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[CANCERRESEARCH54. 2390-2397, May 1, 1994] Intake of Fat, Meat, and Fiber in Relation to Risk of Colon Cancer in Men' Edward Giovannucci,2 Eric B. Rimm, Meir J. Stampfer, Graham A. Colditz, Alberto Ascherio, and Walter C. Willett Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital fE. G., M. J. S., G. A. C., W. C. W.], and Departments of Epidemiology fE. B. R., M. J. S., G. A. C., A. A., W. C. W.J and Nutrition fE. B. R., M. J. S., A. A., W. C. W.J, Harvard School ofPublic Health, Boston, Massachusetts 02115 ABSTRACT Some evidence suggests that diets high in animal fat or red meat may increase the risk of colon cancer, whereas high intake of fiber or vegetables may be protective. Frequently, intake of red meat has been a stronger risk factor than total fat. Because data from prospective cohort studies are sparse, we examined fat, meat, fiber, and vegetable intake in relation to risk of colon cancer in a cohort of 47,949 U.S. male health professionals who were free of diagnosed cancer in 1986. At baseline, these men, 40 to 75 years of age, completed a validated food frequency questionnaire and provided detailed information on other lifestyle and health-related factors. Between 1986 and 1992, 205 new cases of colon cancer were diagnosed in these men. Intakes of total fat, saturated fat, and animal fat were not related to risk of colon cancer. However, an elevated risk of colon cancer was associated with red meat intake (relative risk, 1.71; 95% confidence interval, 1.15—2.55 between high and low quintiles; P 0.005 for trend). Men who ate beef, pork, or lamb as a main dish five or more times per week had a relative risk of 3.57 (95% confidence interval, 1.58—8.06;P 0.01 for trend) compared to men eating these foods less than once per month. The association with red meat was not confounded appreciably by other dietary factors, physical activity, body mass, alcohol intake, cigarette smoking, or aspirin use. Other sources of animal fat, including dairy products, poultry, and fish as well as vegetable fat, were slightly inversely related to risk of colon cancer. No clear association existed between fiber support the hypothesis or vegetable intake and risk of colon cancer. that intake of red meat is related These data to an elevated risk of colon cancer. INTRODUCTION Although a genetic component is well established (1), colon cancer appears to be strongly influenced by environmental factors. The rates of colon cancer generally increase among migrants from low- to high-incidence areas (2), and striking secular trends have occurred within populations, including a sharp increase in Japan after World War II (3). Doll and Peto (4) have suggested that differences in diet may account for 90% of the marked variation in rates of this malig nancy among different countries (5). Studies comparing per capita national consumption levels of various foods and nutrients with na tional colon cancer rates have found high correlations with red meat or animal fat but not with vegetable fat (6, 7). With few exceptions (8—12),a link with fat (13—21)or red meat intake (22—28)has been supported in numerous case-control studies where recalled past diets of persons with and without colon cancer are compared. However, in many of these studies, a positive association between total energy intake and risk of colon cancer has been observed (13—17,19, 21), raising the question of whether it is the total amount of food consumed or the fat composition of the diet that is etiologically important (29). Prospective studies of colon cancer, less prone to selection and recall bias, have demonstrated positive (30, 31), inverse (32, 33), and null associations (34, 35) with fat or meat consumption. However, much of the earlier prospective data have been limited by the small number of cases, crude assessments of diet, and lengthy time periods between assessment of diet and the accrual of cases. A report from the NHS,3 which avoided these limitations, showed a strong association between animal fat, principally from red meat, and risk of colon cancer in women (36). A recent cohort study from the Netherlands found an association between processed meats and colon cancer, but no relationship was observed for fresh meats (37). A second major hypothesis regarding diet and colon cancer was primarily initiated by Burkitt's observation of low rates of colon cancer in regions of Africa which had a high fiber consumption level and a corresponding large stool bulk (38). However, analytical epi demiological studies have been rather inconsistent in supporting the fiber-colon cancer hypothesis. Inverse associations between total fiber intake and risk of colorectal cancer have been observed in some case-control studies (10, 15, 16, 19, 39, 40) but not all (8, 9, 12—14, 17). Prospective data regarding fiber intake and colon cancer are scarce and generally null (41). Overall, it appears that factor(s) present in some vegetables and fruits may be protective (3), but it is unclear whether fiber, some specific component of fiber, or other factors common in plants are the relevant compounds. We examine here the intake of fat, meat, and fiber in relation to the incidence of colon cancer during 6 years of follow-up in a large cohort of U.S. male health professionals. Within this cohort, we have re ported previously that a diet high in animal fat, especially fat from red meat, and low in dietary fiber was associated with an elevated risk of colorectal adenomas, precursors of cancer (42). MATERIALS AND METHODS Study