ICANCER RESEARCH57. 4787-4794, November 1, 1997) Associations of Sedentary Lifestyle, , Smoking, Alcohol Use, and with the Risk of Colorectal '

LoIc Le Marchand,2 Lynne R. Wilkens, Laurence N. Kolonel, Jean H. Hankin, and Li-Ching Lyu

Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813

ABSTRACT in the etiology of colorectal . , both at work and during leisure time, has consistently been inversely associated Variation in rates between countries and within eth with this disease (6—23).A direct association between caloric intake mc groups upon migration and/or Westernization suggests a role for some and colorectal cancer has also been found in some studies and has aspects of Western lifestyle in the etiology of this disease. We conducted a population-based case-control study in the multiethnic population of appeared to be independent of the dietary energy source (15, 16, Hawaii to evaluate associations between colorectal cancer and a number 24—31). Data on obesity and colorectal cancer have been inconsistent, of characteristics of the Western lifestyle (high caloric Intake, physical especially in women (32). Few studies have considered energy intake, inactivity, obesity, smoking, and drinking) and some of their associated energy expenditure, and in combination, although it has . We interviewed in person 698 male and 494 female United been suggested that these factors act in concert (33). States-born or immigrant Japanese, Caucasian, Filipino, Hawaiian, and Western lifestyle is known to often result in a host of other condi Chinese patients diagnosed in 1987-1991 with colorectal cancer and 1192 tions (e.g., diabetes, , dyslipidemia, coronary heart dis population controls matched on age, sex, and ethnicity. Conditional logis ease, gallbladder disease, arthritis, and constipation) that would be tic regression was used to estimate odds ratios adjusting for dietary and expected to aggregate in colorectal cancer patients. It is also associ nondietary risk factors. Place of birth and duration of residence in the ated with a number of lifestyle habits (e.g., smoking and drinking) that United States were unrelated to colorectal cancer risk. Energy intake (independent of the calorie source) and were directly are suspected to be risk factors for the disease and, thus, may act as associated with risk, and lifetime recreational physical activity was in confounders of the energy balance-colorectal cancer association. versely associated with risL The associations with these factors were We report here on the findings for energy intake and expenditure, independent of each other, additive (on the logistic scale) and stronger in body size, smoking, drinking, and “Westerndiseases―from a large men. When individuals were cross-categorized in relation to the medians population-based case-control study of colorectal cancer conducted in of these variables, those with the higher energy intake and body mass Hawaii among ethnic groups with different risks for the disease. index and lower physical activity were at the highest risk (for males, OR, Specific dietary factors associated with colorectal cancer risk in this 3.0; 95% confIdence interval, 1.8—5.0, and for females, OR, 1.7; 95% study were reported elsewhere (3 1, 34). confidence interval, 1.0—3.2). Smoking in the distant, as well as recent, past and alcohol use were directly associated with colorectal cancer in both sexes. Individuals with a history of diabetes or frequent constipation MATERIALS AND METHODS were at increased risk for this cancer, whereas past diagnosis of hyper cholesterolemia was inversely associated with risL The findings were Patients were identified in all main hospitals on the island of Oahu, Hawaii, consistent between sexes, among ethnic groups, and across stages at by the rapid-reporting system of the Hawaii Tumor Registry, a member of the diagnosis, making bias an unlikely explanation. These results confirm the Surveillance, Epidemiology, and End Results Program of the National Cancer data from immigrant studies that suggest that the increase in colorectal Institute. Eligible cases were all Oahu residents who had been diagnosed cancer risk experienced by Asian immigrants to the United States oc between 1987 and 1991 with histologically confirmed adenocarcinoma of the curred in the first generation because we found no difference in risk large bowel. Only patients who had any percentage of native Hawaiian between the immigrants themselves and subsequent generations. They ancestry or at least were 75% Japanese, Caucasian, Filipino, or Chinese were also agree with recent findings that suggest that high energy intake, large included. Patients with a history of previous coloreclal cancer or who were body mass, and physical inactivity Independently increase risk of this over 84 years at diagnosis were excluded. An interview was completed for disease and that a nutritional imbalance, similar to the one involved in 66% (698 men and 494 women) of the eligible cases. The main reasons for diabetes, may lead to colorectal cancer. nonparticipation were before contact (15%), refusal (I I%), severe illness (5%), and inability to locate (3%). INTRODUCTION Controls were randomly selected from a list of Oahu residents interviewed by the Hawaii State Department of as part of a health survey based on Colorectal cancer is predominantly a disease of Westernized coun a 2% random sample of state households. One control was matched to each tries, with about two-thirds of the world cases occurring in developed case on sex, ethnicity, and age within ±2.5 years, using age at diagnosis for nations (1). Rates in immigrants from low-risk areas to these high-risk cases and age at interview for controls. Controls with a previous history of colorectal cancer were excluded. The overall participation rate for the controls areas are known to rapidly increase to the level of the host population was 71%. Reasons for nonparticipation included refusal (18%), inability to (e.g., in Japanese immigrants to the United States; Refs. 2—4).Rates locate (5%), serious illness (3%), and death (3%). in countries undergoing Westernization have also been increasing Interviews were conducted in person, at the subjects' homes, by trained markedly (e.g., in Japan; Ref. 5). interviewers. Generally, members of a case-control pair were interviewed by Thus, some aspects of Western lifestyle, primarily a high caloric the same interviewer. The questionnaire included detailed demographic infor intake and little physical activity, resulting in a positive energy bal mation, including country of birth, number of years spent in the United States, ance, weight gain and, ultimately, obesity, are suspected to play a role and ethnicity of each grandparent; a quantitative food frequency questionnaire; a lifetime history of tobacco and alcohol use; a personal history of various Received 5/14/97; accepted 9/9/97. relevant medical conditions; a family history of colorectal cancer; a history of The costs of publication of this article were defrayed in part by the payment of page constipation and laxative use; information on height and weight at different charges. This article must therefore be hereby marked advertisement in accordance with ages; and a history of recreational sport activities since age 18, including the 18 U.S.C. Section 1734 solely to indicate this fact. type, frequency, and duration of the activities. Usual physical activity was also @ This research was supported in part by NIH Grant P0l-CA-33619 and contract assessed using an adaptation of the Five-City Project questionnaire (35). This NOl-CN-05223 from the National Cancer Institute. 2 To whom requests for reprints should be addressed, at Etiology Program, Cancer method was selected because, when compared to seven other physical activity Research Center of Hawaii, 1236 Lauhala Street, Suite 407, Honolulu, HI 96813. questionnaires, it yielded an average estimate of total caloric expenditure that 4787

Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1997 American Association for Cancer Research. WESTERNLIFESTYLEANDCOLORECTALCANCER most closely approximated caloric intake (96%; Ref. 36). With this method, we Quetelet index 5 years ago; total caloric intake, and dietary fiber, calcium and inquired about the numbers of hours and minutes spent in light, moderate, and egg intake. intense activities, as well as sifting and sleeping, during a typical weekday and We performed likelihood ratio tests comparing models with and without a weekend day during the diet reference period (see below). Cue cards listing trend variable to determine linearity in the logit of colorectal cancer risk across examples of light, moderate, and intense activities were used to help respon dietary intake levels. The trend variable was assigned the median value of each dents to classify the intensity level of their physical activity at home, work, and quantile of dietary intake. We also used likelihood ratio tests to determine leisure. Several days prior to the interviewer's visit, subjects were mailed a interaction among certain variables with respect to colorectal cancer risk. self-administered lifetime occupational history to be filled out in advance of These tests compared a main effects, no interaction model with a fully the interview, documenting the job title, the type of industry, the dates of parameterized model containing all possible interaction terms for the variables employment, and the numbers of hours per week and months per year worked of interest. for each position held. The interviewer checked this form and obtained any The analysis was first conducted for each subsite of the large bowel (right missing information at the time of the interview. The interviewer also meas colon, proximal to the splenic flexure: 30% of the cases; left colon: 39% of the ured the waist and hip circumferences of the subjects at the end of the cases; rectosigmoid junction or rectum: 29% of the cases; the remaining 2% of interview. cases with unknown subsite were excluded from these analyses). The Surveil The food frequency questionnaire used in this study has been described lance, Epidemiology, and End Results summary staging classification was previously (31, 34, 37) and validated in this population (38). Frequencies and used in the stage-specific analyses: in situ tumors (9.4%) had remained amounts consumed were obtained for more than 280 food items or categories. intraepithelial; localized tumors (44.0%) were confined to the colon or rectum; The questionnaire was designed to include all foods commonly consumed in regional tumors (38.8%) had either extended through the muscularis to adja our population and to capture the complete diet, including total caloric intake. cent tissue or metastasized to regional mesenteric lymph nodes; and distant Participants reported their average frequencies of consumption and average tumors (7.0%) had metastasized to distant sites. portion sizes for those items eaten at least 12 times a year during the reference period, which was the 3-year period before onset of symptoms for cases and RESULTS the 3-year period before interview for controls. Color photographs of most food items, showing three different portion sizes, as well as measuring cups Table 1 presents the demographic characteristics of cases and and spoons, were used during the interview to facilitate quantification of controls by sex. Cases were less educated and were more likely to be intakes. The food composition data were primarily based on the nutrient single, divorced, or separated than controls in both sexes. In males, database of the United States Department of Agriculture (39) and supple cases were more often Buddhist and less often non-Catholic Christian mented with data from other primary sources and other research and commer than controls. Cases were more likely to have been regular smokers cial publications (40—43). (i.e., to have smoked daily for at least 6 months) and regular drinkers For lifetime recreational physical activity, two indices were computed; one (i.e. , to have drunk alcoholic beverages once a week for at least 6 was the sum of the time (in hours) spent in the reported activities since age 18; months) in the past than controls in both sexes. the other summed the products of duration and intensity of each activity over The adjusted odds ratios for most of these variables and selected all reported activities. An intensity value (in METs;3 1 MET = 1 Kcal/kg/h) past medical conditions are presented in Table 2. No association was was assigned to each activity using the extensive coding system in Ref. 44. An found with place of birth or length of residency in the United States. index of usual physical activity during the diet reference period was computed for a usual 24-h period by taking the weighted average of the products of the Education and religion were not significantly associated with risk duration (in minutes) and an intensity level (in METs) for each category of after adjustment for confounders (data not shown). Men who were activities over a weekday (multiplied by 5) and a weekend day (multiplied by single, divorced, or widowed were at a 3-fold increased risk for cancer 2). Sleeping was assigned an intensity level of 1 MET; , 1.5 MET; light of the right colon. Marital status was not associated with risk for the activities, 4 METs; moderate activities, 6 METs; and intense activities, 10 other subsites or in females. Former smokers were at somewhat METs. Occupational physical activity was assessed by assigning one of five increased risk of in the left colon and rectum for males and the levels of physical activity (sedentary, light, medium, heavy, and very heavy) to right colon and rectum for females. No association was found with each job as rated by the United States Department of Labor. Occupations held years since quitting. For all three subsites combined, the odds ratios before 1960 were coded according to Department of Labor physical require for increasing quartiles of pack-years of tobacco smoking were 1.0, ments published in 1956 (45). Physical activity ratings published in 1966 (46) 1.2, 1.1, and 1.6 (95% CI, 1.1—2.3;Pfor trend = 0.04) for males and were used to code the occupations held between 1960 and 1969. Those 1.0, 0.9, 1.0, and 1.6 (95% CI, 1.0—2.6;P for trend = 0.04) for published in 1981 (47) were used to rates jobs held after 1969. All physical females. This association was strongest for the left colon in males and activity coding was performed without knowledge of the case-control status of the subject. the right colon and rectum in females. Odds ratio estimates were Smokers and drinkers were considered as current users if they smoked or elevated for past regular drinkers for all subsites but especially for the drank up to the date of diagnosis for cases or the date of interview for controls. right colon in both sexes. Current drinkers were also at increased risk Lifetime tobacco use was computed as pack-years (packs/day X years of for cancer of the right colon in both sexes. For all subsites combined, smoking); cigarettes, pipes, and cigars were treated equivalently. For all the odds ratios for increasing quartiles of drink-years (numbers of analyses, we used conditional logistic regression models (48) to compute ORs drinks/day x duration of drinking in years) were 1.0, 1.5, 1.3, and 1.5 (and 95% CIs) for several levels of an exposure variable, with adjustment for (95%CI, l.l-.2.2;Pfortrend = 0.Il)formalesand 1.0, 1.2, l.6,and relevant covariates. Each matched case-control pair made up a stratum for the 1.6 (95% CI, 0.8—3.0;P for trend 0. 14) for females, respectively. logistic model. Quartile and tertile cutpoints were sex specific and based on This association with lifetime use of alcohol was strongest for the data from the controls. The sex-specific interquartile ranges for each contin right colon in both sexes and was not limited to any specific type of uous variable are presented in the table footnotes for comparison with other alcoholic beverage. A more detailed analysis of the association with populations. Exposure variables were adjusted by entry into the model of the alcohol and its interaction with nutrient intake will be given in a following variables found to be independently associated with risk (continuous unless otherwise specified): age (to account for a differential between cases separate report. and controls within the 5-year matching interval); family history of colorectal An increased risk of cancer in the left colon was observed with a cancer (using an indicator variable); number of alcoholic drinks per week; history of diabetes in both sexes, whereas hypercholesterolemia was pack-years of cigarette smoking; lifetime recreational activity (in hours); inversely associated with cancer risk at all subsites in both sexes. For all subsites combined, the odds ratios for history of diabetes was 1.2

