intake of fat, meat, and fiber in relation to risk of ...intake and risk of colorectal cancer have...

[CANCERRESEARCH54. 2390-2397, May 1, 1994]

null associations (34, 35) with fat or meat consumption. However,much of the earlier prospective data have been limited by the smallnumber of cases, crude assessments of diet, and lengthy time periodsbetween assessment of diet and the accrual of cases. A report from theNHS,3 which avoided these limitations, showed a strong associationbetween animal fat, principally from red meat, and risk of coloncancer in women (36). A recent cohort study from the Netherlandsfound an association between processed meats and colon cancer, butno relationship was observed for fresh meats (37).

A second major hypothesis regarding diet and colon cancer wasprimarily initiated by Burkitt's observation of low rates of coloncancer in regions of Africa which had a high fiber consumption leveland a corresponding large stool bulk (38). However, analytical epidemiological studies have been rather inconsistent in supporting thefiber-colon cancer hypothesis. Inverse associations between total fiberintake and risk of colorectal cancer have been observed in somecase-control studies (10, 15, 16, 19, 39, 40) but not all (8, 9, 12â€”14,17). Prospective data regarding fiber intake and colon cancer arescarce and generally null (41). Overall, it appears that factor(s) presentin some vegetables and fruits may be protective (3), but it is unclearwhether fiber, some specific component of fiber, or other factorscommon in plants are the relevant compounds.

We examine here the intake of fat, meat, and fiber in relation to theincidence of colon cancer during 6 years of follow-up in a large cohortof U.S. male health professionals. Within this cohort, we have reported previously that a diet high in animal fat, especially fat from redmeat, and low in dietary fiber was associated with an elevated risk ofcolorectal 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 thisanalysis. Briefly, this cohort was started in 1986 when 51,529 U.S. maledentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians40 to 75 years of age responded to a mailed questionnaire, which included asemiquantitative food frequency questionnaire. Participants also provided in

formation on smoking history, age, weight, height, physical activity, use ofaspirin and other common medications, parental history of cancer, and historyof professionally diagnosed medical conditions. Every 2 years, we mail afollow-up questionnaire to the men to ascertain newly diagnosed medicalconditions (44).

Semiquantitative Food-Frequency Queslionnaire. The dietary question

naire used in this study, an expanded version of a previously validatedinstrument (45, 46), included 131 food items plus vitamin and mineral supplement 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., oneegg or slice of bread) was specified, and participants were asked how often, onaverage over the past year, they consumed that amount of each food. Subjects

chose from nine possible responses, which ranged from ne@ierto six or moretimes per day. We also inquired about the types of fat used, and we providedan open-ended section for foods that were not specified on the questionnaire.We computed nutrient intakes by multiplying the consumption frequency ofeach unit of food by the nutrient content of the specified portions (47â€”49),alsoaccounting for the specific types of fat used in food preparation. We adjusted

3 The abbreviations used are: NHS, Nurses' Health Study; kcal, kilocalories; RR,

relative risk; CI, confidence interval.

ABSTRACT

Some evidence suggests that diets high in animal fat or red meat mayincrease the risk of colon cancer, whereas high intake of fiber orvegetables may be protective. Frequently, intake of red meat has beena stronger risk factor than total fat. Because data from prospectivecohort studies are sparse, we examined fat, meat, fiber, and vegetableintake in relation to risk of colon cancer in a cohort of 47,949 U.S. malehealth professionals who were free of diagnosed cancer in 1986. Atbaseline, these men, 40 to 75 years of age, completed a validated foodfrequency questionnaire and provided detailed information on otherlifestyle and health-related factors. Between 1986 and 1992, 205 newcases 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 meatintake (relative risk, 1.71; 95% confidence interval, 1.15â€”2.55betweenhigh 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 riskof 3.57 (95% confidence interval, 1.58â€”8.06;P 0.01 for trend)compared to men eating these foods less than once per month. Theassociation with red meat was not confounded appreciably by otherdietary factors, physical activity, body mass, alcohol intake, cigarettesmoking, or aspirin use. Other sources of animal fat, including dairyproducts, poultry, and fish as well as vegetable fat, were slightlyinversely related to risk of colon cancer. No clear association existedbetween fiber or vegetable intake and risk of colon cancer. These data

support the hypothesis that intake of red meat is related to an elevatedrisk of colon cancer.

INTRODUCTION

Although a genetic component is well established (1), colon cancerappears to be strongly influenced by environmental factors. The ratesof colon cancer generally increase among migrants from low- tohigh-incidence areas (2), and striking secular trends have occurredwithin populations, including a sharp increase in Japan after WorldWar II (3). Doll and Peto (4) have suggested that differences in dietmay account for 90% of the marked variation in rates of this malignancy among different countries (5). Studies comparing per capitanational consumption levels of various foods and nutrients with national colon cancer rates have found high correlations with red meator animal fat but not with vegetable fat (6, 7). With few exceptions

(8â€”12),a link with fat (13â€”21)or red meat intake (22â€”28)has beensupported in numerous case-control studies where recalled past dietsof persons with and without colon cancer are compared. However, inmany of these studies, a positive association between total energyintake and risk of colon cancer has been observed (13â€”17,19, 21),raising the question of whether it is the total amount of food consumedor the fat composition of the diet that is etiologically important (29).

