A SIGMOIDOSCOPY-BASED CASE–CONTROL STUDY OF POLYPS:MACRONUTRIENTS, FIBER AND MEAT CONSUMPTION

Robert W. HAILE1*, John S. WITTE2, Matthew P. LONGNECKER3, Nicole PROBST-HENSCH1, Miao-Jung CHEN4, Janice HARPER1,Harold D. FRANKL5 and Eric R. LEE6

1Department of Preventive Medicine, USC School of Medicine, University of Southern California, Los Angeles, CA, USA2Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH, USA3NIEHS Epidemiology Branch, Research Triangle Park, NC, USA4Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA, USA5Kaiser Permanente Sunset, Los Angeles, CA, USA6Kaiser Permanente, Bellflower CA, USA

We conducted a large, sigmoidoscopy-based case–controlstudy to examine the relation of intake of macronutrients,meat, and fiber to occurrence of adenomas of the largebowel. Cases were subjects diagnosed for the first time withone or more histologically confirmed adenomas. Controlshad no polyps of any type at sigmoidoscopy, had no history ofpolyps, and were individually matched to cases by gender,age, date of sigmoidoscopy, and Kaiser Center. The responserate was 84% for cases and 82% for controls. Complete dietarydata for 488 matched pairs were available. All odds ratios arefrom matched analyses adjusted for energy. We observedpositive associations with risk of adenomas for calories,animal fat, saturated fat, red meat, and the ratio of red meatto poultry and fish. Protective effects were observed forvegetable protein, carbohydrates, and dietary fiber. The fibereffects diminished after adjusting for fruits and vegetables.Results after mutually adjusting for the effects of saturatedfat, fiber and the ratio of red meat to chicken and fish suggestthat each of these variables has an effect on risk of adenomasthat is independent of the other 2 exposures. Int. J. Cancer73:497–502, 1997.r 1997 Wiley-Liss, Inc.

Colorectal cancer is the second leading cause of cancer death inthe United States (American Cancer Society, 1995). It is generallyaccepted that adenomas are precursor lesions for the vast majorityof colorectal cancers (Morson, 1974). There are a number ofadvantages to studying adenomas as the endpoint of interest insteadof colorectal cancer in epidemiologic studies. It is possible to selectsubjects who are relatively asymptomatic so that symptoms do notcause a change in diet, which could affect recall of past diet. Theadenomas are small enough that in general they should notthemselves cause symptoms. The induction period for adenomas isshorter than for colon cancer, so one may study exposures closer intime to the date of diagnosis.

Despite the importance of adenomas as a precursor lesion andthe advantages gained by studying them, there have been relativelyfew studies of dietary risk factors for polyps. Most of our leads onwhat to study have come from studies of colorectal cancer. Instudies of colorectal cancer, increased consumption of vegetables(and to a lesser extent, fruits) and sources of fiber have beenconsistently associated with a decreased risk (Potteret al., 1993).Increased consumption of fat (particularly saturated fat), proteinand red meat have generally been associated with an increased risk,although 2 cohort studies (Bosticket al., 1994; Goldbaumet al.,1994) did not observe an effect for red meat or fat. In the studies ofdiet and adenomas that have been reported to date (Sandleret al.,1993; Giovannucciet al., 1992; Neugutet al., 1993; Macquart-Moulin et al.,1987; Kuneet al.,1991; Hoffet al.,1986; Konoetal., 1991, 1993; Littleet al.,1993a,b), a generally similar pattern isemerging with respect to the macronutrients and fiber, althoughmore specific associations (e.g.,with specific types of fat and typesof fiber) are much less clear. It is also not clear from publishedstudies if the effects of fat, red meat and fiber are independent ofeach other. We present here results of a relatively large, sigmoidos-copy-based case–control study of adenomas of the large bowel,

with a focus on macronutrients, meat and fiber. The sample sizewas sufficiently large to enable us to address the question ofindependence of effects.

