table 3). Several methodologic problems exist that may explain the inconsistencies. 35 The definition of dietary fiber has not been standardized7s and ranges from a broad categorization of "crude fiber" intake to the intake of specific food items such as vegetables and cereals. "Fiber" refers to a complex mix of components, each with different chemical and physical properties. The proportion of soluble and insoluble fiber, the fiber chemistry, and changes resulting from storage and cooking may be important considerations. When total dietary fiber is evaluated, it is impossible to know which fiber component may be exerting an effect and by which mechanism of action. Another methodologic problem involves the inverse correlation between dietary fat and fiber intake. The benefits of higher fiber intake may be derived from a concomitant reduction in fat intake. 35 CaseTable 2. SUMMARY OF EPIDEMIOLOGIC STUDIES OF ASSOCIATIONS BETWEEN DIETARY FIBER AND COLON CANCER

Type of Study International correlation Within-country correlation Case-control Metabolic/epidemiologic Cohort Time-trend Total

No. of Studies 7

6 16 7 1 3 40

Associations· Inverse

None

Direct

610 6 0 0 10 4 2 610 1 0 0 3 32

0 6

0 2

'Associations between fiber intake or fiber-rich diet and colon cancer. From Greenwald P, Lanza E, Eddy GA: Dietary fiber in the reduction of colon cancer risk. J Am Diet Assoc 87:1178, 1987.

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Table 3. RECENT CASE-CONTROL STUDIES OF DIETARY FIBER AND COLON CANCER Source

Location

Cases:Controls

Sex

Factor

Max RR*

100:100

M,F

Cereal Vegetable Vegetable High fiber Fiber Fiber Fiber Fiber Vegetable Fiber

1.0 0.3 1.8 1.8 1.3 4.1 0.5 0.4 0.6

Manousos et al 4s

Greece

Pickle et al 60

Nebraska

86:106

M,F

Potter & McMichael62

Australia

Kune et al 37

Australia

Macquart-Moulin et al 44

France

121 :241 99:197 380:398 327:329 399:399

M F M F M,F

'Max RR = relative risk for highest quantile of intake versus lowest quantile of intake. From Korn JE: Colon cancer epidemiology: Fat, fiber, and fertility. In Perspectives in Colon and Rectal Surgery, vol 3, no 2. 51. Louis, Quality Medical Publishing, 1990, pp 297-308; with permission.

control studies are compromised by the inherent inaccuracy that results from trying to ascertain the dietary intake of various food constituents retrospectively. A number of different methods for obtaining a dietary history have been used, but the correlation between methods is only fair.35 It is probable that Western diets are not sufficiently diverse in fat or fiber intake to show a substantial difference in the risk for colorectal cancer for individuals at the high and low ends of the spectrum. This would explain why correlational studies, in which diets are far more discrepant, have produced generally marked and consistent findings, whereas case-control studies have not. 35 A final concern with casecontrol studies is that diet is being assessed at an inappropriate time in the natural history of the disease. The diet 20 or 30 years before the diagnosis of colorectal cancer may be more important than the diet at the time of diagnosis. 35 These methodologic problems may explain why case-control studies have failed to elucidate any real but small differences in the diet of patients with colorectal cancer. Of course, an alternative explanation is that no relation exists. This latter explanation raises the possibility that important dietary risk factors are ubiquitous in Western societies but that only those individuals with an underlying predisposition will manifest the disease. Genetic factors might help to explain some of the discrepancies in the epidemiologic data. 50 The Australian study by Kune et al provides data to support the fiber hypothesis. Patients in the lower two quintiles of dietary fiber intake were found to have a greater risk for developing colorectal cancer.37 This is in contrast to the Australian study by Potter and McMichael, 62 which suggests an opposing effect from dietary fiber intake. The French study" and the smaller Greek study's both suggest a protective effect from vegetable consumption but no benefit from consumption of cereal fiber. In a case-control study conducted in Utah, Slattery et al found that individuals in the highest quartiles of intake of fruits and vegetables had a lower risk for developing colon cancer. Greater intake of grains was not protective, however,,3 Lee et al39 conducted a case-control study of diet and colorectal cancer in Singapore Chinese and found no consistent relation between fat or fiber intake and subsequent cancer risk but identified a protective effect from increased consumption of cruciferous vegetables (e.g., cabbage, broccoli, cauliflower, and Brussels sprouts). In particular, those investigators found that