Prospective studies of colon cancer, less prone to selection andrecall bias, have demonstrated positive (30, 31), inverse (32, 33), and

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 with18 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

Grant 18 from the American Cancer Society. G. A. C. is supported by a Faculty ResearchAward (FRA-398) from the American Cancer Society.

2 To whom requests for reprints should be addressed, at Channing Laboratory, 180Longwood Avenue, Boston, MA 02115.

2390

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 ofEpidemiology 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

Research. on January 13, 2021. © 1994 American Association for Cancercancerres.aacrjournals.org Downloaded from

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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 addedto the mean nutrient level at the mean caloric intake to form the energyadjusted nutrient.

We askedrandomlyselected participantsfromthe Boston areato complete2 weeks of diet records in order to estimate the true variation in nutrient intakeswithin the study population and to evaluate the precision of the questionnaire.The results have been described in detail previously (51). Briefly, 127 participants provided complete information for both 1-week detailed weighed dietrecords, administered approximately 6 months apart, and a second semiquantitative food-frequency questionnaire administered by mail after the dietrecords were received. Mean intakes for the lowest and highest quintilesdetermined by the diet records were 24 and 41% of energy for total fat, 7 and14% 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 correlationcoefficients between the second questionnaire and the average of the two1-week diet records for energy-adjusted nutrients (adjusting for week-to-weekvariation in the diet records) were 0.67 for total fat, 0.75 for saturated fat, 0.68for monounsaturated fat, 0.76 for cholesterol, 0.44 for protein, and 0.68 fordietary fiber.

Identification of Cases of Colon Cancers. We mailed follow-up questionnaires to all study participants in 1988, 1990, and 1992 and asked them toreport any diagnosis of cancer during the past 2 years. We mailed up to sixquestionnaires per follow-up cycle to nonrespondents, including two certifiedmailings. For this analysis, the follow-up response rate was 95% of totalpossible 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 postalsystem in response to the follow-up questionnaires. In addition, we used theNational Death Index, a highly sensitive method of identifying deaths amongnonrespondents (52). We expect to capture essentially all of the fatal cancersduring the study period and approximately 95% of the nonfatal cancers asprevious experience suggests that nonresponse is not strongly correlated withdisease status.

When a subject (or next of kin for decedents) reported a diagnosis of cancerof the colon or rectum on our follow-up questionnaire, we asked him (or nextofkin) for permission to obtain hospital records and pathology reports. A studyphysician, blinded to exposure information, reviewed all medical records andextracted 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. Weconfirmed 251 new cases of colorectal cancer (excluding carcinoma-in-situ),

226 (90%) by medical records, and 25 with corroborating information ondiagnosis and treatment from the cohort member. For the primary analysis, wedid not include 46 cases that occurred in the rectum because rectal cancersappear to have a different epidemiological pattern and are less clearly associated with dietary variables. This left 205 cases of colon cancer for analyses.

Data Analysis. For these analyses, we excluded men with implausibly highor low scores for total energy intake (outside the range of 800 to 4200 kcal perday) or with 70 or more items left blank and men who reported previous cancer(other than nonmelanoma skin cancer), ulcerative colitis, or a familial polyposis syndrome at baseline, leaving 47,949 men. Each man contributed follow-up time beginning on the month of return of the initial questionnaire in1986 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 thenumber of person-years) in each category (usually quintile) of intake by therate among those in the lowest category. We used stratified analysis to controlfor 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), orprior endoscopy (yes/no) as well as other nutrients (quintiles). For the stratifiedanalyses, we used the Mantel-Haenszel summary estimator (53) and tested forlinear trends using the Mantel Extension test (54). To adjust simultaneously for

two or more covariates, we used proportional hazards regression (55). Criteriafor inclusion into the multivariate model included a priori belief that the factorwas related to colon cancer for biological reasons (e.g., family history) ordiagnostic reasons (e.g., prior screening) and that the factor was related to

colon cancer in this cohort. For nutrients or food groups adjusted by proportional 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 fatand protein (vegetable and animal) and fiber (vegetable, cereal, and fruit). Wealso evaluated separately sources of animal fats (red meat, chicken, fish, anddairy) and the red meat to chicken and fish ratio. This ratio, the mostsignificant 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 substitutionpattern of chicken and fish for red meat mainly among those eating anappreciable amount of these foods, we limited our analyses to men eating atleast one serving of these foods daily on average.