3 The abbreviations used are: MET, metabolic equivalent; CI, confidence interval; OR, (95% CI, 0.8—1.7)in males and 1.8 (95% CI, 1.1—2.8)infemales. This odds ratio; BMI, body mass index. association was stronger when diabetes had been diagnosed at least 9 4788

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Table 1 Selected characteristics1987—1991@Males of colorectal cancer cases and controls bysex, Hawaii. (698 case-control pairs)Females pairs)Cases (494 case-control

(%)Age (%)Cases(%) Controls (%)Controls 656565Ethnicity(median in years)67

Japanese (50) 347 (50) (49) (49) Caucasian 180(26) 180(26) 116(23) 116(23) Filipino 70 ( I0) 70 ( 10) 50 ( I0) 50 ( I0) Hawaiian 52 (7) 52 (7) 42 (9) 42(9) 42(9)BiiihplaceChinese347 49(7) 49(7)244 42(9)244

UnitedStates 615(88) Asia 75(11) 75(11) 78(16) 80(16) 6(1)EducationOther614(88) 6(1) 6(1) 11(2)P=0.47402(82) P=l.Ob399(82)

None (16) 106(15) Catholic 156(22) 147(21) 123(25) 124(25) Other Christian 209 (30) 257 (37) 183 (37) 173 (35) Buddhist 213(31) 175(25) 149(30) 154(31) 3(l)SmokingOther111 5(1) 9(1) 3(1)P=0.9738(8) P=0.0435(7) status Never 217(31) Former 434(62) 364(52) 135(27) 102 (21) 64(13)DrinkingCurrent167(24) 97(14) 117(17) 60(12)P=0.05328(66) P=0.00l299(60) status Never (28) 248 (36) (74) (79) Former 226(33) 164(24) 62(13) 43(9) Current191 277 (40) 284 (41) 67 (14)P=0.ll388 62 (I3) P=0.OOl363

a Numbers do not always add up to total number of cases and controls because of missing values. @ a p@ were computed from the test of association.