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a high meat-to-vegetable ratio was positively associated with an increased risk for colon cancer. Willett'" noted that the data supporting a beneficial effect from consumption of grain products is weaker than the evidence for fruits and vegetables. He found that in eight case-control studies in which fiber sources were identified separately, grain and cereal intake was either unrelated or positively associated with colon cancer risk, whereas intake of fruits and vegetables was protective. A prospective trial has examined the effects of various amounts of dietary fiber on the rate of adenoma formation in patients with familial adenomatous polyposis. The data suggest that a high fiber intake exerts a protective effect. 15 The results from experiments in rodent models are inconsistent, reflecting a variety of methodologic differences, including the type of animal; amount and type of fiber consumed; amounts, type, and mode of administration of carcinogen; timing of administration of fiber; and length of the study.78 Several studies in rodents have demonstrated a protective effect of dietary fiber consumption. Nigro et al found that diets containing 35% beef fat and 10% fiber (as wheat bran, alfalfa, or cellulose) did not inhibit development of azoxymethane (AOM)induced colon cancer, whereas a diet of 5% fat and 20% or 30% fiber did. 54 The addition of 15% pectin to a diet containing 20% fat did not inhibit colon cancer induced by methylnitrosourea (MNU) but did inhibit development of AOMinduced tumors. The addition of 15% wheat bran inhibited both AOM- and MNU-induced colon cancers."2 Pectin does not increase stool bulk significantly, and it has no effect on the direct-acting carcinogen MNU. The authors postulated that pectin interferes with the conversion of AOM in the liver or colon that is necessary for its carcinogenic effect. There are a number of conceivable mechanisms by which fiber might diminish the risk for developing colorectal cancer. The effects of dietary fiber include increased fecal weight, greater frequency of defecation, decreased intestinal transit time, dilution of colonic contents, greater microbial growth, alteration of energy metabolism, decreased bile acid hydroxylation, and greater production of hydrogen, methane, carbon dioxide, and short-chain fatty acids. 36 Fecal weight and intestinal transit time do not seem to influence the risk for colon cancer. In a study of Finnish and Danish men, no relation was found between transit time, fecal weight, and cancer risk. 3D A study of Japanese immigrants to Hawaii and their Hawaiian-born sons showed that transit times and fecal bulk were similar in the two groups and much different from Hawaiian Caucasians.23 However, the prevalence of colon cancer in the Hawaiian-born sons and the Caucasians was similar and much greater than the prevalence in the Japanese-Hawaiian fathers. A comparative study of the Japanese and English populations revealed that intestinal transit times and stool mass were similar despite a significantly higher incidence of colon cancer in the English population. 20 The greater fecal bulk provided by dietary fiber dilutes other fecal constituents. Fecal bile acid concentration has been correlated with the risk for colon cancer.3D The amount of fecal bile acid excreted by Americans and Finns is equivalent, but the concentration of fecal bile acid is significantly lower in the Finnish population, as is the incidence of colorectal cancer. 66 Dietary fiber binds with bile acids and reduces fecal bile acid concentration. This action has been proposed as one mechanism by which increased dietary fiber may reduce the risk for colorectal cancer. However, attempts to reduce fecal bile acid concentration by the administration of bile acid-binding resins to carcinogen-fed rats enhanced carcinogenesis. 53 Higher fecal fiber concentration is associated with lower numbers of colonic