RESULTS

A slight inverse but nonsignificant association existed between totalenergy intake and colon cancer incidence (Table 1). Energy-adjustedtotal fat intake was also unrelated to risk of colon cancer. Animal fathad no clear association with risk of colon cancer; a significantlyelevated risk was evident in the second highest quintile relative to thelowest, but the rate in the highest quintile was slightly lower than thatin the lowest quintile. Fat from vegetable sources had a modest,nonsignfficant inverse association with colon cancer. The major typesof fat from animal sources and saturated and monounsaturated fatwere unrelated with risk of colon cancer, and linoleic acid, the majorpolyunsaturated fat, was slightly inversely associated with risk. Cholesterol intake, exclusively from animal sources, was unrelated to therisk of colon cancer.

In contrast to the absence of an association between total andanimal fat and risk of colon cancer, a significant associationexisted between red meat intake and risk of colon cancer (Table 2).Beef, pork, or lamb as a main dish was significantly related to riskof colon cancer; an association also existed with processed meats,although this did not achieve statistical significance (P = 0.06). Ofthe other sources of meat, poultry intake was slightly inverselyrelated to the risk of colon cancer, and fish intake was unrelated torisk. The red meat to chicken and fish ratio, representing thesubstitution of chicken and fish for red meat, was significantlyrelated to higher risk of colon cancer.

We conducted multivariate analyses to assess whether otherpotentially confounding variables influenced the relation betweenred meat consumption and colon cancer. In a multiple logisticmodel which included age, body mass index, history of previouspolyp and prior endoscopy, parental history of colon cancer, aspirin use, physical activity, and intake of dietary fiber, methionine,and alcohol, the elevated risk associated with red meat intake (RR= 1.66; 95% CI = 1.04â€”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 = 1.35â€”6.98between 5 servings per week versus lessthan once per month; P = 0.04 for trend) persisted. The modestdegree of confounding, represented by the change in relative riskin the full multivariate model, was due primarily to physicalactivity and cigarette smoking before the age of 30 years. Furtheradjustment for folic acid, calcium, and vitamins A, C, D, and E andmultivitamin use did not influence the results.

Because red meat is an important dietary source of both protein andfat, we examined the association between sources of fat and proteinand the risk of colon cancer in detail. The correlations between intakesof red meat and total fat (r = 0.51) and animal fat (r = 0.57) were notso high to preclude our ability to discriminate statistically among thesources of fat. The combination of the positive association with redmeat and the inverse associations with other major sources of fat

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Table 1 Relative risk of colon cancer according to quintile of total energy intake and dietary fats

Quintilexfortrendâ€•

(P)Variable 1 2 3 45Total

energy(mediankcal/day) 1229 1586 1884 23082820CaseWperson-@ears34/52,982 64/52,871 44/53,126 35/53,134 28/52,567

RR (95% Cl) 1.0 1.92 (1.28â€”2.90) 1.33 (0.85-2.08) 1.12 (0.70â€”1.80) 0.94(037â€”135)â€”1.42(0.16)Total

fat (mediang/day) 54.2 65.3 72.3 79.089.0Cases/person-years34/53,278 55/52,150 55/53,287 27/52,83434/53,132RR

(95% Ct)c 1.0 1.80 (1.18â€”2.74) 1.82 (1.19â€”2.77) 0.95 (037â€”1.56) 1.19(0.74â€”1.90)â€”0.47(0.64)Animal

fat (median g/day) 25 33 40 4656Cases/person-years42/55,158 40/50,612 40/56,035 53/52,86930/50,006RR

(95% Cr)c 1.0 1.12 (0.73â€”1.72) 1.06 (0.69â€”1.63) 131 (1.02â€”2.24) 0.87(035â€”1.38)0.42(0.67)Vegetable

fat (median g/day) 20 27 32 3746Cases/person-years54/52,812 40/54,1 14 33/52,593 41/52,86537/52,304P.R

(95%Ct)c 1.0 0.79(032â€”1.19) 0.70(0.45â€”1.07) 0.90(0.60â€”1.35) 0.76(030â€”1.16)â€”0.98(0.33)Saturated

fat (median g/day) 17.4 22.2 25.2 28.333.0Cases/person-years47/53,305 44/54,212 44/56,650 39/52,33531/52,178RR

(95% @)C 1.0 1.01 (0.67â€”133) 1.13 (0.75â€”1.70) 1.07 (0.70â€”1.63) 0.88(036â€”1.37)â€”0.27(0.79)Monounsaturated

fat (median g/day) 19.1 23.8 26.9 29.734.2Cases/person-years39/53,526 42/52,838 48/54,660 41/52,74035/50,916RR

(95%CI)c 1.0 1.21(0.78â€”1.87) 139 (0.91â€”2.12) 1.24(0.80â€”1.93) 1.07(0.68â€”1.69)0.41(0.68)Linoleic

acid (median g/day) 8.0 10.1 11.6 13.216.2Cases/person-years49/54,614 42/52,005 37/52,498 43/52,80134/52,762RR