Population. The Health Professionals Follow-up Study cohort, which has been described previously (43), formed the base population for this analysis. Briefly, this cohort was started in 1986 when 51,529 U.S. male dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians 40 to 75 years of age responded to a mailed questionnaire, which included a semiquantitative food frequency questionnaire. Participants also provided in formation on smoking history, age, weight, height, physical activity, use of aspirin and other common medications, parental history of cancer, and history of professionally diagnosed medical conditions. Every 2 years, we mail a follow-up questionnaire to the men to ascertain newly diagnosed medical conditions (44). Semiquantitative Food-Frequency Queslionnaire. The dietary question naire used in this study, an expanded version of a previously validated instrument (45, 46), included 131 food items plus vitamin and mineral sup plement use that collectively accounted for over 90% of the major nutrients. For each food or beverage item, a commonly used unit or portion size (e.g., one egg or slice of bread) was specified, and participants were asked how often, on average over the past year, they consumed that amount of each food. Subjects chose from nine possible responses, which ranged from ne@ierto six or more times per day. We also inquired about the types of fat used, and we provided Received 12/6/93; accepted 3/3/94. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I Supported by Grants CA 55075 and HL 35464 from the NIH and Special Institution an open-ended section for foods that were not specified on the questionnaire. We computed nutrient intakes by multiplying the consumption frequency of each unit of food by the nutrient content of the specified portions (47—49), also accounting for the specific types of fat used in food preparation. We adjusted Grant 18 from the American Cancer Society. G. A. C. is supported by a Faculty Research Award (FRA-398) from the American Cancer Society. 2 To whom requests for reprints should be addressed, at Channing Laboratory, Longwood Avenue, Boston, MA 02115. 180 3 The abbreviations used are: NHS, Nurses' Health Study; kcal, kilocalories; relative risk; CI, confidence interval. 2390 Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research. RR, MEAT, FAT, FIBER, AND COLON CANCER nutrient values for total energy intake using regression analysis (50). Briefly, after appropriate transformations, the specific nutrient intake is regressed (using linear regression) on total calories, and the individual's residual is added to the mean nutrient level at the mean caloric intake to form the energy adjusted nutrient. We askedrandomlyselected participantsfromthe Boston areato complete 2 weeks of diet records in order to estimate the true variation in nutrient intakes within the study population and to evaluate the precision of the questionnaire. The results have been described in detail previously (51). Briefly, 127 partic ipants provided complete information for both 1-week detailed weighed diet records, administered approximately 6 months apart, and a second semiquan titative food-frequency questionnaire administered by mail after the diet records were received. Mean intakes for the lowest and highest quintiles determined by the diet records were 24 and 41% of energy for total fat, 7 and 14% of energy from saturated fat, 85 and 232 mg per 1000 kcal for cholesterol, and 7.5 and 15.7 g per 1000 kcal for dietary fiber. Pearson correlation coefficients between the second questionnaire and the average of the two 1-week diet records for energy-adjusted nutrients (adjusting for week-to-week variation in the diet records) were 0.67 for total fat, 0.75 for saturated fat, 0.68 for monounsaturated fat, 0.76 for cholesterol, 0.44 for protein, and 0.68 for dietary fiber. Identification of Cases of Colon Cancers. We mailed follow-up question naires to all study participants in 1988, 1990, and 1992 and asked them to report any diagnosis of cancer during the past 2 years. We mailed up to six questionnaires per follow-up cycle to nonrespondents, including two certified mailings. For this analysis, the follow-up response rate was 95% of total possible person-years through January 31, 1992, the end of the study period. Most of the deaths in the cohort were reported by family members or the postal system in response to the follow-up questionnaires. In addition, we used the National Death Index, a highly sensitive method of identifying deaths among nonrespondents (52). We expect to capture essentially all of the fatal cancers during the study period and approximately 95% of the nonfatal cancers as previous experience suggests that nonresponse is not strongly correlated with disease status. When a subject (or next of kin for decedents) reported a diagnosis of cancer of the colon or rectum on our follow-up questionnaire, we asked him (or next ofkin) for permission to obtain hospital records and pathology reports. A study physician, blinded to exposure information, reviewed all medical records and extracted data on histological type, anatomic location, and stage of the cancer. Proximal cancers were considered those from the cecum to the splenic flexure, and distal cancers included those in the descending and sigmoid colon. We confirmed 251 new cases of colorectal cancer (excluding carcinoma-in-situ), 226 (90%) by medical records, and 25 with corroborating information on diagnosis and treatment from the cohort member. For the primary analysis, we did not include 46 cases that