SUBJECTS AND METHODS

Subjects were eligible for the study if they underwent screeningsigmoidoscopy at either of 2 Southern California Kaiser Perman-ente Medical Centers (Bellflower and Sunset) from January 1,1991, through August 25, 1993. Eligible men and women wereaged 50–74 years; they were free of invasive cancer, inflammatorybowel disease and familial polyposis; they were fluent in English;they had no previous bowel surgery; they were residents of LosAngeles or Orange County; and they had no physical or mentaldisability precluding an interview. In addition, a small number ofsubjects who had significant gastro-intestinal symptoms (deter-mined from medical records) were excluded. Given the ages of oursubjects, we did not consider occasional gas or infrequent bloodnoticed with a bowel movement as grounds for exclusion. Caseswere subjects diagnosed for the first time with 1 or morehistologically confirmed adenomas. Controls had no polyps of anytype at sigmoidoscopy, had no history of polyps, and wereindividually matched to cases by gender, age (within 5-yr cat-egory), date of sigmoidoscopy (within 3-month category) andKaiser Center. Recruitment of subjects began after appropriateinstitutional review board (IRB) approvals were obtained. Allsubjects signed a written informed consent form approved by theIRB.

During the accrual period, we identified 628 cases and 689controls who were potentially eligible. Of these, 70 cases and 94controls refused interview, and we were unable to contact 29 casesand 32 controls. Thus, we obtained interview data for 529 cases and563 controls. The response rate (number interviewed/numbereligible) was 84% among cases and 82% among controls. If thecontrol initially matched to a case was not interviewed, a replace-ment control was identified.

Among interviewed subjects, the indications for sigmoidoscopywere routine for 45% of cases and 44% of controls, referred due tospecific minor symptoms for 16% of cases and 13% of controls andwere not given for 39% of cases and 43% of controls. The averagedepth of penetration of the flexible sigmoidoscope was 55 cm forcases (standard deviation [SD] 11 cm) and 59 cm for controls (SD 5

Contract grant sponsor: National Cancer Institute; Contract grant num-bers: CA66794, CA51923; Contract grant sponsor: Swiss League AgainstCancer.

*Correspondence to: USC/Norris Comprehensive Cancer Center, Depart-ment of Preventive Medicine, 1441 Eastlake Avenue MS #44, P.O. Box33800, Los Angeles, CA 90033-0800, USA. Fax: (213) 764-0140. E-mail:haile@hsc.usc.edu

Received 24 March 1997; Revised 4 July 1997

Int. J. Cancer:73,497–502 (1997)

r 1997 Wiley-Liss, Inc.

Publication of the International Union Against CancerPublication de l’Union Internationale Contre le Cancer

cm). Fifteen cases had carcinomain situ in addition to adenomas.The size and number of polyps was indicated on a study formcompleted by the sigmoidoscopist.

Participants provided data on smoking, therapeutic drug use,physical activity, height, weight, family history of cancer and otherfactors during a 45-min in-person interview. The interview wasadministered in the subjects’ homes on average 5 months aftersigmoidoscopy. The interviewer remained unaware of participants’case and control status for 70% of cases and 87% of controls.

Five hundred nineteen cases and 556 controls completed a126-item semi-quantitative food frequency questionnaire (Rimmetal., 1992) that inquired about diet in the year before sigmoidos-copy. The questionnaire was mailed; it was to be completedbeforehand and then reviewed and collected at the time of theinterview. Standard methods were used to calculate nutrient intake(Willett, 1990). Specific foods corresponding to items on thequestionnaire were selected based on the relative frequency ofconsumption among participants in the 1988–1989 NationwideFood Consumption Survey (US Department of Agriculture Nutri-tion Monitoring Division, 378, 1991), southwest region; theNutrition Data System (NDB V2.4) (Schakelet al.,1988) was usedas a nutrient database for foods. Data on the nutrient content ofsupplements was obtained from the Harvard School of PublicHealth (L. Sampson, personal communication, 1992).

The present analysis was restricted to matched pairs withcomplete dietary data. Unmatched controls occurred when, forexample, the case to whom they were matched was found not tospeak English (n5 41) or was found to have invasive large bowelcancer at follow-up colonoscopy (n5 16). Unmatched casesoccurred when we were unable to interview a correspondingeligible control.