years before diagnosis for cases or interview for controls [OR, 1.4 terms for the time periods 1—5,6—10,11—20,21—30,31—40,41—50, (95% CI, 0.2—2.3)for males and 2. 1 (95% CI, 1.2—3.7)for females]. and 5 1 years prior to colorectal cancer diagnosis for cases and Men or women with a history of elevated serum cholesterol had half interview for controls. Never smokers were assigned 0 for all pack the risk of colorectal cancer of those who did not [OR, 0.5 (95% CI, year variables. ORs are given for a arbitrarily chosen difference of 10 0.3—0.6) for males and 0.5 (95% CI, 0.4—0.7) for females]. This pack-years (i.e. , the values given are the incremental odds ratio for 1 inverse association was observed even when hypercholesterolemia pack-year raised to the 10th power). Although estimates of the odds was diagnosed at least 7 years earlier. Frequency of episodes of ratios for pack-years progressively increase with the remoteness of the constipation during the past 5 years was directly associated with risk smoking period, risk was significantly elevated for the most recent of cancer of the left colon in both sexes and the right colon in females periods as well, for both colon and rectal cancers. These data imply in a dose-dependent manner. It was not associated with rectal cancer. that the effect of smoking in the distant past may be greater [as The OR for colorectal cancer (all sites combined) for subjects who recently suggested (49)] but that recent smoking also increases risk of reported having experienced constipation once a year compared to colorectal cancer. once a month during the past 5 years was 0.5 (95% CI, 0.4—07)for The adjusted odds ratios for caloric intake, physical activity, and males and 0.6 (95% CI, 0.4—0.9)for females. Use of laxatives during body size are included in Table 4 and by subsite of the large bowel in the past 5 years was inversely associated with risk after adjusting for Table 5. Energy intake was directly associated with colorectal cancer frequency of constipation [OR, 0.5 (95% CI, 0.3—0.8) for males and in males only. This association was stronger for the left colon and 0.6 (95% CI, 0.3—1.1)for females]. There was no significant associ rectum than for the right colon. Hours spent in recreational physical ation between colorectal cancer and history of coronary heart disease, activity during the subjects' lifetimes were inversely associated with high blood pressure, stroke, arthritis, duodenal or gastric ulcers, risk in both sexes, although a monotonic trend was seen in men only. cholecystectomy, appendectomy, adenoidectomy, or asthma (data not Odds ratios below 1.0 were observed for all subsites of the large shown). bowel. Very similar risk estimates were found when the intensity (in Table 3 presents the colon and rectal cancer risks associated with METs) of these recreational activities was taken into consideration pack-years of smoking during various periods of time in the past. A (data not shown), suggesting that intensity may not be as important as model was fit that simultaneously included continuous pack-year duration in decreasing risk. There was no indication in our data that 4789

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Table 2 OR? (95% CIs)for 1987—1991MalesFemalesRightcolorectal cancerby selected demographic, snwking, drinking.and medical history vanables, Hawaii

colon colon colon colon 129)Place (n 197)bLeft (n 270)Rectum (n = 221)Right (n 164)Left (n 194)Rectum (n ofBirthUnited States1.01.01.01.01.01.0Asia1.8 (0.4—2.9)Years (0.5—5.8)0.7 (0.3—2.0)0.9 (0.4—2.1)0.7 (0.3—1.8)1.1 (0.6—2.1)1.1 States591.01.01.01.01.01.060—680.8in the United

(0.4—1.7)1.4(0.5—4.1)@691.4 (0.3—1.9)1.1 (0.6—2.3)0.8 (0.3—1.7)2.0 (0.7—5.8)0.8 (0.5—4.1) (0.5—3.0) (0.2—2.0) (0.5—6.7) (0.3—2.4) (0.2—3.3) 0.90Marital P = 0.78c1.2 P = 0.700.7 P = 0.451.9 P = 0.210.9 P = 0.630.9 P = statusMarried1.01.01.01.01.01.0Divorced/single/widowed3.1

(0.7—2.3)Smoking (1.5—6.5)1.3 (0.7—2.2)1.0 (0.6—1.7)1.0 (0.5—1.9)0.8 (0.5—1.4)1.2 statusNeverI .01.0Former1.0(0.5—1.9)1.4(0.9—2.4)1.4(0.8—2.3)2.4(1.0—5.6)1.1.01 .01 .01 .01 (0.6—2.0)1.6(0.7—3.4)Current0.7 (0.5—3.7)Pack-years―T11.01.01.01.01.01.0T,1.1(0.3—1.6)0.9 (0.4—1.9)0.8 (0.4—1.8)1.1 (0.4—2.6)0.7 (0.3—1.5)1.3

(0.5—4.4)T30.8 (0.6—2.2)0.9 (0.5—1.6)1.2(0.7—2.1)2.1 (0.9—5.1)0.5 (0.3—1.2)1.5 (0.4—1.6) (1.1—3.5) (0.7—2.5) (0.7—3.6) (0.7—2.5) (0.7—3.0) 0.35Drinking P = 0.412.0 P = 0.0061.3 P = 0.411.6 P = 0.471.3 P = 0.411.5 P = statusNever1 .01.0Past2.6 .01 .0I .01 .01 (0.6—4.1)Current1.8 (1.4—5.2)1.7 (0.8—3.3)1.4 (0.8—2.4)3.1 (1.0—9.4)1.3 (0.5—3.4)1.5 (0.5—2.3)1.0(0.3—3.0)Drink-years―T11.01.01.01.01.01.0T22.2(1.0—3.4)1 .1 (0.7—2.0)1.1 (0.6—2.0)2.5 (0.9—7.0)1.0