occurred in the rectum because rectal cancers appear to have a different epidemiological pattern and are less clearly associ ated with dietary variables. This left 205 cases of colon cancer for analyses. Data Analysis. For these analyses, we excluded men with implausibly high or low scores for total energy intake (outside the range of 800 to 4200 kcal per day) or with 70 or more items left blank and men who reported previous cancer (other than nonmelanoma skin cancer), ulcerative colitis, or a familial polyp osis syndrome at baseline, leaving 47,949 men. Each man contributed fol low-up time beginning on the month of return of the initial questionnaire in 1986 and ending at the month of diagnosis of colorectal cancer, month of death for other causes of death, or at the end of the study period, January 31, 1992. We computed relative risks by dividing the incidence rate (cases divided by the number of person-years) in each category (usually quintile) of intake by the rate among those in the lowest category. We used stratified analysis to control for potentially confounding variables including age (five-year categories), parental history of colon or rectal cancer (yes/no), obesity (quintiles of body mass index), physical activity (quintiles), smoking (categories of pack-years), alcohol intake (categories), aspirin use (yes/no), history of polyp (yes/no), or prior endoscopy (yes/no) as well as other nutrients (quintiles). For the stratified analyses, we used the Mantel-Haenszel linear trends using the Mantel Extension summary estimator (53) and tested for test (54). To adjust simultaneously for two or more covariates, we used proportional hazards regression (55). Criteria for inclusion into the multivariate model included a priori belief that the factor was related to colon cancer for biological reasons (e.g., family history) or diagnostic reasons (e.g., prior screening) and that the factor was related to colon cancer in this cohort. For nutrients or food groups adjusted by propor tional hazards regression, we tested for trend by modeling the quintile of the nutrient ordered from 1 to 5 as a continuous variable. Our primary analyses focused on total fat, types of fat (saturated, monoun saturated, and polyunsaturated), both crude and dietary fiber, and sources of fat and protein (vegetable and animal) and fiber (vegetable, cereal, and fruit). We also evaluated separately sources of animal fats (red meat, chicken, fish, and dairy) and the red meat to chicken and fish ratio. This ratio, the most significant predictor for colon cancer among women in the NHS, approximates the effect of substituting red meat with chicken and fish as often recommended (56, 57). Becausethis ratio is a meaningfulrepresentationof the substitution pattern of chicken and fish for red meat mainly among those eating an appreciable amount of these foods, we limited our analyses to men eating at least one serving of these foods daily on average. RESULTS A slight inverse but nonsignificant association existed between total energy intake and colon cancer incidence (Table 1). Energy-adjusted total fat intake was also unrelated to risk of colon cancer. Animal fat had no clear association with risk of colon cancer; a significantly elevated risk was evident in the second highest quintile relative to the lowest, but the rate in the highest quintile was slightly lower than that in the lowest quintile. Fat from vegetable sources had a modest, nonsignfficant inverse association with colon cancer. The major types of fat from animal sources and saturated and monounsaturated fat were unrelated with risk of colon cancer, and linoleic acid, the major polyunsaturated fat, was slightly inversely associated with risk. Cho lesterol intake, exclusively from animal sources, was unrelated to the risk of colon cancer. In contrast to the absence of an association between total and animal fat and risk of colon cancer, a significant association existed between red meat intake and risk of colon cancer (Table 2). Beef, pork, or lamb as a main dish was significantly related to risk of colon cancer; an association also existed with processed meats, although this did not achieve statistical significance (P = 0.06). Of the other sources of meat, poultry intake was slightly inversely related to the risk of colon cancer, and fish intake was unrelated to risk. The red meat to chicken and fish ratio, representing the substitution of chicken and fish for red meat, was significantly related to higher risk of colon cancer. We conducted multivariate analyses to assess whether other potentially confounding variables influenced the relation between red meat consumption and colon cancer. In a multiple logistic model which included age, body mass index, history of previous polyp and prior endoscopy, parental history of colon cancer, aspi rin use, physical activity, and intake of dietary fiber, methionine, and alcohol, the elevated risk associated with red meat intake (RR = 1.66; 95% CI = 1.04—2.65 between high and low quintiles; P = 0.02 for trend) and beef, pork, or lamb as a main dish (RR = 3.07; 95% CI = 1.35—6.98between 5 servings per week versus less than once per month; P = 0.04 for trend) persisted. The modest degree of confounding, represented by the change in relative risk in the full multivariate model, was due primarily to physical activity and cigarette smoking before the age of 30 years. Further adjustment for folic acid, calcium, and vitamins A, C, D, and E and multivitamin use did not influence the results. Because red meat is an important dietary source of both protein