(95% C1)c 1.0 0.99 (0.66â€”1.49) 0.87 (037â€”134) 1.01 (0.67â€”132) 0.79(031â€”1.22)â€”0.84(0.40)Cholesterol

(median mg/day) 198 262 313 369467Cases/person-years40/53,188 46/53,320 37/53,522 40/52,57042/52,080RR

(95% @)C 1.0 1.27 (0.83â€”1.93) 0.99 (0.64â€”135) 1.07 (0.69â€”1.66) 1.07(0.70-1.63)â€”0.07(0.94)a

x-ststi@ticisequivalenttoZvaluefromstandardnormaltableswithanegativevaluerepresentinganinverseassociation.b Adjusted for age using stratifiedanalysis.C

Adjusted for age usingstratified analysis.Nutrients are adjustedfor intake of total energy usingresidualanalysis.Table

2 Age-adjustedrelativeriskof coloncanceraccordingto intakeof variousanimalfoodgroupsCategoryx

for trend(P)Variable 1 2 3 45Red

meata(mediang/day) 18.5 42.9 64.1 883 1293@b/p@_.@n@years 39/51,897 35/52,448 32/52,805 40/52,87155/529,689RRC

(95% CI) 1.0 0.97 (0.62â€”134) 0.98 (0.62â€”136) 1.21 (0.77â€”1.88) 1.71 (1.15â€”235)2.83(0.005)Beef,

pork,or lambas maindish(servings) 0 1â€”3/month 1/week 2-4/week5/weekCases/person-years12124,870 44/49,307 57/85,194 72/88,71316/14,906RR

(95% Cl) 1.0 1.92 (1.03â€”3.60) 1.69 (0.92â€”3.10) 2.11 (1.13â€”3.92) 337 (138â€”8.06)239(0.01)Processed

meats (servings) 0 1-3/month 1/week 2-4/week5/weekCases/person-years52/70,150 63/79,387 41/55,113 39/44,2117/13,305RR

(95% Cl) 1.0 1.25 (0.87â€”1.80) 1.40 (0.92â€”2.13) 1.67 (1.06â€”2.61) 1.16 (0.44â€”3.04)1.89(0.06)Poultry

(median gjthy)d 8.8 15.8 29.2 42.263.1Cases/person-years54/52,186 39/53,062 36/53,1 10 40/52,79036/53,532RR

(95% CI) 1.0 0.81 (034â€”1.23) 0.76 (030â€”1.17) 0.79 (032â€”1.18) 0.82 (034â€”1.24)â€”1.10(0.27)Fish

(median g/day)â€• 8.4 20.9 31.0 47.883.4Cases/person-years41/52,817 35/53,071 43/52,789 35/52,78851/53,215RR

(95% CI) 1.0 0.85 (0.54â€”1.33) 1.05 (0.68â€”1.61) 0.80 (031â€”1.26) 1.06 (0.70â€”1.60)0.26(0.79)Ratio

of red meat to chicken and fish (median)'@ 0.20 036 1.0 1.73.6Cases/person-years31/43,534 31/42,650 33/428,232 28/44,10249/44,642RR

(95% Cl) 1.0 1.20 (0.73â€”1.96) 1.30 (0.80â€”2.12) 1.09 (0.65â€”1.82) 1.83 (1.17â€”2.85)2.43 (0.015)


aDataonredmeatrelatetothefollowing:beef,pork,orlambasamaindish(e.g.,steak,roast,andham);beef,pork,orlambasasandwichoramixeddish(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 missinginformationon 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 dayofthesefoods.

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).

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(poultry, dairy, and vegetable) balanced each other to yield the overall lated to the risk of colon cancer. In addition, fat from dairy productsnull association observed between total and animal fat intake and risk (RR = 0.66; 95% CI = 0.43â€”1.01between high and low quintiles; Pof colon cancer. As seen in Table 1, vegetable fat and the major = 0.23 for trend) and from chicken (RR = 0.60; 95% CI = 0.38â€”polyunsaturated fat linoleic acid were nonsignificantly inversely re- 0.95; P = 0.08 for trend) were slightly inversely related to the risk of




Table 3 Relative risk of colon cancer according to quintile of total dietary protein and sources of protein