We used conditional logistic regression to estimate matchedodds ratios across quintiles, adjusting for the following covariates:ethnicity, (white, Africa-American, Asian, Hispanic), body massindex (#27.5 kg/m2 vs. .27.5), smoking (never, past, current),vigorous leisure time activity (continuous as MET-hr/week) andenergy (continuous as calories). The residual energy adjustmentapproach was used; using the standard or decomposition ap-proaches yielded results similar (slightly stronger) to those pre-sented below. Nineteen subjects with missing or ‘‘other’’ ethnicvalues were assumed to be white. One control missing body massindex was given the mean value for controls. If family history ofcolorectal cancer was missing (12% of subjects), we assigned acategory of no such history. As a test for trend in effect acrosscategories, we used the two-sidedp values associated with acoefficient fit to the ordinal value of the category.

RESULTS

Overall, 650 men (325 matched pairs) and 326 women (163matched pairs) were included in the analyses. Characteristics ofthis study population are provided in Table I. The mean age ofsubjects was 62 years. Fifty-five percent were white, 17% African-American, 17% Hispanic and 11% Asian. Cases had higher meandaily intakes of calories, fat, protein, carbohydrates, cholesteroland sugar and had lower mean intakes of fiber.

Energy intake was associated with increased prevalence ofadenomas (Table II). The odds ratio comparing the highest tolowest quintile was 1.76 (95% confidence interval [CI] 1.14–2.72;p value for trend5 0.01). There was also a weak association withfat consumption. Stronger associations were observed with intakeof animal fat and saturated fat. For carbohydrates, the odds ratiocomparing the highest to lowest quintile was 0.68 (95% CI0.43–1.06). There was no apparent increase in risk for intake oftotal or animal protein. Intake of vegetable protein was protective.When the total protein variable was split into red meat proteinvs.

other protein, we observed an increase in risk with consumption ofred meat protein (e.g., odds ratio comparing highestvs. lowestquintile 5 1.51 [95% CI 0.98–2.33],p for trend5 0.04) and aprotective effect for other (non-red meat) protein (e.g.,odds ratiocomparing highest to lowest quintile5 0.54 [95% CI 0.35–0.84],ptrend, 0.01).

Consumption of red meat was associated with increased risk ofadenomas (Table III). A similar trend was observed with intake ofbeef. Eating chicken or fish appeared to be protective. Thestrongest odds ratios were observed for the ratio of red meat tochicken and fish, where the odds ratio comparing the highest tolowest quintile was 1.86 (95% CI 1.19–2.90;p value fortrend, 0.01).

Consumption of dietary fiber appeared to be protective (TableIV). We also investigated the separate effects for vegetable, fruitand grain fiber. All 3 appeared to be protective, although thestrongest effects were observed for vegetable fiber (Table IVA). In asecond analysis (Table IVB), we also adjusted for fruit andvegetable intake. After this adjustment, the effects for dietary fiber,fruit fiber and vegetable fiber were weaker and non-significant.

Finally, we present the results for saturated fat, dietary fiber andthe ratio of red meat to chicken and fish, each mutually adjusted forthe other variables (Table V). All three variables appeared to retainsome effect on risk of adenomas. In fact, the effect of saturated fatincreased from 1.44 (Table II) to 2.33 (95% CI 1.10–4.93).

TABLE I – CHARACTERISTICS OF STUDY POPULATION (488 MATCHED PAIRS)1

Cases Controls

Mean age 61.9 (6.7) 61.8 (6.8)Gender—male (%) 66.6 66.6Ethnicity (%)

White 55.3 53.9Black 15.8 17.8Hispanic 17.2 17.6Asian 11.7 10.7

Body mass index, (%.27 kg/m2) 49.0 41.7Alcohol (g/day) 10.2 (20.1) 7.4 (14.7)Smoking (%)

Current 21.7 12.1Never 34.4 42.8Former 43.9 45.1

Physical activity (MET-hr/week)(%)

0 76.8 67.41–13 11.7 14.2.13.9 11.5 18.4

Colorectal cancer in family (%) 8.6 10.5Non-steroidal anti-inflammatory

drug use (%)28.1 32.8

Mean daily dietary intakesTotal energy (cal) 2047 (842) 1922 (804)Fat (g)

Total 72.3 (34.9) 65.0 (33.7)Animal 37.4 (21.3) 33.1 (21.7)

Vegetable 34.8 (20.6) 31.9 (18.5)Saturated 25.2 (13.0) 22.2 (12.3)Monounsaturated 26.7 (13.3) 23.7 (13.1)Polyunsaturated 14.5 (7.8) 13.5 (7.5)

Protein (g)Total 80.5 (34.6) 78.3 (33.7)Animal 55.5 (27.5) 52.9 (26.9)Vegetable 24.2 (11.6) 24.6 (11.5)

Carbohydrates (g) 259 (122) 252 (116)Fiber (g)

Total dietary 19.1 (9.6) 20.1 (9.7)Vegetable 6.9 (4.6) 7.4 (4.8)Fruit 4.4 (4.6) 4.7 (3.8)Grain 5.6 (4.0) 6.1 (4.9)

Cholesterol (mg) 252 (139) 222 (131)

1For means, standard deviations are given in parentheses.