and fat, we examined the association between sources of fat and protein and the risk of colon cancer in detail. The correlations between intakes of red meat and total fat (r = 0.51) and animal fat (r = 0.57) were not so high to preclude our ability to discriminate statistically among the sources of fat. The combination of the positive association with red meat and the inverse associations with other major sources of fat 2391 Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research. MEAT, FAT, FIBER, AND COLON CANCER Table 1 Relative risk of colon cancer according to quintile of total energy intake and dietary fats Quintilex 5Total 1 (P)Variable 2820CaseWperson-@ears energy(mediankcal/day) 2 1229 1586 1884 2308 64/52,871 44/53,126 35/53,134 1.0 1.92 (1.28—2.90) 89.0Cases/person-years fat (mediang/day) 54.2 1.33 (0.85-2.08) 65.3 28/52,567 1.12 (0.70—1.80) 72.3 55/52,150 55/53,287 27/52,834 1.0 1.80 (1.18—2.74) 1.82 (1.19—2.77) 0.95 (037—1.56) 56Cases/person-years fat (median g/day) 25 33 40 46 42/55,158 40/50,612 40/56,035 53/52,869 1.0 1.12 (0.73—1.72) 1.06 (0.69—1.63) 131 (1.02—2.24) (035—1.38)0.42(0.67)Vegetable (95% Cr)c 46Cases/person-years fat (median g/day) 20 27 32 37 37/52,304P.R (0.33)Saturated (95%Ct)c 54/52,812 40/54,1 14 33/52,593 41/52,865 33.0Cases/person-years fat (median g/day) 31/52,178RR 17.4 47/53,305 22.2 44/54,212 25.2 44/56,650 28.3 39/52,335 1.0 1.01 (0.67—133) 1.13 (0.75—1.70) 1.07 (0.70—1.63) 19.1 39/53,526 23.8 42/52,838 26.9 48/54,660 29.7 41/52,740 1.0 (036—1.37)—0.27(0.79)Monounsaturated (95% @)C 34.2Cases/person-years fat (median g/day) 35/50,916RR (0.68)Linoleic (95%CI)c 1.21(0.78—1.87) 8.0 34/52,762RR 0.87 139 (0.91—2.12) 0.88 1.24(0.80—1.93) 10.1 11.6 13.2 42/52,005 37/52,498 43/52,801 1.0 0.99 (0.66—1.49) 0.87 (037—134) 1.01 (0.67—132) 0.79 198 40/53,188 1.0 262 46/53,320 1.27 (0.83—1.93) 313 37/53,522 0.99 (0.64—135) 369 40/52,570 1.07 (0.69—1.66) 1.07 x-ststi@tic isequivalent toZvalue from standard normal tables with anegative value representing aninverse association. b Adjusted analysis.C for age using 1.07(0.68—1.69)0.41 49/54,614 (031—1.22)—0.84(0.40)Cholesterol (95% C1)c 467Cases/person-years (median mg/day) 42/52,080RR (0.70-1.63)—0.07(0.94)a (95% @)C 1.19 0.79(032—1.19) 0.70(0.45—1.07) 0.90(0.60—1.35) 0.76(030—1.16)—0.98 1.0 16.2Cases/person-years acid (median g/day) 0.94 79.0 34/53,278 (0.74—1.90)—0.47(0.64)Animal (95% Ct)c 30/50,006RR 4 34/52,982 (037—135)—1.42(0.16)Total RR (95% Cl) 34/53,132RR fortrend― 3 stratified Adjusted for age using stratified analysis.Nutrients analysis.Table are adjustedfor intake of total energy using residual 2 Age-adjustedrelativeriskof coloncanceraccordingtogroupsCategoryx intakeof variousanimalfood for trend 5Red 1 (P)Variable meata(mediang/day) 55/529,689RRC @b/p@_.@n@years 2 3 18.5 42.9 39/51,897 35/52,448 (95% CI) (0.005)Beef, 1.0 5/weekCases/person-years pork,or lambas maindish(servings) 0.97 0 64.1 (0.62—134) 0.98 44/49,307 (95% Cl) (0.01)Processed 1.0 1.92 (1.03—3.60) 0 1293 40/52,871 (0.62—136) 1—3/month 12124,870 7/13,305RR (95% Cl) (0.06)Poultry 883 32/52,805 16/14,906RR 5/weekCases/person-years meats (servings) 4 1.21 (0.77—1.88) 1/week 2-4/week 57/85,194 72/88,713 1.69 (0.92—3.10) 2.11 (1.13—3.92) 1-3/month 1/week 2-4/week 52/70,150 63/79,387 41/55,113 39/44,211 1.0 1.25 (0.87—1.80) 63.1Cases/person-years (median gjthy)d 1.71 1.40 (0.92—2.13) 1.67 (1.06—2.61) 8.8 15.8 29.2 42.2 36/53,532RR (95% CI) (0.27)Fish 54/52,186 1.0 39/53,062 0.81 (034—1.23) 36/53,1 10 0.76 (030—1.17) 40/52,790 0.79 (032—1.18) 83.4Cases/person-years (median g/day)― 51/53,215RR (95% CI) (0.79)Ratio 8.4 41/52,817 20.9 35/53,071 31.0 43/52,789 47.8 35/52,788 1.0 0.85 (0.54—1.33) 3.6Cases/person-years of red meat to chicken and fish (median)'@ 49/44,642RR (95% Cl) 0.20 31/43,534 1.0 1.05 (0.68—1.61) 0.80 (031—1.26) 036 1.0 1.7 31/42,650 1.20 (0.73—1.96) 33/428,232 1.30 (0.80—2.12) 28/44,102 1.09 (0.65—1.82) (1.15—235)2.83 337 (138—8.06)239 1.16 (0.44—3.04)1.89 0.82 (034—1.24)—1.10 1.06 (0.70—1.60)0.26 1.83 (1.17—2.85)2.43 (0.015) aData onred meat relate tothe following: beef, pork, orlamb asamain dish (e.g., steak, roast, and ham); beef, pork, orlamb asasandwich oramixed dish (e.g., stew, casserole, and lasagna); hamburger, hot dog; preserved meats (e.g., sausage, salami, and bologna); and bacon. To@ casesfor food groupsand items may not add up to 205 due to missinginformation on food items. C Red meat, poultry, and fish were adjusted for total energy using residual analysis and beef, pork, or lamb, and processed meats were adjusted by standard stratified analysis because of non-normality. Computed from the energy-adjusted values in g/day for red meat and chicken plus fish. The ratio analysis was limited to those who had at least one serving per day of thesefoods. d Data on poultry and fish relate to the following: chicken or turkey with skin, chicken or turkey without skin, canned tuna fish, dark meat fish, other fish, shellfish (e.g., shrimp, lobster, and scallops). (poultry, dairy, and vegetable) balanced each other to yield the overall null association observed between total and animal fat intake and risk of colon cancer. As seen in Table 1, vegetable fat and the major lated to the risk of colon cancer. In addition, fat from dairy products (RR = 0.66; 95% CI = 0.43—1.01between high and low quintiles; P = 0.23 for trend) and from chicken (RR = 0.60; 95% CI = 0.38— polyunsaturated fat linoleic acid were nonsignificantly inversely re- 0.95; P = 0.08 for trend) were slightly inversely related to the risk of 2392 Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research. MEAT, FAT, FIBER, AND COLON CANCER Table 3 Relative risk of colon cancer according to quintile of total dietary protein and sources of protein Quintile 12345Total (P) protein― (median g/day) 70 C@sb/permnyears (0.52—1.17)—1.17(0.24)Animal RRc (95% CI) 46/46,834 1.080 protein―(median g/day) 48/54,390 1.055 meat proteina (median g/day) Cases―/person-years 5 40/51,876 RRC (95% CI) (0.01)Animal 1.010 protein excluding red meata (median g/day) @@sb/permn@years 1.027 protein―(median g/day) @@sb/permn@ye@ RRC (0.45—1.10)—1.48(0.14)a (95% CI) adjusted for total 47/59,001 42/52,607 0.88 (0.58—1.33)95 34/50,945 0.71 (0.46-1.10)108 0.78 0.93 (0.61—1.41)63 43/56,165 0.89 (039—1.35)72 36/50,474 0.81 (033—1.25)85 37/51,942 0.76 34/52,295 0.93 (0.59—1.47)16 33/53,05 1 0.97 (0.61—1.53)22 42/52,778 52/52,990 1.25 (0.81—1.92)32 134 (1.03—2.31)2.53 energy 41/51,709 19 56/52,542 RRC (0.46—1.02)—1.86(0.06)Vegetable (95% CI) Nutrients 36/53,294 0.74 (0.48—1.15)88 44 @sb/p@_,@n.ye@ (0.49—1.16)—1.42(0.16)Red RRc (95% CI) @ x for trend Variable 34/52,580 39/53,139 34/53,168 42/52,253 0.64 (0.42—0.97)33 0.70 (0.47—1.06)40 0.60 (0.40—0.92)54 0.68 18 44/52,804 1.022 using residual 40/52,776 0.93 49/54,058 (0.61—1.43)25 1.09 (0.73—1.63)28 39/5 1,727 33/53,316 0.88 (037—1.36)33 0.70 analysis. fornutrients maynotaddupto205duetomissing information. C Relative risks adjusted for age using stratified analysis. colon cancer. As expected, fat from red meat sources was related to colon cancer (RR = 1.39; 95% CI = 0.82—2.36;P = 0.02 for trend). These data suggest that fat intake, at least that from non-red meat sources, does not increase the risk of colon cancer. Despite the strong positive association with red meat consumption, intake of total protein from both animal and vegetable sources was inversely associated (nonsignificantly) with the risk of colon cancer (Table 3). We explored further the association with animal protein from sources other than red meat in a model that included intake of energy-adjusted protein from red meat, energy-adjusted protein from animal sources other than red meat, age, body mass index, history of previous polyp and prior endoscopy, parental history of colon cancer, aspirin use, physical activity, and alcohol intake. In this model, animal protein from sources other than red meat was associated with a reduced risk of colon cancer (RR = 0.63; 95% CI = 0.41—0.97 between high and low quintiles of intake; P = 0.03 for trend). The slightly stronger association between non-red meat animal protein and risk of colon cancer when controlling for red meat protein suggests that this inverse association may not be due entirely to the displace cream, P = 0.17; chicken with skin, P = 0.06) or were unrelated to risk (hard cheese and butter). We had reported an association between smoking at early ages and risk of colorectal cancer in this cohort (Ref. 58 and in the NHS, Ref. 59). Based on the age-adjustedrelativerisk of 1.60 among those who had smoked before the age of 30 years relative to nonsmokers, we estimated that 38% of the colon cancers diagnosed among smokers could be attributable to smoking. If colon cancers related to smoking and those related to red meat occur via different etiological pathways, smoking-related cancers would attenuate the relative risks associated with the intake of red meat among smokers. Thus, we examined the risk of colon cancer in relation to consumption of red meat separately among smokers and nonsmokers. Among nonsmokers before age 30 years (75 cases of colon cancer among 24,817 men), we found strong associations between colon cancer and the intake of red meat (RR = 2.18; 95% CI = 1.14—4.16 between high and low quintiles; P = 0.008 for trend) and intake of beef, pork, and lamb as a main dish (RR = 5.11; 95% CI 1.38—18.9 between 5 servings per week versus less than once per month; P 0.008 for trend). Among men who had smoked before age 30 years (126 cases among 22,812 men) there were ment of red meat in the diet. We examined the relationship with red meat by subsite within the considerably weaker associations between colon cancer and the intake of red meat (RR = 1.38; 95% CI = 0.83—2.30;P = 0.21 for trend) large bowel (among cases for which subsite information was avail and the intake of beef, pork, and lamb (RR = 1.60; 95% Cl = able), including the rectum. The association between red meat intake 0.67—3.85;P = 0.75 for trend). and large bowel cancer was suggested for the distal colon (89 cases, Intake of total dietary fiber or of crude fiber was unrelated to risk age and energy-adjusted RR = 1.78; 95% CI = 0.97—3.25between of colon cancer (Table 4). For both types of fiber, men in the lowest high and low quintiles of intake; P = 0.07 for trend) but not in the quintile of intake appeared to be at the highest risk. However, no proximal colon (69 cases, RR = 0.87; 95% CI = 0.43—1.76;P = 0.85 obvious trend was evident from quintiles 2 to 5. Furthermore, in the for trend). There were too few cases of rectal cancer (46) to provide informative relative risk estimates (RR 1.22; 95% CI = 0.36— full multivariate model, any suggestion of a protective effect of fiber disappeared. The major contributors to confounding were intake of 4. 14). For total colorectal cancer, entailing 25 1 cases, associations red meat and level of physical activity. None of the sources of fiber, existed with red meat intake (RR = 1.66; 95% CI = 1.14—2.42;P = fruit, vegetable, or cereal, appeared related to risk. The relation with 0.003 for trend) and the red meat to chicken and fish ratio (RR = 1.81; fiber intake did not vary appreciably by subsite within the colon. 