Quintilex for trend

(P)Variable12345Total

proteinâ€•(median g/day) 70C@sb/permnyears 46/46,834RRc (95% CI) 1.080

36/53,2940.74 (0.48â€”1.15)88

42/52,6070.88 (0.58â€”1.33)95

34/50,9450.71 (0.46-1.10)108

47/59,0010.78(0.52â€”1.17)â€”1.17(0.24)Animal

proteinâ€•(median g/day) 44@sb/p@_,@n.ye@ 48/54,390

RRc (95% CI) 1.05541/51,709

0.93 (0.61â€”1.41)6343/56,165

0.89 (039â€”1.35)7236/50,474

0.81 (033â€”1.25)8537/51,942

0.76(0.49â€”1.16)â€”1.42(0.16)Red

meat proteina (median g/day) 5Casesâ€•/person-years 40/51,876RRC (95% CI) 1.010

34/52,2950.93 (0.59â€”1.47)16

33/53,05 10.97 (0.61â€”1.53)22

42/52,7781.25 (0.81â€”1.92)32

52/52,990134 (1.03â€”2.31)2.53(0.01)Animal

protein excluding red meata (median g/day) 19@@sb/permn@years 56/52,542

RRC (95% CI) 1.027

34/52,5800.64 (0.42â€”0.97)33

39/53,1390.70 (0.47â€”1.06)40

34/53,1680.60 (0.40â€”0.92)54

42/52,2530.68(0.46â€”1.02)â€”1.86(0.06)Vegetable

proteinâ€•(median g/day) 18@@sb/permn@ye@ 44/52,804

RRC (95% CI) 1.022

40/52,7760.93 (0.61â€”1.43)25

49/54,0581.09 (0.73â€”1.63)28

39/5 1,7270.88 (037â€”1.36)33

33/53,3160.70(0.45â€”1.10)â€”1.48(0.14)a

Nutrients adjusted for total energy using residual analysis.

@ fornutrientsmaynotaddupto205duetomissinginformation.C Relative risks adjusted for age using stratified analysis.

colon cancer. As expected, fat from red meat sources was related tocolon cancer (RR = 1.39; 95% CI = 0.82â€”2.36;P = 0.02 for trend).These data suggest that fat intake, at least that from non-red meatsources, 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 wasinversely associated (nonsignificantly) with the risk of colon cancer(Table 3). We explored further the association with animal proteinfrom sources other than red meat in a model that included intake ofenergy-adjusted protein from red meat, energy-adjusted protein fromanimal sources other than red meat, age, body mass index, history ofprevious polyp and prior endoscopy, parental history of colon cancer,aspirin use, physical activity, and alcohol intake. In this model, animalprotein from sources other than red meat was associated with areduced risk of colon cancer (RR = 0.63; 95% CI = 0.41â€”0.97between high and low quintiles of intake; P = 0.03 for trend). Theslightly stronger association between non-red meat animal protein andrisk of colon cancer when controlling for red meat protein suggeststhat this inverse association may not be due entirely to the displacement of red meat in the diet.

We examined the relationship with red meat by subsite within thelarge bowel (among cases for which subsite information was available), including the rectum. The association between red meat intakeand large bowel cancer was suggested for the distal colon (89 cases,age and energy-adjusted RR = 1.78; 95% CI = 0.97â€”3.25betweenhigh and low quintiles of intake; P = 0.07 for trend) but not in theproximal colon (69 cases, RR = 0.87; 95% CI = 0.43â€”1.76;P = 0.85for trend). There were too few cases of rectal cancer (46) to provideinformative relative risk estimates (RR 1.22; 95% CI = 0.36â€”4. 14). For total colorectal cancer, entailing 25 1 cases, associations

existed with red meat intake (RR = 1.66; 95% CI = 1.14â€”2.42;P =0.003 for trend) and the red meat to chicken and fish ratio (RR = 1.81;95% CI = 1.22â€”2.67;P = 0.02 for trend).

Of all the food items included in the questionnaire, beef, pork, andlamb as a main dish had the strongest positive association with coloncancer. Other red meat products, processed meats (P = 0.06), hamburger (P = 0.04), and bacon (P = 0.11) were positively associatedwith the risk of colon cancer, whereas hotdogs and beef and pork orlamb served as a sandwich or mixed dish were unrelated to risk. Incontrast, other high-fat foods of animal origin had nonsignificantinverse associations with colon cancer (whole milk, P = 0.08; ice

cream, P = 0.17; chicken with skin, P = 0.06) or were unrelated torisk (hard cheese and butter).

We had reported an association between smoking at early ages andrisk of colorectal cancer in this cohort (Ref. 58 and in the NHS, Ref.59). Based on the age-adjustedrelativerisk of 1.60 among those whohad smoked before the age of 30 years relative to nonsmokers, weestimated that 38% of the colon cancers diagnosed among smokerscould be attributable to smoking. If colon cancers related to smokingand those related to red meat occur via different etiological pathways,smoking-related cancers would attenuate the relative risks associatedwith the intake of red meat among smokers. Thus, we examined therisk of colon cancer in relation to consumption of red meat separatelyamong smokers and nonsmokers. Among nonsmokers before age 30years (75 cases of colon cancer among 24,817 men), we found strongassociations between colon cancer and the intake of red meat (RR =2.18; 95% CI = 1.14â€”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 1.38â€”18.9 between 5 servings per week versus

less than once per month; P 0.008 for trend). Among men who hadsmoked before age 30 years (126 cases among 22,812 men) there wereconsiderably weaker associations between colon cancer and the intakeof red meat (RR = 1.38; 95% CI = 0.83â€”2.30;P = 0.21 for trend)and the intake of beef, pork, and lamb (RR = 1.60; 95% Cl =0.67â€”3.85;P = 0.75 for trend).