498 HAILE ET AL.

DISCUSSION

We focused on macronutrients, meat consumption and fiber. Weobserved an increased prevalence of adenomas of the large bowelassociated with increased consumption of fat (particularly animalfat and saturated fat), red meat and beef and a higher ratio of redmeat to poultry and fish. Apparent protective effects were observedfor increased consumption of carbohydrates, vegetable protein and

fiber, especially vegetable fiber. Controlling for consumption offruits and vegetables weakened the apparent protective effect offiber.

Giovannucciet al. (1992) have reported results of a cohortanalysis of diet and colorectal adenomas. As in our study, theirresults were also limited to left-sided adenomas because controlsmost often underwent a sigmoidoscopy as opposed to a colonos-

TABLE II – RISK OF COLORECTAL POLYP BY QUINTILE FOR INTAKE OF TOTAL ENERGY AND MACRONUTRIENTS1

Quintile2p fortrend3

1 2 3 4 5

Total energy, Kcal/day 1100 1510 1852 2261 3082OR 1.00 0.89 0.95 1.22 1.76 0.0195% CI 0.58–1.35 0.63–1.45 0.80–1.87 1.14–2.72

Total fat 49.1 62.6 69.9 76.9 89.8OR 1.00 1.12 1.46 1.40 1.40 0.0695% CI 0.73–1.72 0.94–2.26 0.92–2.12 0.91–2.16Animal fat 18.8 28.5 34.4 40.5 52.5

OR 1.00 1.59 1.65 1.81 1.52 0.0495% CI 1.02–2.46 1.04–2.60 1.15–2.87 0.97–2.37

Vegetable fat 20.2 28.1 33.3 38.6 48.7OR 1.00 1.68 1.38 1.32 1.35 0.2495% CI 1.10–2.56 0.90–2.12 0.86–2.01 0.89–2.06

Saturated fat 15.5 20.5 23.6 26.6 32.0OR 1.00 1.19 1.75 1.75 1.44 0.0295% CI 0.77–1.83 1.13–2.72 1.14–2.69 0.93–2.24

Monounsaturated fat 17.3 22.4 25.5 28.6 34.0OR 1.00 1.04 1.27 1.95 1.13 0.0895% CI 0.68–1.60 0.83–1.93 1.25–3.02 0.74–1.72

Polyunsaturated fat 9.2 11.9 13.5 15.5 18.7OR 1.00 1.09 0.93 1.05 0.92 0.7195% CI 0.70–1.69 0.60–1.45 0.68–1.62 0.58–1.44

Protein 60.4 72.4 79.1 86.3 97.9OR 1.00 0.89 0.81 0.60 0.81 0.0895% CI 0.57–1.39 0.53–1.23 0.39–0.92 0.53–1.25

Animal protein 33.4 46.1 53.5 60.7 74.5OR 1.00 1.10 1.00 0.82 0.95 0.4695% CI 0.71–1.70 0.64–1.57 0.53–1.27 0.62–1.45

Vegetable protein 16.5 21.4 24.1 27.1 32.3OR 1.00 0.56 0.86 0.54 0.49 ,0.0195% CI 0.36–0.87 0.55–1.34 0.35–0.84 0.32–0.76

Carbohydrates 193 234 255 277 313OR 1.00 0.80 0.95 0.93 0.68 0.2095% CI 0.53–1.23 0.61–1.49 0.60–1.45 0.43–1.06

1Adjusted for matching variables, body mass index, calories (to mean intake of 1,984 calories), physicalactivity, smoking and ethnicity.–2For each macronutrient, the first row gives the energy adjusted median ofquintiles in g per day.–3p value for slope of parameter corresponding to quintiles.