95% CI = 1.22—2.67;P = 0.02 for trend). We also examined associations between frequency of total vegeta Of all the food items included in the questionnaire, beef, pork, and ble and fruit consumption and risk of colon cancer. Intakes of vege lamb as a main dish had the strongest positive association with colon tables (RR = 1.02; 95% CI 0.64—1.63for >5 versus @2servings cancer. Other red meat products, processed meats (P = 0.06), ham per day; P = 0.83 for trend) and fruits (RR = 0.98; 95% CI burger (P = 0.04), and bacon (P = 0.11) were positively associated 0.54—1.77for >4 versus <1 servings per day; P = 0.52 for trend) were with the risk of colon cancer, whereas hotdogs and beef and pork or lamb served as a sandwich or mixed dish were unrelated to risk. In unrelated to risk. Of all fruits and vegetable items examined individ ually (see footnote for Table 4 for list), none were statistically sig contrast, other high-fat foods of animal origin had nonsignificant nificantly related to the risk of colon cancer in an age- and energy inverse associations with colon cancer (whole milk, P = 0.08; ice 2393 Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research. MEAT, FAT, FIBER, AND COLON CANCER Table 4 Relative risk of colon cancer according to quintile of total dietary and crude fiber and dietary fiber from fruits, vegetables, and cereals Quintile x for trend Variable12345Total (F) g/day)14.218.321.725.632.8Cases/person-years53/55,56128/52,32225/51,88652/52,15747/52,754Age-adjusted dietaryfiber(median (0.36)Multivariate RR (95% CI)1.0032 (0.68-1.70)137(0.12)Total RR (95% C])―1.00.63 (0.33—0.81)0.43 (0.39—1.01)039 (0.27—0.68)0.82 (0.36-0.97)1.19 (036—1.19)0.65 (0.78—1.82)1.08 (0.44—0.97)—0.91 (037—1.29)0.69 (0.81—1.98)1.05 (0.45—1.05)—1.13 (0.61—1.63)—0.23 g/day)3.64.65.66.68.6Cases/person-years42/51,58834/53,79434/52,72451/53,41444/53,159Age-adjusted crude fiber (median (0.44-1.07)0.64 (032—1.32)0.87 (0.26)Multivariate RR (95% CI)1.00.68 (0.65—1.71)0.95(0.34)Fruit RR (95% CI)―1.00.83 (0.41—1.00)0.86 (034—139)1.27 g/day)b1.22.64.15.89.2Cases/person-years33/62,29343/54,28255/52,25038/49,29136/46,564Age-adjusted fiber (median (0.82)Multivariate RR (95% CI)1.01.23 (0.78—1.94)131 (0.99—2.31)1.05 (0.65—1.69)1.00 (0.98—2.81)1.74(0.08)Vegetable RR (95% CI)―1.01.60 (1.01—235)2.03 (1.29—3.20)1.61 (0.98—2.81)1.66 @@y)C2.8436.07.911.7Cases/person-years43/55,73345/55,15149/54,54330/48,75738/50,496Age-adjusted fiber (median (0.63—135)—0.72(0.47)Multivariate RR (95% CI)1.00.98 (0.71—1.63)0.71 (0.64—130)1.08 (0.74—1.73)1.26 RR (95% CI)―1.01.13 (0.45—1.14)0.99 (032—1.40)1.17 (0.82—1.94)0.86 (0.72—1.90)0.11 Cereal fiber (median g/thy)d Cases/person-years 2.3 40/50,343 4.4 48/56,520 6.6 38/56,575 9.4 46/55,039 15.3 33/46,205 Age-adjusted RR (95% CI) Multivariate RR (95% CI)― 1.0 1.0 1.15 (0.75—1.76) 1.27 (0.83—1.96) 0.99 (0.61—139) 1.22 (0.77—1.93) 1.38 (0.89—2.16) 1.63 (1.04—237) 1.06 (0.66—1.73) 1.28 (0.78—2.09) a RR adjusted for age, total energy, previous polyps, previous endoscopic screening, parental history of colorectal cancer, total pack-years of cigarette (0.91) 0.35 (0.73) 1.42(0.16) smoking, aspirin use, and intake of red meat, methionine and alcohol, using the Cox model. b Includes raisins, C Includes string avocados, beans, bananas, broccoli, cantaloupes, sauerkraut, watermelon, coleslaw, cauliflower, apples, brussels pears, oranges, sprouts, grapefruits, carrots, corn, strawberries, peas, mixed blueberries, vegetables, peaches, beans, cabbage, apricots, lentils, plums, alfalfa and fruit sprouts, juices. celery, mushrooms, yellow squash, eggplant, yams, spinach, iceberg or romaine lettuce, green pepper, garlic, tomatoes, tomato juice and sauce, red chili sauce, and kale or chard greens. d Includes cold breakfast cereal, cooked oatmeal, other cooked breakfast cereal, white bread, dark bread, English muffins, bagels, rolls, brown rice, white rice, pasta, other grains, pancakes, crackers, and added bran. adjusted analysis. The item with the strongest evidence of an inverse association was garlic intake (RR 0.77; 95% CI 0.51—1.16for 2 servings versus 0 servings per week; P = 0.14 for trend), an association limited to the distal colon (RR = 0.63; 95% CI = 0.38—1.65;P = 0.07 for trend). scopic procedures during the study period. Thus, a higher detection rate for colon cancer among the heavier consumers of red meat is unlikely to explain the observed associations. Controlling for total energy, parental history of colorectal cancer, physical activity, body mass index, aspirin use, smoking, and intake of alcohol and other nutrients did not alter markedly the association between meat intake and colon cancer incidence. Because the population consisted of a DISCUSSION relatively homogeneous group of male health professionals, any re sidual confounding from other factors potentially related to socioeco nomic status was unlikely to be substantial. While our study does not support a general effect of fat intake on These data support the hypothesis that high consumption of red meat increases the risk of colon cancer, particularly of the distal colon, but do not provide evidence for a protective effect of dietary fiber. In contrast to the findings for red meat, fat from dairy, poultry, and vegetable sources tended to be inversely associated with the risk of colon cancer. No overall relationship existed between total or satu colon cancer risk, it is still plausible that the fat content of red meat is deleterious. It has been hypothesized that