Intake of total dietary fiber or of crude fiber was unrelated to riskof colon cancer (Table 4). For both types of fiber, men in the lowestquintile of intake appeared to be at the highest risk. However, noobvious trend was evident from quintiles 2 to 5. Furthermore, in thefull multivariate model, any suggestion of a protective effect of fiberdisappeared. The major contributors to confounding were intake ofred meat and level of physical activity. None of the sources of fiber,

fruit, vegetable, or cereal, appeared related to risk. The relation withfiber intake did not vary appreciably by subsite within the colon.

We also examined associations between frequency of total vegetable and fruit consumption and risk of colon cancer. Intakes of vegetables (RR = 1.02; 95% CI 0.64â€”1.63for >5 versus @2servingsper day; P = 0.83 for trend) and fruits (RR = 0.98; 95% CI0.54â€”1.77for >4 versus <1 servings per day; P = 0.52 for trend) wereunrelated to risk. Of all fruits and vegetable items examined individually (see footnote for Table 4 for list), none were statistically significantly related to the risk of colon cancer in an age- and energy

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Table 4 Relative risk of colon cancer according to quintile of total dietary and crude fiber and dietary fiber from fruits, vegetables, and cereals

Quintilex for trend

(F)Variable12345Total

dietaryfiber(mediang/day)14.218.321.725.632.8Cases/person-years53/55,56128/52,32225/51,88652/52,15747/52,754Age-adjusted

RR (95% CI)1.0032 (0.33â€”0.81)0.43 (0.27â€”0.68)0.82 (036â€”1.19)0.65 (0.44â€”0.97)â€”0.91(0.36)MultivariateRR (95% C])â€•1.00.63 (0.39â€”1.01)039 (0.36-0.97)1.19 (0.78â€”1.82)1.08(0.68-1.70)137(0.12)Total

crude fiber (mediang/day)3.64.65.66.68.6Cases/person-years42/51,58834/53,79434/52,72451/53,41444/53,159Age-adjusted

RR (95% CI)1.00.68 (0.44-1.07)0.64 (0.41â€”1.00)0.86 (037â€”1.29)0.69 (0.45â€”1.05)â€”1.13(0.26)MultivariateRR (95% CI)â€•1.00.83 (032â€”1.32)0.87 (034â€”139)1.27 (0.81â€”1.98)1.05(0.65â€”1.71)0.95(0.34)Fruit

fiber (mediang/day)b1.22.64.15.89.2Cases/person-years33/62,29343/54,28255/52,25038/49,29136/46,564Age-adjusted

RR (95% CI)1.01.23 (0.78â€”1.94)131 (0.99â€”2.31)1.05 (0.65â€”1.69)1.00 (0.61â€”1.63)â€”0.23(0.82)MultivariateRR (95% CI)â€•1.01.60 (1.01â€”235)2.03 (1.29â€”3.20)1.61 (0.98â€”2.81)1.66(0.98â€”2.81)1.74(0.08)Vegetable

fiber (median@@y)C2.8436.07.911.7Cases/person-years43/55,73345/55,15149/54,54330/48,75738/50,496Age-adjusted

RR (95% CI)1.00.98 (0.64â€”130)1.08 (0.71â€”1.63)0.71 (0.45â€”1.14)0.99(0.63â€”135)â€”0.72(0.47)MultivariateRR (95% CI)â€•1.01.13 (0.74â€”1.73)1.26 (0.82â€”1.94)0.86 (032â€”1.40)1.17 (0.72â€”1.90)0.11 (0.91)

Cereal fiber (median g/thy)d 2.3 4.4 6.6 9.4 15.3Cases/person-years 40/50,343 48/56,520 38/56,575 46/55,039 33/46,205Age-adjusted RR (95% CI) 1.0 1.15 (0.75â€”1.76) 0.99 (0.61â€”139) 1.38 (0.89â€”2.16) 1.06 (0.66â€”1.73) 0.35 (0.73)Multivariate RR (95% CI)â€• 1.0 1.27 (0.83â€”1.96) 1.22 (0.77â€”1.93) 1.63 (1.04â€”237) 1.28 (0.78â€”2.09) 1.42(0.16)

a RR adjusted for age, total energy, previous polyps, previous endoscopic screening, parental history of colorectal cancer, total pack-years of cigarette smoking, aspirin use, and

intake of red meat, methionine and alcohol, using the Cox model.b Includes raisins, avocados, bananas, cantaloupes, watermelon, apples, pears, oranges, grapefruits, strawberries, blueberries, peaches, apricots, plums, and fruit juices.