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anaerobes and a resultant decrease in secondary bile acid formation. However, efforts to correlate the incidence of colorectal cancer with the ratio of primary to secondary bile acids in feces have not been rewarding. 36 Acetic, propionic, and butyric acids are produced by the fermentation of fiber in the colon, and these short-chain fatty acids may influence carcinogenesis. Butyrate has been shown to suppress cellular proliferation. Short-chain fatty acids influence intraluminal pH. It has been demonstrated that subjects with colon cancer have higher fecal pH than controls. 36 Reduction of the intraluminal pH to 6 or below alters bile salt solubility and reduces bile acid concentration. 7 The damaging effect of deoxycholic acid on the perfused rat colon is extensive at an intraluminal pH of 7.9 but is minimized at pH 5.9. Animal studies have demonstrated that fecal acidification can counteract the effect of cholic acid on colonocyte proliferation rates. Reduction of fecal pH can be achieved by greater intake of wheat bran fiber.> Experimental data regarding the influence of dietary fiber on colon carcinogenesis are not consistent, however, and it is likely that this is a complex relation. Grain fiber or cereal may have a different effect than fruit and vegetable fiber. In fact, other components of the high-fiber diet, such as vitamins and minerals, may be the factors responsible for any reduction in cancer risk. 78 ENERGY BALANCE

Case-control studies investigating the influence of diet on the risk for colorectal cancer have demonstrated a positive correlation between cancer risk and total energy intake. 84 High energy expenditure seems to decrease the risk of colon cancer. 23 The correlation between colorectal cancer and total energy intake has an important impact on the interpretation of dietary data. It may be necessary to stratify subjects according to total energy intake in order to distinguish the effect of overall food intake from that related to the consumption of individual dietary components. For example, there is a strong correlation between fat consumption and total energy intake. In some studies, the association between the dietary intake of saturated fat and the risk for colorectal cancer has been independent of total energy intake. 84 A case-control study of colorectal cancer in Utah demonstrated a strong correlation between cancer risk and energy intake. 43 The authors of that report concluded that the influence of total energy intake must be controlled before attempting to assign a causal role to any food or nutrient in the etiology of colorectal cancer. Prospective studies have not demonstrated a consistent association between body weight and the risk for colorectal cancer. In rodents, caloric restriction inhibits the growth of spontaneous, transplanted, or induced tumors, and chemically induced colon cancer is inhibited significantly when caloric intake is reduced by 25% to 40%.32 Given the fact that dietary fiber enhances fecal energy loss, the issue of energy balance may be relevant to the proposed influence of dietary fiber on colon carcinogenesis. 36 ADDITIONAL DIETARY FACTORS

Although current data are insufficient to confirm an association, other dietary factors may influence the development of colorectal cancer. Proposed protective agents include calcium and vitamin D,20. 41 selenium,51 vitamin A and its precursor beta-carotene,88 vitamin C,5 vitamin E,33 and naturally occurring

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vegetable inhibitors such as indoles and protease inhibitors. 85 Dietary factors that may enhance colon carcinogenesis include alcohol31 and mutagenic byproducts of food preparation. 14, 85

Calcium and Vitamin 0

Alterations in calcium and vitamin D metabolism have been proposed as an explanation for the geographic variation in colon cancer death rates, which tend to increase with increasing latitude and decreasing sunlight intensity. ,. Sunlight exposure profoundly effects vitamin D metabolism. The mortality rates from colorectal cancer in the American Northeast are nearly threefold those in the American South for both urban and rural populations. Colon cancer is uncommon at low latitudes, almost disappearing within 10 degrees of the equator. 20 An exception to this general pattern occurs in Japan, a country situated at a relatively high latitude but having a low incidence of colon cancer. However, the Japanese diet is extremely rich in fish containing large amounts of vitamin D, and the mean intake of vitamin D in the Japanese population is estimated to range from 800 to 1000 IV per day.23 Epidemiologic studies of dietary and serum vitamin D levels have supported the proposition that colon cancer is associated with insufficient intake of vitamin D or diminished serum concentrations of 25-hydroxyvitamin D. This may result from inadequate exposure to ultraviolet sunlight, which is the primary source of vitamin D in the United States, or to inadequate dietary consumption of vitamin D.2I Greater dietary calcium consumption has been associated with a lower incidence of colon cancer.21 A comparison of geographic variation in calcium intake and colorectal cancer mortality rates in the United States revealed an inverse relation between calcium intake and the colon cancer mortality rate for both men and women,74 but the results of case-control studies investigating the influence of calcium on the incidence of colorectal cancer have been inconsistent." 37, 72 A 19-year prospective study of 1954 men in metropolitan Chicago identified a 75% reduction in the incidence of colorectal cancer in those individuals who consumed more than 1200 mg of calcium per day.22 There was a 50% reduction in the incidence of colorectal cancer in those men whose dietary intake of vitamin D exceeded 3.75 f.l.g per day. The incidence of colorectal cancer in this population was not influenced by variations in total caloric intake or the consumption of fat or dietary fiber. Most Americans do not consume the recommended daily allowance of calcium (800 mg per day) or vitamin D (5 f.l.g per day).21 Animal studies have demonstrated a reduction in the incidence of intestinal tumors with greater dietary intake of vitamin D and calcium. 58 Newmark et a152 reported a lower incidence of colon tumors in rats receiving a diet containing 12% corn oil and larger amounts of vitamin D and calcium than were fed control animals, which also received more corn oil. Calcium reduces the proliferative response of colonic epithelial cells to dietary consumption of excess fat or of bile or fatty acids,81 but the mechanism by which calcium exerts its protective effect has not been defined. A relatively simplistic hypothesis proposes that the protective effect is mediated through the luminal binding of bile salts and free fatty acids. Fatty acids and bile salts are irritating to colonic epithelium, resulting in loss of colonocytes and increasing cellular proliferation. 78 Supplementation of dietary calcium intake reduces colonocyte proliferative activity. Lipkin and Newmark examined the labeling index in 10 patients from families with non-polyposis colon cancer whose diet was supplemented