diacylglycerides aris ing from the incomplete breakdown of dietary triglycerides induce mitogenesis of adenoma and some carcinoma cells but not normal cells in primary culture (60). Conceivably, fat from red meat may rated fat and this malignancy, despite a marked range in fat intake (means of 24 to 41% of energy from total fat and 7 to 14% from saturated fat between extreme quintiles). These findings are consistent with those from a similar cohort in women, the NHS, and from an analysis of adenomas of the distal colorectum in the same cohort of be less readily digested or absorbed in the small intestine, perhaps because men. In all three analyses, the specific food item most strongly associated with increased risk of colon cancer or adenoma was beef, pork, or lamb as a main dish. Although an association between animal association was attributable to consumption of red meat. Furthermore, in an analysis of the NHS data with red meat and animal fat in the Biased recall was not likely to explain our findings because the dietary data were collected before the diagnosis of colon cancer. We controlled for history of colonoscopy or sigmoidoscopy prior to 1986, and high red meat consumers tended to have slightly fewer endo or due to its physical some fatty acids (e.g., palmitic acid) that appear to be strong mitogens of adenoma cells in culture. Alternatively, it has been hypothesized that a high consumption of or saturated fat and colon cancer incidence existed in the NHS, this same model, red meat remained significantly predictive of colon cancer, whereas the association with animal fat was eliminated (un published data). Overall, the results from these three analyses provide evidence for an association between red meat intake and colorectal neoplasia but do not support the hypothesis that fat consumption per se increases risk of colorectal tumors. of its high stearic acid content imbediment in muscle tissue, and thus more of it may reach the large bowel. Moreover, the specific fatty acid profile of red meat could be particularly harmful. For example, red meat is high in protein rather than fat increases the risk of cancer (61). However, the results from the NHS cohort and this cohort actually suggest an inverse association between non-red meat sources of protein and colon tumors. Similarly, among the many published reports from dietary epidemiological studies of colon cancer and adenomas, we are aware of none which have reported a significant positive association with intake of non-red meat protein; on the contrary, most other prospective studies have similarly reported either significant or non significant inverse associations with high protein foods (poultry, fish, and dairy) or with total protein (30, 32, 33, 36, 37). An inverse 2394 Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research. MEAT, FAT, FIBER, AND COLON CANCER association between non-red meat protein and risk of colorectal ade noma has also been observed in most studies (42, 62—65). Some case-control studies of colon cancer have indicated a positive associ ation with total protein; however, because these studies generally have found a positive association with total energy intake and colon cancer, energy from protein as a percentage of total energy is often actually lower among cases. Moreover, a clearer inverse association with protein may have emerged if non-red meat protein sources were analyzed separately from red meat. A possible explanation for a protective effect of protein is that low intakes of methionine may contribute to DNA methylation abnormalities, which appear to be important in the initiation and progression of colon cancer (66). cancers and adenomas, could be due to limitations of ecological studies. National per capita levels of protein consumption are corre lated with various factors that could explain the higher risk of colon cancer in affluent countries (e.g., red meat, fat, physical inactivity, obesity, low fiber, and long-term smoking). Yet within high-risk populations, data from some epidemiological investigations (30, 32, 33, 36, 37, 42, 62—65)including the current study suggest ample protein intake during adulthood may actually be beneficial for the risk of colon cancer, although the effects of high intakes of total energy or protein during developmental years could be quite different. Besides macronutrients, other factors in red meat may account for its association with colon cancer. Babbs (67) hypothesizes that high consumption of red meat may increase concentrations of fecal iron, which could influence risk of colon cancer via the generation of hydroxyl radicals. Dietary iron enhances lipid peroxidation in the mouse colon (68) and augments dimethyihydrazine-induced colorec tal tumors in mice (69) and rats (70). Alternatively, some evidence suggests that carcinogens formed when meat is cooked may be critical (71). Human data are sparse, but in one case-control study, the risk of colorectal cancer was markedly elevated among frequent meat eaters who preferred a heavily browned surface but was not increased among those who consumed meat fried with a medium or lightly browned surface (28). Thermolyzed protein promotes precursor lesions and cancers of the rat colon, an influence that is dose-dependent and proportional to the cooking time (72). Others speculate that diets high in meat increase the risk of colon cancer by raising the concentration of endogenous nitrosamines (73) or tryptophan metabolites (74). For this analysis, we did not have data on cooking practices. Total energy intake was not directly