C Includes string beans, broccoli, sauerkraut, coleslaw, cauliflower, brussels sprouts, carrots, corn, peas, mixed vegetables, beans, cabbage, lentils, alfalfa sprouts, 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 inverseassociation was garlic intake (RR 0.77; 95% CI 0.51â€”1.16for2 servings versus 0 servings per week; P = 0.14 for trend), anassociation limited to the distal colon (RR = 0.63; 95% CI =0.38â€”1.65;P = 0.07 for trend).

DISCUSSION

These data support the hypothesis that high consumption of redmeat increases the risk of colon cancer, particularly of the distal colon,but do not provide evidence for a protective effect of dietary fiber. Incontrast to the findings for red meat, fat from dairy, poultry, andvegetable sources tended to be inversely associated with the risk ofcolon cancer. No overall relationship existed between total or saturated 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% fromsaturated fat between extreme quintiles). These findings are consistentwith those from a similar cohort in women, the NHS, and from ananalysis of adenomas of the distal colorectum in the same cohort ofmen. In all three analyses, the specific food item most stronglyassociated with increased risk of colon cancer or adenoma was beef,pork, or lamb as a main dish. Although an association between animalor saturated fat and colon cancer incidence existed in the NHS, thisassociation was attributable to consumption of red meat. Furthermore,in an analysis of the NHS data with red meat and animal fat in thesame model, red meat remained significantly predictive of coloncancer, whereas the association with animal fat was eliminated (unpublished data). Overall, the results from these three analyses provideevidence for an association between red meat intake and colorectalneoplasia but do not support the hypothesis that fat consumption perse increases risk of colorectal tumors.

Biased recall was not likely to explain our findings because thedietary data were collected before the diagnosis of colon cancer. Wecontrolled for history of colonoscopy or sigmoidoscopy prior to 1986,and high red meat consumers tended to have slightly fewer endo

scopic procedures during the study period. Thus, a higher detectionrate for colon cancer among the heavier consumers of red meat isunlikely to explain the observed associations. Controlling for totalenergy, parental history of colorectal cancer, physical activity, bodymass index, aspirin use, smoking, and intake of alcohol and othernutrients did not alter markedly the association between meat intakeand colon cancer incidence. Because the population consisted of arelatively homogeneous group of male health professionals, any residual confounding from other factors potentially related to socioeconomic status was unlikely to be substantial.

While our study does not support a general effect of fat intake oncolon cancer risk, it is still plausible that the fat content of red meatis deleterious. It has been hypothesized that diacylglycerides arising from the incomplete breakdown of dietary triglycerides inducemitogenesis of adenoma and some carcinoma cells but not normalcells in primary culture (60). Conceivably, fat from red meat maybe less readily digested or absorbed in the small intestine, perhapsbecause of its high stearic acid content or due to its physicalimbediment in muscle tissue, and thus more of it may reach thelarge bowel. Moreover, the specific fatty acid profile of red meatcould be particularly harmful. For example, red meat is high insome fatty acids (e.g., palmitic acid) that appear to be strongmitogens of adenoma cells in culture.

Alternatively, it has been hypothesized that a high consumption ofprotein rather than fat increases the risk of cancer (61). However, theresults from the NHS cohort and this cohort actually suggest aninverse association between non-red meat sources of protein andcolon tumors. Similarly, among the many published reports fromdietary epidemiological studies of colon cancer and adenomas, we areaware of none which have reported a significant positive associationwith intake of non-red meat protein; on the contrary, most otherprospective studies have similarly reported either significant or nonsignificant inverse associations with high protein foods (poultry, fish,and dairy) or with total protein (30, 32, 33, 36, 37). An inverse

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association between non-red meat protein and risk of colorectal adenoma has also been observed in most studies (42, 62â€”65). Somecase-control studies of colon cancer have indicated a positive associ

ation with total protein; however, because these studies generally havefound a positive association with total energy intake and colon cancer,energy from protein as a percentage of total energy is often actuallylower among cases. Moreover, a clearer inverse association withprotein may have emerged if non-red meat protein sources wereanalyzed separately from red meat. A possible explanation for aprotective effect of protein is that low intakes of methionine maycontribute to DNA methylation abnormalities, which appear to beimportant in the initiation and progression of colon cancer (66).

The positive association between protein intake and colon cancerincidence observed in ecological studies, in contrast to the inverseassociation observed in case-control and prospective studies of coloncancers and adenomas, could be due to limitations of ecologicalstudies. National per capita levels of protein consumption are correlated with various factors that could explain the higher risk of coloncancer in affluent countries (e.g., red meat, fat, physical inactivity,obesity, low fiber, and long-term smoking). Yet within high-riskpopulations, data from some epidemiological investigations (30, 32,33, 36, 37, 42, 62â€”65)including the current study suggest ampleprotein intake during adulthood may actually be beneficial for the riskof colon cancer, although the effects of high intakes of total energy orprotein during developmental years could be quite different.