TABLE III – RISK OF COLORECTAL POLYP BY QUINTILE FOR INTAKE OF RED MEAT, CHICKEN AND FISH AND RATIOOF RED MEAT TO CHICKEN AND FISH1

Quintile2p fortrend3

1 2 3 4 5

Red meat 78.5 211 378 644 1083OR 1.00 1.26 1.79 1.40 1.62 0.02

95% CI 0.83–1.89 1.19–2.70 0.91–2.16 1.00–2.63Beef 42.5 155 310 548 930

OR 1.00 1.67 1.70 1.73 1.83 0.0495% CI 1.10–2.54 1.13–2.58 1.15–2.60 1.12–2.99

Processed meat 0.0 13.5 39.0 81.0 175OR 1.00 1.07 1.32 1.06 1.48 0.1895% CI 0.71–1.62 0.87–2.00 0.70–1.60 0.92–2.39

Chicken, fish 148 319 435 632 1032OR 1.00 1.06 0.92 0.80 0.60 0.0395% CI 0.71–1.60 0.61–1.38 0.52–1.22 0.38–0.94

Red meat/chicken, fish4 0.1 0.5 0.9 1.6 3.9OR 1.00 1.59 1.40 1.86 1.86 ,0.0195% CI 1.05–2.42 0.91–2.15 1.20–2.88 1.19–2.90

1Adjusted for matching variables, body mass index, calories, physical activity, smoking and ethnicity.–2For each meat, first row gives median of quintiles in g per week.–3p value for slope of parametercorresponding to quintiles.–4Ratio of red meat consumption to chicken and fish consumption.

499POLYPS: MACRONUTRIENTS, FIBER, AND MEAT

copy, which would have examined the entire colon. Saturated fatwas positively associated with risk of adenomas with a relative risk(RR) for the highestvs. lowest quintile of intake5 2.0 (1.2–3.2;pfor trend5 0.006). Dietary fiber was inversely associated with riskwith an RR for highestvs.lowest quintile5 0.36 (0.22–0.60;p fortrend, 0.0001). Each source of fiber (vegetables, fruits andgrains) was associated with a protective effect. The fiber effect wasthe strongest of the dietary factors examined in their study. Ourhighest quintile of fiber was lower than their highest quintile (24vs.28.3 g/day as the lower bound), and our highest quintiles for animaland saturated fat were higher (45 and 29 g/day, respectively,compared with 39 and 23.5 g/day). For subjects in the Giovannucciet al. (1992) study eating a high–saturated-fat, low-fiber dietcompared with those eating a low–saturated-fat, high-fiber diet, theOR was 3.7 (1.5–8.8). The comparable estimate from our data is2.5 (1.3–4.7). In their study, increased consumption of carbohy-drates was also associated with a protective effect. In addition,consumption of red meat and a higher ratio of red meat to chicken

and fish were positively associated with risk (e.g.,the p for trendfor the ratio effects5 0.02, with an RR for the highestvs. lowestquintile 5 1.83 [1.12–3.00]). In general, our results were verysimilar to the results from this cohort study. Both studies focussedon effects on left-sided adenomas. Their study had the advantage ofobtaining information on diet before diagnosis. In our study, wewere able to limit subjects to relatively asymptomatic individuals,and most interviews were conducted in a blinded manner; thus,differentially misclassified assessment of prior diet should havebeen minimized. We were also able to mutually adjust for theeffects of saturated fat, fiber and the ratio of red meat to chicken andfish, and our results suggest that each of these variables has anindependent effect on the risk of polyps.

Other informative case–control studies of adenomas have to datebeen colonoscopy based (Sandleret al.,1993; Neugutet al.,1993).Sandleret al. (1993) and have reported that carbohydrate intakewas inversely related to risk in women; odds ratio for highestvs.