related to colon cancer risk, as had been suggested by numerous case-control studies (3). Our finding was consistent with other prospective studies of colon cancer and adenoma, which also did not show an association with total energy. This difference observed between prospective and some case-control studies may be due to a general overreporting of past food intake by cases relative to controls when diet is assessed after the diagnosis of cancer. When we examined the risk of colon cancer in relation to the consumption of red meat separately among smokers and nonsmok ers, we found markedly stronger relative risks among nonsmokers. The most likely explanation for this finding is that the smoking related colon cancers, estimated to be 37.5% of colon cancers among smokers, attenuated the relative risks associated with the intake of red meat among smokers. An association between smok ing at young ages and risk of colorectal cancer needs to be taken into account in future studies. with the earlier report among female nurses, sure of fiber intake. Despite a relatively wide acceptance of the fiber-colon cancer hypothesis, evidence from epidemiological studies is weak. A meta analysis The positive association between protein intake and colon cancer incidence observed in ecological studies, in contrast to the inverse association observed in case-control and prospective studies of colon Consistent from the substudy, the overall median intake of dietary fiber was 21 g daily, with medians of 13 g for the low quintile and 34 g for the high quintile. We were thus able to examine the effects of fiber at recom mended intakes (25 to 35 g daily; Ref. 75), which are considerably higher than the mean dietary fiber intake in the U.S. adult population (13.3 g per day; Ref. 76). The fact that a strong inverse association between fiber intake and symptomatic diverticular disease was found in this cohort4 indicates that we had a physiologically relevant mea we did not of case-control case-control of colon cancer demonstrated a com studies which examined sources of fiber separately, grain fiber or cereal intake was either unrelated or positively associated with colon cancer risk, whereas intake of fruits or vegetables was protec tive (3). Possibly, some specific component or type of fiber rather than total dietary fiber may be protective, or perhaps the influence of fiber occurs during earlier stages of carcinogenesis. Several studies of adenomatous precursors (60—63), including data from this cohort, do support a protective effect of fiber. Alternatively, the lack of an association with cereal fiber intake and inverse associations between vegetable intake and malignancies at other sites where a direct influence of fiber is unlikely suggest that chemopreventative factors in plant foods other than fiber may be the active agents. We did not observe a statistically significant inverse association between intake of any single fruit or vegetable item and the risk of colon cancer. The absence of strong associations between fruits and vegetables and colon cancer in this cohort and in the NHS contrasts with findings in numerous case-control studies. One possible explanation is that the influence of the protective agent(s) occurs at deficient or very low intakes and that consumption of fruits and vegetables in these self-selected cohorts is considerably higher than that in general population studies. A recent report from a cohort study of women in Iowa also did not show a clear inverse association with fruit and vegetable intake (78). Of note, garlic was the specific vegetable item with the strongest inverse association with risk of cancer of the distal colon, a finding remarkably similar to that ob served in the Iowa women (78). Garlic and other allium vegetables including onions and chives may have a anticarcinogenic effect, possibly due to an induction of enzymatic detoxification systems, antibacterial activity, or a reduction in tumor proliferation (79). As very little study has been conducted regarding allium compounds and cancer in humans, this finding requires further investigation. In summary, these findings provide further evidence for the hy pothesis that consumption of red meat increases the risk of colon cancer, the second leading cause of death from malignancies in the United States (80). Major sources of protein and fat other than red meat do not appear to have this deleterious effect. These data provide direct support for existing dietary recommendations to substitute fish and poultry for red meat (56, 57). 4 w. H. Aldoori, observe an important effect of fiber. The absence of an association was not due to a limited range in fiber intake; based on diet records studies bined odds ratio of 0.58 between highest and lowest quintiles based on fiber intake but a stronger odds ratio of 0.48 based on vegetable consumption (77). These estimates, however, may be biased because of the exclusion of several studies that did not support the hypothesis. Furthermore, as suggested by our study, some confounding by red meat intake and physical activity level may have occurred. In the E. Giovannucci, E. B. Rimm, A. L. Wing, D. V. Trichopoulos, and w. 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Intake of Fat, Meat, and Fiber in Relation to Risk of Colon Cancer in Men Edward Giovannucci, Eric B. Rimm, Meir J. Stampfer, et al. Cancer Res 1994;54:2390-2397. Updated version E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/54/9/2390 Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1994 American Association for Cancer Research.