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with 1.25 gm per day of calcium carbonate in a nonrandomized, uncontrolled, prospective trial. Significant reductions in the labeling index were seen during calcium supplementation. 4O In contrast, Gregoire et aF6 could not demonstrate a reduction in the colonocyte labeling index with calcium supplementation in a double-blind, randomized, placebo-controlled trial conducted in patients with a history of colonic resections for adenocarcinoma, although calcium supplementation resulted in higher fecal pH and enhanced fecal bile acid concentration. Vitamin D enhances the transport of calcium from the intestinal lumen to the circulation, suggesting that the protective effect of calcium may be systemic rather than local. However, receptors for 1,25-dihydroxyvitamin D are present on cultured human colon cancer. In addition, vitamin D decreases the rate of colonic epithelial-cell proliferation in mice. 21 Selenium

Investigation of the role of trace elements in colorectal carcinogenesis has focused primarily on selenium, an essential element that serves as a cofactor for glutathione peroxidase to protect cells from oxidative damage. Selenium may also be involved in prostaglandin and antibody synthesis. The anticarcinogenic effect of selenium was proposed in 1973 following the identification of lower serum concentrations of the trace element in cancer patients compared with control subjects without cancer. Beef contains small amounts of selenium, but cereal grains and seafood are the primary dietary sources for this element, although there is wide geographic variation in the concentration of selenium in soils and grains. Correlation studies examining the relation between selenium intake and cancer risk have documented the protective effect of selenium against death from cancers of the colon, rectum, prostate, lung, breast, and ovary. Casecontrol studies have conSistently demonstrated lower serum concentrations of selenium in patients with cancers of the colon and rectum. Two prospective studies evaluating cancers arising in a variety of organs identified significantly lower serum selenium concentrations in patients with cancer compared with controls. This significance persisted for cancers arising throughout the gastrointestinal tract. 51 Studies in rodents have documented an inhibitory effect of selenium on colorectal carcinogenesis, although the relevance of these studies to human colorectal cancer is uncertain in view of the fact that dietary supplementation with selenium grossly exceeded the quantity normally contained in human diets. 51 There are several mechanisms by which selenium might inhibit cancer induction or promotion, including an antioxidant effect resulting from augmentation of glutathione peroxidase activity. Data from animal experiments have failed to support this hypothesis, however. 51, 78 Vitamin A

Dairy products, eggs, liver, and fortified cereals are the primary dietary sources of vitamin A (retinol) and related retinoids. 78, 88 Provitamin A carotenoids including beta-carotene can be metabolized to substances with vitamin A activity.88 Vegetables and fruits are the primary sources for carotenoids and provide 25% of vitamin A found in Western diets. Case-control studies in France88 and in Australia 62 have shown little relation