TABLE IV – RISK OF COLORECTAL POLYP BY QUINTILE FOR INTAKE OF FIBER1

Quintile2p fortrend3

1 2 3 4 5

A.Dietary fiber 12.1 16.0 18.7 22.0 27.6

OR 1.00 0.83 0.82 0.55 0.52 ,0.0195% CI 0.53–1.30 0.52–1.30 0.35–0.85 0.33–0.80

Vegetable fiber 3.1 5.1 6.5 8.3 11.8OR 1.00 0.71 0.50 0.48 0.48 ,0.0195% CI 0.45–1.13 0.31–0.81 0.31–0.76 0.31–0.75

Fruit fiber 0.9 2.5 3.7 5.4 8.6OR 1.00 0.90 0.84 0.70 0.68 0.0595% CI 0.57–1.42 0.54–1.31 0.45–1.08 0.43–1.07

Grain fiber 2.6 3.9 5.1 6.8 9.7OR 1.00 0.82 0.96 0.72 0.71 0.0895% CI 0.53–1.28 0.62–1.49 0.47–1.10 0.46–1.08

B.4Dietary fiber

OR 1.00 0.95 0.99 0.75 0.85 0.4095% CI 0.60–1.51 0.61–1.59 0.46–1.23 0.48–1.49

Vegetable fiberOR 1.00 0.79 0.60 0.65 0.77 0.1695% CI 0.49–1.26 0.37–0.97 0.39–1.06 0.45–1.34

Fruit fiberOR 1.00 1.06 1.12 1.07 1.34 0.4495% CI 0.67–1.70 0.70–1.80 0.66–1.75 0.76–2.38

Grain fiberOR 1.00 0.83 0.97 0.77 0.71 0.1195% CI 0.53–1.30 0.62–1.52 0.50–1.19 0.46–1.09

1Adjusted for matching variables, body mass index, calories (to mean intake of 1,984 calories), physicalactivity, smoking and ethnicity.–2For each source of fiber, the first row gives the energy adjusted median ofquintiles in g per day.–3p value for slope of parameter corresponding to quintiles.–4Also adjusted for fruitand vegetable intake.

TABLE V – RISK OF COLORECTAL POLYP BY QUINTILE FOR MUTUALLY ADJUSTED DIETARY FACTORS1

Quintile2p fortrend3

1 2 3 4 5

Saturated fat (g/day) 10.61.00

15.71.48

21.41.83

28.11.32

40.22.33 0.06

0.94–2.32 1.13–2.94 0.76–2.27 1.10–4.93Red meat/chicken, fish4 0.1

1.000.51.54

0.91.29

1.61.61

3.91.60 0.05

1.01–2.35 0.83–2.01 1.00–2.59 0.98–2.61Dietary fiber (g/day) 9.7

1.0014.20.72

18.10.72

22.60.51

30.60.46 0.01

0.46–1.10 0.46–1.14 0.31–0.84 0.26–0.84

1Adjusted for matching variables, body mass index, calories, physical activity, smoking, ethnicity and allother variables in the model.–2For each exposure, first row gives median of quintiles.–3p value for slope ofparameter corresponding to quintiles.–4Ratio of red meat consumption to chicken and fish consumption.

500 HAILE ET AL.

lowest quintile5 0.39 (0.19–0.80) (p for trend5 0.002). Intake offiber derived from fruits and vegetables also appeared to beprotective, particularly in women. Total fat (odds ratio5 2.69,CI 5 1.31–5.50 for highestvs. lowest quintile) and saturated fat(odds ratio5 2.05, CI5 1.00–4.20) were positively associatedwith risk in women. A higher beef to chicken and fish ratio was alsopositively associated with risk in women (odds ratio5 2.51,CI 5 1.15–5.48 for highestvs. lowest quintile). Generally, effectsin men were in the same direction as in women but were notstatistically significant (there were fewer male subjects). Theprotective effects of fiber were generally not as strong as we andGiovannucciet al. (1992) observed. As they note, the mean fiberintake of their subjects was lower (13.5 g/dayvs.21 in their studyvs.19–20 in ours), which may have limited their ability to detectfiber effects. Neugutet al. (1993) reported results similar to thoseof Sandleret al. (1993). The study was conducted in New YorkCity. For women, there was an increased risk associated withsaturated fat (odds ratio5 2.3) and a higher ratio of meat tochicken and fish. There appeared to be a weak protective effectfrom total fiber (odds ratio5 0.9).

Hoff et al. (1986) reported results from a sigmoidoscopy-basedstudy of asymptomatic subjects in Norway that is quite similar indesign to our study. They reported that total dietary fat waspositively associated with risk of polyps and observed a trendtoward higher intake with increasing size of the polyp. They alsoreported that intake of fiber and carbohydrates were protectiveamong both men and women with adenomas 5 mm or larger. Weobserved no substantial differences in our results between men andwomen or by size of the polyp (#1 cm vs..1 cm; results notshown).