(0.4—2.7)T32.0 (1.2—4.0)1.2 (0.7—2.0)1.6(0.9—2.8)2.7(1.1—6.9)0.8 (0.3—2.0)1.1 (1.1—3.6) (0.7—2.1) (0.6—1.8) (0.5—3.9) (0.4—1.8) 0.40History P = 0.141.3 P = 0.641.0 P = 0.591.4 P = 0.680.8 P = 0.681.6(0.6—4.5)P = ofdiabetes―No1.01.01.01.01.01.0Yes0.9

(0.7—4.4)History (0.4—1.8)1.9 (1.1—3.5)0.7 (0.3—1.6)1.3 (0.6—2.7)3.0 (1.2—7.1)1 .7 ofhypercholesterolemiINo1.01.01.01.01.01.0Yes0.5

(0.3—1.3)Frequency (0.3—0.9)0.4 (0.3—0.7)0.4 (0.2—0.7)0.5 (0.2—0.9)0.4 (0.2—0.7)0.7 yrI/month1.01.01.01.01.01.01/3—6of constipation in past 5

(0.4—3.1)1/year0.8mo.1.0 (0.5—2.3)0.7 (0.3—1.5)0.4 (0.2—1.0)0.5 (0.2—1.3)0.6 (0.3—1.3)1.1 (0.4—1.5) (0.1—0.5) (0.4—1.6) (0.2—0.7) (0.3—1.0) P = 0.340.3 P = 0.00010.8 P = 0.990.3 P = 0.0050.5 P = 0.061.0(0.5—1.9)P= 0.91 a Adjustedby conditionallogistic regressionfor age; family historyof colorectalcancer;alcoholicdrinks/week(except in modelsfor drinking statusand drink-years);pack-years (except in models for smoking status and pack-years); lifetime recreational physical activity; BMI 5 years ago; and egg, dietary fiber, calcium, and caloric intakes. b No. of case-control pairs. These numbers do not add up to the total number of cases and controls because of missing subsite information. ‘P for trend. T tertile. The interquartile range (25th—75th percentiles) for pack-years was 0—39for males and 0—28for females, and for drink-years, 0—83 for males and 0—29 for females. Drink-years = no. of alcoholic drinks/day X duration of drinking in years. e No. of subjects with positive history: males, 122 cases and 87 controls; females, 82 cases and 51 controls. I No. of subjects with positive history: males, 111 cases and 208 controls; females, 92 cases and 163 controls. the effect of recreational physical activity was greater for any life was also the suggestion of a direct association between the number of period in the past. An inverse association was also present for usual years spent in jobs involving only sedentary or light work and cancer daily physical activity, but it was present in females only. This of the right colon in both sexes. association in females was almost limited to the right colon. There No association was found with height, whereas an inverse associ

Table 3 Colon and rectal cancer risks―associatedwith1987—1991Colon 10 pack-years of tobacco smoking in various time periods, Hawaii, RectumMale Female Male Female CI1—5 ORb 95% Cl OR 95% Cl OR 95% CI OR 95% years ago 1.09 (1.04—1.14) 1.16 (1.06—1.28) 1.08 (1.01—1.16) 1.08 (0.94—1.24) 6—10years ago 1.09 (1.04—1.15) 1.18 (1.07—1.31) 1.09 (1.01—1.16) 1.08 (0.94—1.18) I 1—20yearsago 1.10 (1.05—1.16) 1.21 (1.08—1.35) 1.09 (1.01—1.18) 1.08 (0.92—1.28) 21—30yearsago 1.13 (1.06—1.20) 1.30 (1.11—1.51) 1.12 (0.98—1.28) 1.11 (0.87—1.35) 31—40yearsago 1.17 (1.07—1.29) 1.54 (1.19—1.99) 1.12 (0.98—1.28) 1.11 (0.78—1.57) 41—50yearsago 1.25 (1.07—1.46) 1.94 (1.14—3.28) 1.20 (0.97—1.50) 1.13 (0.58—2.20) (0.20—35.17)a5l years ago 1.40 (1.01—1.94) 2.77 (0.69—11.0) 1.46 (0.93—2.30) 2.66

The ORs represent the risk associated with a difference of 10 pack-years (i.e., they are the incremental OR for 1 pack-year raised to the 10th power). b ORs adjusted by conditional logistic regression for age; family history of colorectal cancer; alcoholic drinks/week; lifetime recreational physical activity; BMI 5 years ago; egg, dietary fiber, calcium, and caloric intakes; and the other variables in the table. 4790

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Table 4 ORs―(95% CIs)for colorectal1987—1991Males cancer by quartile of energy intake, physical activity, and body size, Hawaii, pairs)Qb (698 case-control pairs) Females (494 case-control