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between the intake of retinol or beta-carotene and the risk for developing carcinoma of the colon despite the inverse relation between vegetable consumption and the prevalence of this disease. 37,88 Two prospective studies have not found that the dietary intake of carotenoids reduces the risk for developing carcinoma of the colon. 59, 69 Among five prospective studies that examined serum concentrations of carotenoids, two found an inverse association between beta-carotene concentration and colon cancer. 56, 79, 88 Animal studies have produced conflicting results, but retinol-deficient diets have generally been shown to enhance rodent susceptibility to cancers at various sites, including the colon.?8 The compounds of the vitamin A group are antioxidants and have the potential to protect membranes, DNA, and other cellular constituents from oxidative damage. B8 Vitamin C

Epidemiologic studies have not provided convincing evidence that vitamin C prevents the development of colorectal carcinoma. B6 Conflicting results have been obtained from correlational studies designed to evaluate a relation between colorectal cancer and the dietary intake of vegetables containing vitamin C. Several studies have revealed a negative correlation between the risk for colon cancer and the consumption of vegetables, especially the cruciferous type,>4, 28,45 whereas other studies have failed to confirm this association. 27,4B A high vegetable intake is associated with a low-fat, high-fiber diet, which emphaSizes the difficulty encountered when trying to isolate a protective variable in nutritional studies. B6 A randomized trial evaluating the influence of vitamin C on subsequent development of rectal adenomas in 49 patients with an ileorectal anastomosis after colectomy for familial adenomatous polyposis identified fewer polyps at 3-, 6-, and 9-month follow-up in patients who received vitamin C (3000 mg per day) than in the placebo-treated controls. These differences were not statistically significant, however, and did not persist at 12 months, although epithelial proliferative studies at 18 and 24 months revealed significantly lower labeling indices in the patients treated with vitamin C. A prospective study evaluating the influence of diet supplementation with vitamins C and E (400 mg of each per day) on metachronous polyp formation in 200 patients with a history of colorectal adenomas found no statistically significant difference in subsequent polyp formation compared with placebo-treated controls after correction for confounding variables. 46 The results of animal studies have both confirmed and refuted the theory that dietary supplementation with vitamin C reduces the incidence of carcinogen-induced colorectal cancer'?' 78 Like selenium and vitamin A, vitamin C exhibits antioxidant properties and may exert an anticarcinogenic effect by this mechanism. 86 Vitamin C inhibits the spontaneous conversion of nitrates and nitrites to carcinogenic nitrosamines in vegetables and preserved foods. 78 Vitamin E, another antioxidant, may likewise exert anticarcinogenic effects.33 Alcohol

Epidemiologic evidence supports a strong correlation between beer consumption and the development of rectal carcinoma,18, 63 although these data are not consistent. 24,29 In 1988, Klatsky et aPI identified 12 studies that suggested

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an association between alcohol consumption and bowel cancer and 9 studies that reported no correlation. Their prospective study evaluating the influence of alcohol consumption on the risk for developing colorectal cancer in more than 100,000 subjects identified a relative risk for rectal cancer of 3.17 and for colon cancer of 1.71 in individuals reporting a daily consumption of three or more alcoholic beverages compared with individuals who abstained from alcohol. 31 These results were not influenced by the type of alcoholic beverage consumed. Although the study was controlled for many variables, the confounding influence of other dietary factors could not be excluded. From this prospective analysis, it was concluded that a weak causal relation exists between excessive consumption of any alcoholic beverage and the risk for developing carcinoma of the rectum. A prospective study involving 8000 Hawaiian men of Japanese descent identified a relative risk for rectal carcinoma of 3.05 in those individuals consuming more than 42 cans of beer per month. 61 A similar case-control study from Australia identified an association between lifetime beer consumption and the risk for developing rectal carcinoma. 38 The risk for colorectal cancer was not influenced by consumption of other forms of alcohol. Experiments investigating the effect of ethanol on the development of colorectal cancer in animals have produced conflicting results. 78 The mechanism by which alcohol consumption influences carcinogenesis is unknown. 31 This relation may reflect the alterations in the consumption of fat, fiber, and micronutrients that accompany excessive alcohol use. Although ethanol has been shown to exhibit cocarcinogen activity in rat experiments, no direct carcinogenic influence on the colonic mucosa has been confirmed. 68 After oral consumption, it is unlikely that sufficient quantities of ethanol escape absorption in the proximal intestinal tract to exert a direct effect of any consequence on the colonic mucosa. Dietary Carcinogens