A number of characteristics about the current study are worthnoting. It is one of the largest studies of colorectal adenomas todate. We restricted the study to subjects who were largelyasymptomatic and who were ascertained through sigmoidoscopy.Cases had a first-time diagnosis of adenomas, and controls had anegative sigmoidoscopy and no history of polyps. Interviews wereconducted in person in the subjects’ homes, and the interviewerswere blinded to case–control status for the vast majority ofinterviews. Also, our response rates were relatively high (84% forcases and 82% for controls). We believe these characteristicshelped to minimize any potential selection and information biases.The concern with colonoscopy-based studies is that symptoms mayhave led to the colonoscopy. These same symptoms may havecaused a change in diet or other exposures of interest (e.g.,aspirin),which may affect recall of past exposures in case–control studies.These concerns are reduced in our study. On the other hand,because our study is sigmoidoscopy based, the entire colon is notexamined in controls. Approximately 15–17% (Rexet al., 1993;Foutchet al.,1991) of subjects with no family history who have nopolyps detectable by sigmoidoscopy may have one or more polypsbeyond the reach of a sigmoidoscope. If we assume that theetiology of left- and right-sided adenomas is different, as suggestedby some of the epidemiologic and molecular results (Potteret al.,1993), then our study addresses only risk factors for left-sided

adenomas. If the etiology is similar between left- and right-sidedadenomas, then our results would probably be slightly biased to thenull due to misclassification of adenoma status.

The other issue that one should address in any study of polyps isthe issue of prevalencevs. incidence (and durationvs. etiologiceffects). Unless preceded by previous negative results of sigmoidos-copy or colonoscopy, most polyps that are diagnosed are prevalent.Consequently, any effects one observes may be due to associationswith etiology or duration. In the extreme (and unlikely) case, if afactor has nothing to do with causing a polyp but speeds upprogression of that polyp to colorectal cancer after it has formed, itcould appear to be protective (i.e., less prevalent in the cases thanthe controls). We therefore stratified our results by history of a priornegative sigmoidoscopy and by size of the polyp. We did notobserve substantial differences in results from those presented.

We believe that the results of our study add to the evidence fromstudies with varying designs that fat intake (particularly animal orsaturated fat) and consumption of red meat are associated with anincreased risk of adenomas. Likewise, evidence is growing thatconsumption of fiber (or fruits and vegetables) and carbohydrates isassociated with protective effects. It is less clear whether totaldietary fiber from all sources or specific sources is most stronglyassociated with reduced risk or whether part or all of the fiber effectis due to consumption of fruits and vegetables and protectiveconstituents other than fiber.

One hypothesis to explain the fat/red meat effect involves theproduction of secondary bile acids and their carcinogenic effects(Potter et al., 1993). Another hypothesis focusses more on themethods of cooking meat and the production of heterocyclicamines, which may be metabolized to carcinogenic compounds.Some epidemiologic evidence indicates that fast acetylators, asdetermined by NAT2 phenotypes, are at increased risk of colorectalcancer. A fast acetylator effect would be consistent with at least partof the red meat effect being due to the heterocyclic amines. AsPotter et al. (1993) note, however, the 2 hypotheses are notmutually exclusive and both are supported by some experimentaland epidemiologic data. The protective effect of fiber is the otherconsistent finding. As Potteret al. (1993) note, fiber may bind bileacids, reduce transit time, increase stool bulk, ferment to volatilefatty acids that may be anticarcinogenic and reduce the conversionof primary to secondary bile acids by lowering stool pH.

In summary, our results generally add to others that suggest adiet high in fat and red meat and low in fiber (or fruits andvegetables) and carbohydrates is associated with an increased riskof polyps, the major precursor lesion for colorectal cancer, and thatthese effects appear to be independent of each other. The effects ofspecific components of fat, red meat and fiber await furtherclarification from both experimental and epidemiologic studies.

ACKNOWLEDGMENTS

We are grateful to Mrs. E. Harmon and S. Higginbotham for theirwork on this study. N. P.-H. was supported in part by a fellowshipfrom the Swiss League Against Cancer.

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