(high);(low) Q4 (high); QI Q4 trendCaloric Q2 Q3 95%CI P fortrend (low) Q2 Q3 95%CI P for 0.61Lifetimeintake 1.0 1.1 1.2 2.0(1.3—3.0) 0.001 1.0 0.9 1.0 1.1(0.7—1.8) 0.32Dailyrecreational physical activity (h) 1.0 0.8 0.7 0.6 (0.4—0.8) 0.007 1.0 0.7 0.7 0.7 (0.5—1.1) 0.05Yearsphysical activity (METs) I.0 1.2 1.5 1.0 (0.7—1.5) 0.94 1.0 0.9 0.8 0.6 (0.4—1.0) 0.10Heightin sedentary or light work I.0 1.5 1.1 1.3 (0.9—1.9) 0.61 1.0 0.8 0.9 1.5 (0.9—2.3) 0.70Current 1.0 0.7 0.6 0.9 (0.6—1.4) 0.15 1.0 1.0 1.0 1.1 (0.6—2.0) 0.04Weightweight 1.0 0.8 0.9 0.9 (0.6—1.3) 0.64 1.0 0.8 0.7 0.6 (0.4—1.0) 0.28BMI5 years ago 1.0 1.3 1.8 2.1 (1.4—3.3) 0.0003 1.0 1.3 1.3 1.3(0.8—2.1) 0.21BMI5 years ago 1.0 1.2 1.5 2.2 (1.5—3.2) 0.0001 1.0 0.8 0.4 1.2(0.8—1.9) 0.03BMIat age 35 1.0 1.0 1.2 1.5 (1.0—2.2) 0.02 1.0 0.9 1.0 1.6 (1.0—2.5) 0.06BMIat age25 1.0 1.2 1.2 1.5(1.0—2.2) 0.05 1.0 1.0 1.3 1.5(0.9—2.3) 0.06Adultat age 15 1.0 0.8 1.0 1.0(0.7—1.5) 0.62 1.0 1.2 1.1 1.6(1.0—2.6) 0.56Currentweight changec 1.0 1.0 1.6 1.6 (1.0—2.4) 0.003 1.0 0.7 0.9 0.8 (0.5—1.3) 0.71a waist-to-hip ratio 1.0 1.2 1.3 1.2(0.8—1.8) 0.26 1.0 0.9 1.1 1.1(0.7—1.7) (exceptinAdjusted by conditional logistic regression for age; family history of colorectal cancer; alcoholic drinks/week; pack-years; egg, dietary fiber, and calcium intakes; calories models for caloric intake); lifetime recreational physical activity (except in models for physical activity variables); and BMI 5 years ago (except in models for body size variables). @ physicalactivityb quartile. The interquartile range (25th—75th percentiles) for the variables were as follows: calories (kcal), males, 1671—2761, females, 1281—2096; lifetime recreational (h), males, 408—10,080,females,864—3,300;dailyphysical activity (METs), males, 47—62,females,49—61;yearsin sedentary or light work, males, 0—35,females,6—30; height (cm), males, 165—175,females, 152—163;current weight (kg), males, 63—78,females, 50—64;weight 5 years ago (kg), males, 63—78,females, 50—64;BMI 5 years ago (kg/m2). 18—21,females,males, 22—26,females, 21—26;BMI at age 35 (kg/rn2), males, 21—25,females, 20—23;BMI at age 25 (kg/m2), males, 20—23,females, 19—22;BMI at age 15 (kg/m2), males, 0.78—0.87.C17—21;adultweight change (kg), males, 2—14,females,2—I1;waist:hip ratio, males, 0.88—0.96,females, Weight change between age 25 and 5 years ago (i.e., 5 years prior to diagnosis for cases or interview for controls).

ation was found with current weight (i.e., at diagnosis for cases and at weight in the latter period. No association was found with the waist interview for controls) in females. In contrast, weight S years prior to to-hip ratio in men or women. that time was directly associated with risk, especially in men. The Table 6 presents the odds ratios for lifetime recreational physical association with BMI was strongest for BMI 5 years ago in men and activity for each ethnic group. Decreased odds ratios were found for for BMI at age 35 in females. The association with BMI S years ago 8 of the 10 ethnic-sex groups, although monotonic trends were not in men extended to all segments of the large bowel, whereas the always observed, and some of the risk estimates were unstable due to association with BMI at age 35 in women was present for the colon small sample sizes. Similarly, an increased colorectal cancer risk was only. The association with weight change between age 25 and S years observed in 8 of the 10 ethnic-sex groups for BMI (data not shown). prior to diagnosis or interview in men was weaker than that with The association with history of hypercholesterolemia was also ob

Table 5 OR?for cobrectal1987—1991Rightcancer by tertile ofenergy mtake, physical activity, and body size. Hawaii. (270/194)Rectum(221/129)T1T2colon (197/1f,4)bLeft colon

T3PCaloriesMale1.00.6 T3PT1T2T3PT1T2

1.80.051.01.72.70.001Female1.01.7 1.30.251.01.5 1.50.231.00.80.80.67Lifetime 1.10.961.01.3 activityMale1.01.4recreational physical 0.70.341.00.50.50.07Female1.01.9 0.70.101.00.8 0.60.221.00.40.80.97Daily 0.60.081.00.7 (METs)Male1.01.2physical activity 1.00.921.02.01.20.51Female1.00.3 0.90.601.01.2 1.10.861.01.00.60.19Years 0.20.0031.01.8 workMale1.01.6in sedentary or light 1.30.261.00.90.80.49Female1.00.8 1.80.061.01.6 1.00.881.01.71.10.87BMI 2.10.051.00.7 5 yearsagoMale1.01.4 1.80.031.01.72.90.001Female1.01.6 1.90.041.01.2 1.10.841.01.00.80.45BMI 2.00.091.01.3 at age35Male1 .00.92.00.02Female1.01.6 .01 .0 1.50. 131 .01 .2 0.80.451 2.60.021.01.9 1.80.051.00.71.40.24 a Adjusted by conditional logistic regression for the same variables as in Table 4. b No. of male case-control pairs/no. of female case-control pairs. These numbers do not add up to the total number of cases and controls because of missing subsite information.