Besides macronutrients, other factors in red meat may account forits association with colon cancer. Babbs (67) hypothesizes that highconsumption of red meat may increase concentrations of fecal iron,which could influence risk of colon cancer via the generation ofhydroxyl radicals. Dietary iron enhances lipid peroxidation in themouse colon (68) and augments dimethyihydrazine-induced colorectal tumors in mice (69) and rats (70). Alternatively, some evidencesuggests that carcinogens formed when meat is cooked may be critical(71). Human data are sparse, but in one case-control study, the risk ofcolorectal cancer was markedly elevated among frequent meat eaterswho preferred a heavily browned surface but was not increased amongthose who consumed meat fried with a medium or lightly brownedsurface (28). Thermolyzed protein promotes precursor lesions andcancers of the rat colon, an influence that is dose-dependent andproportional to the cooking time (72). Others speculate that diets highin meat increase the risk of colon cancer by raising the concentrationof endogenous nitrosamines (73) or tryptophan metabolites (74). Forthis 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). Ourfinding was consistent with other prospective studies of coloncancer and adenoma, which also did not show an association withtotal energy. This difference observed between prospective andsome case-control studies may be due to a general overreporting ofpast food intake by cases relative to controls when diet is assessedafter the diagnosis of cancer.

When we examined the risk of colon cancer in relation to theconsumption of red meat separately among smokers and nonsmokers, we found markedly stronger relative risks among nonsmokers.The most likely explanation for this finding is that the smokingrelated colon cancers, estimated to be 37.5% of colon cancersamong smokers, attenuated the relative risks associated with theintake of red meat among smokers. An association between smoking at young ages and risk of colorectal cancer needs to be takeninto account in future studies.

Consistent with the earlier report among female nurses, we did not

observe an important effect of fiber. The absence of an associationwas not due to a limited range in fiber intake; based on diet records

from the substudy, the overall median intake of dietary fiber was 21g daily, with medians of 13 g for the low quintile and 34 g for the highquintile. We were thus able to examine the effects of fiber at recommended intakes (25 to 35 g daily; Ref. 75), which are considerablyhigher 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 associationbetween fiber intake and symptomatic diverticular disease was foundin this cohort4 indicates that we had a physiologically relevant measure of fiber intake.

Despite a relatively wide acceptance of the fiber-colon cancerhypothesis, evidence from epidemiological studies is weak. A metaanalysis of case-control studies of colon cancer demonstrated a com

bined odds ratio of 0.58 between highest and lowest quintiles based onfiber intake but a stronger odds ratio of 0.48 based on vegetableconsumption (77). These estimates, however, may be biased becauseof 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 thecase-control studies which examined sources of fiber separately, grain

fiber or cereal intake was either unrelated or positively associated withcolon cancer risk, whereas intake of fruits or vegetables was protective (3). Possibly, some specific component or type of fiber rather thantotal dietary fiber may be protective, or perhaps the influence of fiberoccurs during earlier stages of carcinogenesis. Several studies ofadenomatous precursors (60â€”63), including data from this cohort, dosupport a protective effect of fiber.

Alternatively, the lack of an association with cereal fiber intake andinverse associations between vegetable intake and malignancies atother sites where a direct influence of fiber is unlikely suggest thatchemopreventative factors in plant foods other than fiber may be theactive agents. We did not observe a statistically significant inverseassociation between intake of any single fruit or vegetable item andthe risk of colon cancer. The absence of strong associations betweenfruits and vegetables and colon cancer in this cohort and in the NHS

contrasts with findings in numerous case-control studies. One possibleexplanation is that the influence of the protective agent(s) occurs atdeficient or very low intakes and that consumption of fruits andvegetables in these self-selected cohorts is considerably higher thanthat in general population studies. A recent report from a cohort studyof women in Iowa also did not show a clear inverse association withfruit and vegetable intake (78). Of note, garlic was the specificvegetable item with the strongest inverse association with risk ofcancer of the distal colon, a finding remarkably similar to that observed in the Iowa women (78). Garlic and other allium vegetablesincluding 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). Asvery little study has been conducted regarding allium compounds andcancer in humans, this finding requires further investigation.

In summary, these findings provide further evidence for the hypothesis that consumption of red meat increases the risk of coloncancer, the second leading cause of death from malignancies in theUnited States (80). Major sources of protein and fat other than redmeat do not appear to have this deleterious effect. These data providedirect support for existing dietary recommendations to substitute fishand poultry for red meat (56, 57).

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ACKNOWLEDGMENTS

We are indebted to Mira Koyfman, Mildred Wolff, Elizabeth Frost-Hawes,KerryPillsworth,CindyDyer,Jan Vomacka,andJill Arnoldfor experthelp.

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1994;54:2390-2397. Cancer Res Edward Giovannucci, Eric B. Rimm, Meir J. Stampfer, et al. Cancer in MenIntake of Fat, Meat, and Fiber in Relation to Risk of Colon

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