It is possible that carcinogens generated during food preparation are responsible for the influence of dietary factors on the development of colorectal cancer. 7, 14, 85 The surface of charcoal-broiled fish or meat contains powerful mutagens. Similar agents accumulate on fried and broiled foods. Fried meat and fish contain heterocyclic amines that are capable of inducing colorectal carcinomas in animal models. Smoked foods also exhibit enhanced carcinogenic activity.70 Vegetables and fish may contain polycyclic aromatic hydrocarbons secondary to contamination of the water supply by these products of incomplete fuel combustion. The potential role of these compounds in colorectal carcinogenesis has not been defined. 3 IMPLICATIONS FOR CANCER PREVENTION

. Investigation of the relation between diet and colorectal cancer should result in recommendations for diet modifications that will minimize the risk for developing colorectal cancer. 51 The potential for reducing the incidence of colorectal cancer through diet modification seems great. Doll and Peto have suggested that 35% of all cancers and 90% of colorectal carcinomas might be prevented by changes in diet. 16 The means for accomplishing this goal remain uncertain. A variety of dietary recommendations have been proposed on the

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basis of results from epidemiologic studies, animal experiments, and investigations of the biochemical mechanisms by which dietary factors may influence carcinogenesis." 10, 13 Generally accepted recommendations include restriction of fat consumption to less than 30% of the total caloric intake, greater intake of dietary fiber, weight reduction for obese individuals, and moderation of alcohol consumption. The Dietary Guidelines for Americans advocate the consumption of two or three servings of fruit and three to five servings of vegetables per day. Surveys of food consumption in the United States indicate that only 10% of the population meets these guidelines for fruit and vegetable consumption. 6

SUMMARY Although the etiology of colorectal cancer is multifactorial, experimental evidence suggests a role for dietary factors in the promotion of this disease. The complex interrelations governing energy balance and the consumption of fat, fiber, and micronutrients make it difficult to define the precise role of specific dietary factors in the etiology of colorectal neoplasms. Epidemiologic studies have demonstrated a correlation between the prevalence of colorectal cancer and per capita consumption of meat and fat. Case-control studies investigating the relation between colorectal cancer and dietary fat consumption have yielded inconsistent results. Prospective studies have failed to demonstrate a relation between fat consumption and subsequent risk for colorectal cancer. There is an inverse correlation between fiber intake and the prevalence of colorectal carcinoma. A more detailed analysis of the influence of various types of dietary fiber on the subsequent risk for colorectal cancer will provide a better understanding of this relation. Fiber derived from fruits and vegetables may provide more effective protection than cereal fibers. Correlational studies have established an association between total caloric intake and the prevalence of colorectal carcinoma. The design of future studies investigating the influence of individual dietary constituents on the risk for colorectal cancer must control for variations in energy balance as a confounding variable. Recent evidence suggests that a variety of micronutrients, including calcium, vitamin D, selenium, and vitamins A, C, and E, exert an anticarcinogenic effect. Studies designed to evaluate the influence of alcohol consumption on colorectal carcinogenesis have yielded inconclusive results. The potential influence of food preparation methods on colorectal carcinogenesis requires further evaluation. There is no conclusive evidence to support any of the hypotheses proposed to explain the role of dietary factors in colorectal carcinogenesis. Intervention trials designed to monitor intermediate markers for colorectal cancer such as increased epithelial-cell proliferation rates and the development of aberrant crypt architecture provide the opportunity for testing these hypotheses in relatively short-term studies. 7, 50 The results from such studies can be utilized in the design of large-scale, long-term prospective studies to evaluate the influence of dietary factors on the development of colorectal neoplasms. These trials should generate the information required to develop strategies for diet modification to reduce the incidence of colorectal carcinoma.

ACKNOWLEDGMENT I thank Linda White and Raquelle Reid for help in preparing the manuscript.

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J. Burnstein, MD, MSc, FRCSC St. Michael's Hospital 38 Shuter Street Toronto, Ontario M5B lA6 Canada