Table 6 ORs―forcolorectal991MalesFemalesT1T2T3PT1 cancer by tertile of lifetime recreational physicaI activity by ethnicity, Hawaii.1987—1

T3P―Japanese T2 (337/236)c I.0 0.8 0.8 .0 .0 Caucasian (174/1 12) 1.0 0.5 0.6 0.40 1.0 0.5 0.3 0.03 Filipino(69/48) 1.0 0.6 0.4 0.19 1.0 0.2 0.9 0.87 Hawaiian (49/41) 1.0 0.7 0.2 0.37 1.0 6.9 0.9 0.33 0.17aChinese (44/38) 1.0 0.8 0.20.30 0.071 1.00.5 0.81 0.30.43 Adjusted by conditional logistic regression for the same variables as in Table 4. b p for linear trend. C No. of male case-control pairs/no. of female case-control pairs. 4791

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Table 7ORs―for colorectal cancerby the diree.way interactionbetweencaloric intake.1987—199!Lifetime lifetime recreational activity, and BMI 5 years ago, Hawaii, activityMalesFemalesMedian>Median hours in recreational

MedianCaloriesBMI >Median

5 yr agoOR95% CIOR95% CI OR 95% CI OR 95% Cl

Median @Median 1.0 1.2 (0.7—2.1) 1.0 0.8 (0.4—1.5) @Median >Median 2.4 (1.4—3.9) 1.5 (0.9—2.5) 1.5 (0.8—2.6) 1.5 (0.8—2.7) >Median @Median 1.8 (1.0—3.0) 1.5 (0.9—2.4) 1.3 (0.7—2.4) 0.9 (0.4—1.7) >Median >Median 3.0 (1.8—5.0) 1.8 (1.1—3.0) 1.7 (1.0—3.2) 1.2 (0.6—2.2) a Adjusted by conditionallogistic regressionfor age; family historyof colorectalcancer;alcoholicdrinks/week;pack-years;and egg, dietary fiber, and calcium intakes. served in 8 and that with history of diabetes in 6 of the 10 groups. the four studies that partitioned energy intake by dietary sources of Stratified analyses by stage showed that the associations with calories, calories, only one study found that the caloric effect was due to a obesity, smoking, alcohol, and high serum cholesterol were observed single source of calories (15); the others found associations with for early, as well as advanced, stages, and associations with lifetime several sources (27, 28, 30). Thus, in agreement with our results, data recreational physical activity were observed for the regional and from case-control studies support an independent effect of energy on distant stages. colorectal cancer risk. This is in contrast to the findings from cohort Table 7 explores the three-way interaction between caloric intake, studies, which generally did not show an association with caloric BMI 5 years ago, and lifetime hours in recreational physical activity. intake (50—53).The most frequently proposed explanation for this Each of these three risk factors appears to be independent and to have discrepancy has been recall bias in case-control studies. Although this an additive effect (on the coefficients in the logistic model), especially is possible, differential measurement error does not appear likely in men. In both sexes, the most elevated ORs were observed for the because findings from recent studies using both types of design have highest categories of caloric intake and BMI and the lowest category been very consistent for a multitude of dietary and nondietary risk of physical activity. Similarly, there was no interaction between factors (e.g., red meat, dietary fiber, calcium, fruits and vegetables, smoking and drinking on the risk of colorectal cancer. alcohol, and physical activity). Other possibilities are selection bias and inadequate caloric intake assessment in cohort studies because DISCUSSION they are rarely population-based and, by necessity, use a shortened In this study, because we matched on ethnicity, we were unable to dietary questionnaire. compare the colorectal cancer risks among ethnic groups. However, Physical activity has consistently been associated with a decreased cancer registry data have clearly shown that rates for this cancer are risk of coborectal cancer in past studies. Although most studies have high for Asians in the United States (1, 5). This study confirms the focused on occupational physical activity (6—8, 12—17,19), studies observation made in ecological studies, namely, that Asians who examining leisure time and total physical activity (9, 11, 13, 15, 16, migrated as young adults to the United States do not develop cob 18, 20) or participation in college athletics (20) have also shown a rectal cancer less frequently than their local-born counterparts and, reduced risk for the most active. Also consistent with our results, this thus, in contrast to other cancers, such as , that this protective effect has been observed across a gradient of activity levels increase in risk occurred as early as the first generation. We also found and is not limited to strenuous (7, 9, 10, 13, 18, 19, 20, 28). that duration of residence in the United States was not associated with A subsite specificity has not been shown for physical activity, al risk, in contrast to the case-control study of Whittemore et al. (15) though rectal cancer studies have been more inconsistent. Occupa among American Chinese, in which an association was found with tional studies have usually examined cumulative lifetime physical number of years spent in North America. This discrepancy probably activity, whereas most other studies have examined activity levels a reflects the fact that the majority of Chinese Americans in the latter few years before diagnosis. Few studies have attempted to determine study had immigrated 5—15years previously to North America, an at which period in life physical activity has its greatest impact. Marcus interval that may have been too short to modify their risk, whereas et a!. (21) found that strenuous activity during ages 14—22was not Japanese, Chinese, and Filipino immigrants in our study had lived in associated with colon cancer in women. Lee et a!. (20) reported that Hawaii for many more years (42 years for males and 29 years for adult physical activity assessed on two occasions 11—15years apart females, on the average). What characteristics of the Western lifestyle was associated with risk, whereas either measurement alone was not. adopted by Asian immigrants to Hawaii may have contributed to their increased risk of coborectal cancer? In our data, although there was the suggestion of an association with Intake of energy beyond what is needed for energy expenditure, recent overall physical activity and lifetime occupational physical resulting in obesity, is observed commonly in Westernized countries activity, the strongest association was found with cumulative recre and rarely in Asia. In this study, we found that caloric intake [inde ational physical activity during adulthood. pendently of the source of calories (31)], physical activity, and obesity Most past studies have also shown a direct association between were all independently associated with coborectal cancer risk and that body mass and coborectal cancer (9, 15, 16, 26, 32, 54—57),with men individuals with high caloric intake and little physical in the highest exposure category having approximately a 2-fold in activity had the highest risk. The data suggested that these associa creased risk. Data for women have been more inconsistent. with a tions were quite consistent across ethnic groups but were somewhat majority of studies showing no association (9, 15, 16, 26, 56—58).Our stronger in men, especially for caloric intake and obesity. There was results suggest that this discrepancy may be due to either a somewhat no clear specificity of these associations for any subsite of the large weaker effect in women, an age-specificity for the association, or bowel. due to the disease process, because weight was usually In many case-control studies, cases have reported a higher total assessed only a few years prior to diagnosis. The only other study that caloric intake than controls, usually in both sexes (15, 23—30). Among examined body fat distribution also found no association between the 4792

Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1997 American Association for Cancer Research. WESTERNLIFESTYLEANDCOLORECTALCANCER waist-to-hip ratio and colorectal cancer risk (51). Height has usually risk of colon and rectal cancers (78). Alcohol may promote carcino not been associated with risk (32, 55, 58—60). genesis by inducing metabolic activation of procarcinogens by cyto Several biological mechanisms have been pmposed to explain the chrome P450 enzymes by delaying DNA repair or by disrupting DNA associations of coborectal cancer with energy balance, physical activity, methylation. and obesity. Animal studies have well documented that moderate energy Potential limitations of our study deserve consideration. A propor restriction reduces tumor development (61). Physical activity stimulates tion of eligible subjects was not interviewed. It is possible that the colon peristalsis, decreasing the time that dietary carcinogens reside in the associations with physical activity observed in this study may reflect colon. Exercise is also known to enhance the immune defense by affect an over-representation of health conscious individuals in the control ing T cells, B cells, natural killer cells, and interleukin 1 levels (62). In group. However, this does not appear likely because our participation recent years, two related unifying hypotheses have been proposed based rate was high (71%) and because the associations were found with on similarities of risk factors for coborectal cancer and metabolic profiles surprising consistency among ethnic groups that vary in their cultural that may promote cobonic tumors. McKeown-Eyssen (33) noted that beliefs and socioeconomic status. Similarly, we were unable to inter several aspects of Western diets, including alcohol use and physical view the 15% of eligible cases who died before contact, potentially inactivity, increase serum glucose and triglycerides, which themselves limiting the generalizability of our results to the entire patient popu correlate with increased levels of putative colon tumor promoters (e.g., lation. However, the associations found in this study were equally fecal bile acids) or growth factors (e.g., insulin) or may provide energy to strong for each stage, except the associations with physical activity, neoplastic cells. Giovannucci (63) focused on hyperinsulinemia as a which was more marked for the most advanced stages. Thus, the risk tumor promoter because the main determinants of estimates were probably not overestimated but could have been un (obesity, particularly central obesity, physical inactivity, and possibly a derestimated for exercise because patients who were missed due to low ratio of dietary polyunsaturated fat to saturated fat) and hyperinsu early death were more likely to have an advanced form of the disease. linemia (a diet high in refined carbohydrates and low in water-soluble In summary, these findings confirm the data from immigrant stud fiber) may also be related to coborectal cancer. Our study brings some ies suggesting that coborectal cancer risk in Asian immigrants to the support to Giovannucci's hypothesis because we found inverse associa United States increased rapidly, as early as in the first generation. tions with physical activity, vegetable fiber (34), and ratio of dietary They also agree with recent findings suggesting that high energy polyunsaturated fat to saturated fat (31) and direct associations with intake, large body mass, and physical inactivity independently in energy intake, obesity (although not central obesity), and a history of crease risk of this disease and with the proposal that a metabolic diabetes. However, our data are not completely consistent with the imbalance, leading to hyperinsulinemia and diabetes, may be involved hyperinsulinemia hypothesis because the association with diabetes was in the etiology of coborectal cancer. limited to the left colon (in both sexes), whereas those with the risk factors common to coborectal cancer and hyperinsulinemia did not show ACKNOWLEDGMENTS such site specificity. Few past studies have reported on diabetes and colorectal cancer We thank the Hawaii Tumor Registry, Castle Medical Center, Kaiser risk. Most have found no association (64—67). However, our results Permanente Medical Center, Kuakini Medical Center, Queen's Medical Cen agree with those of two other retrospective studies (68—69) and a ter, Straub Clinic and Hospital, St. Francis Medical Center, Tripler Medical prospective study (70) in which an increased risk was found among Center, and Wahiawa General Hospital for their support of this study. 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Loïc Le Marchand, Lynne R. Wilkens, Laurence N. Kolonel, et al.

Cancer Res 1997;57:4787-4794.

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