Body Mass Index and Colon Cancer Mortality in a Large Prospective Study
Terrell K. Murphy,
Eugenia E. Calle,
Carmen Rodriguez,
Henry S. Kahn and
Michael J. Thun
From the Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.
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ABSTRACT
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Obesity has been reported to increase the risk of colon cancer, especially in men. The authors examined this relation in the American Cancer Society's Cancer Prevention Study II, a nationwide mortality study of US adults. After 12 years of follow-up, 1,616 deaths from colon cancer in women and 1,792 in men were observed among 496,239 women and 379,167 men who were cancer free at enrollment in 1982. The authors used Cox proportional hazards analyses to control for effects of age, race, education, smoking, exercise, alcohol, parental history of colon cancer, fat intake, vegetable and grain intake, aspirin use and, in women, estrogen replacement therapy. In men, death rates from colon cancer increased across the entire range of body mass index (BMI). The rate ratio was highest for men with BMI
32.5 (rate ratio (RR) = 1.90, 95% confidence interval (CI): 1.46, 2.47) compared with men with BMI between 22.00 and 23.49. In women, a weaker association was seen in the three BMI categories of 27.529.9 (RR = 1.26, 95% CI: 1.03, 1.53), 30.032.4 (RR = 1.37, 95% CI: 1.09, 1.72), and
32.5 (RR = 1.23, 95% CI: 0.96, 1.59). These prospective data support the hypothesis that obesity increases the risk of colon cancer death and that the relation is stronger and more linear in men than in women. Am J Epidemiol 2000;152:84754.
body mass index; cohort studies; colonic neoplasms; obesity
Abbreviations:
BMI, body mass index; CI, confidence interval; RR, rate ratio.
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INTRODUCTION
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Colon cancer is the third leading cause of cancer mortality in the United States in both men and women (1
). Evidence that factors that increase the risk of colon cancer are more common to Westernized cultures comes from international comparisons, from temporal increases in colon cancer within countries coincident with industrialization, and from observations of rate increases in populations as they migrate from low- to high-risk regions (2
, 3
). Nutritional factors, obesity, and physical activity have been the primary focus of etiologic research.
Several epidemiologic studies have examined the association between obesity, measured by body mass index (weight (kg)/height (m)2) (BMI), and colon cancer risk. Results from these case-control and cohort studies in men consistently indicate positive associations (4















21
), whereas results of studies in women suggest either no association or weak positive associations (4
, 8
, 10
, 12
, 14
, 16








26
). At present, there is no clear explanation for these apparent gender-related differences.
In this study we extended follow-up of a large prospective American Cancer Society study of US adults (18
) and further examined the association between BMI and colon cancer mortality in both men and women. We also investigated whether other established colon cancer risk factors modify this association in men or women.
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MATERIALS AND METHODS
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Men and women for this study were selected from the 1,184,659 participants of Cancer Prevention Study II, a prospective mortality study of American men and women begun by the American Cancer Society in 1982 (27
, 28
). Participants were friends and acquaintances of over 77,000 American Cancer Society volunteers in all 50 states, the District of Columbia, and Puerto Rico. To be eligible for enrollment through this volunteer network, individuals had to be 30 years of age or older and to reside in a household in which at least one person was 45 years of age or older. The median age at cohort entry in 1982 was 57 years for men and 56 years for women. Participants completed a confidential self-administered questionnaire in 1982 that included personal identifiers; demographic characteristics; personal and family history of cancer and other diseases; and various behavioral, occupational, environmental, and dietary exposures.
During the first 6 years of follow-up, the vital status of the participants was ascertained every 2 years through personal inquiries by the volunteers who enrolled the study participants. Since 1988, automated linkage using the National Death Index was used to extend follow-up through December 31, 1994, and to identify deaths among 21,704 (1.8 percent) individuals lost to follow-up between 1982 and 1988 (29
). At completion of mortality follow-up in December 1994, 988,145 participants (83.4 percent) were still living, 193,622 (16.3 percent) had died, and 2,892 (0.2 percent) had follow-up truncated on September 1, 1988, because of insufficient data for the National Death Index linkage. Death certificates or multiple cause of death codes were obtained for 98.3 percent of all participants known to have died.
Colon cancer deaths were defined as those individuals who died through December 31, 1994, with colon cancer (International Classification of Diseases, Ninth Revision, codes 153.0153.9) as the underlying cause. We excluded from the analysis 20,453 women and 15,313 men with unknown or extreme (
0.15th percentile or
99.85th percentile) height, weight, or calculated BMI values and 22,278 women and 15,529 men who reported weight loss of more than 20 lb (9.07 kg) within the year prior to entry (table 1). We excluded 62,847 women and 43,682 men who gave a positive response to the question "Are you sick now?" and 26,887 women and 27,542 men who had a history of colonic or rectal polyps. We also excluded 41,048 women and 16,322 men who reported prevalent cancer (except nonmelanoma skin cancer) at study entry. To minimize confounding by undiagnosed disease, we excluded the first 3 years of follow-up time and 6,554 women and 10,798 men who died within the first 3 years. After 12 years of follow-up, 1,616 eligible cases among 496,239 women and 1,792 eligible cases among 379,167 men were observed.
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TABLE 1. Exclusion criteria and eligible cohort for analysis, Cancer Prevention Study II (CPS-II), United States, 19821994
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In the baseline questionnaire, weight in pounds and height in feet and inches were written by participants on blank lines after the words "Current weight with indoor clothing," "Weight 1 year ago," and "Height (without shoes)." BMI (kg/m2) was calculated from the reported values. For 0.1 percent of men and 0.3 percent of women, "Current weight with indoor clothing" was missing, and the nonmissing value for "Weight 1 year ago" was substituted. In our analyses, BMI categories for women were defined as follows: <18.5, 18.520.49, 20.521.99, 22.023.49, 23.524.99, 25.027.49, 27.529.99, 30.032.49, and
32.5. Since the distribution of BMI differed in men and women, we used the following categorization for men: <20.5, 20.521.99, 22.023.49, 23.524.99, 25.025.99, 26.027.49, 27.529.99, 30.032.49, and
32.5. The BMI category 22.0023.49 served as the referent group for analyses of both men and women. These categories were chosen to maximize category overlap between men and women and to enable a detailed examination of the association of BMI and colon cancer mortality across a wide range of BMI. In addition, the above categorization included the cutpoints proposed by the World Health Organization (30
) for the underweight (BMI < 18.50), normal range (BMI 5 18.5024.99), grade 1 overweight (BMI = 25.0029.99), grade 2 overweight (BMI = 30.0039.99), and grade 3 overweight (BMI
40.00). When World Health Organization-recommended categories were used, we collapsed BMI < 18.50 with BMI = 18.5024.99 and BMI = 30.0039.99 with BMI
40.00 categories because of insufficient numbers in the underweight and grade 3 overweight categories. When World Health Organization-recommended categories were used, BMI < 25.00 was used as the referent group for analyses in both men and women.
We used Cox proportional hazards modeling to compute rate ratios and to adjust for other potential risk factors. All Cox models were stratified on age at entry (1-year strata). Multivariate Cox models also included the following potential cancer risk factors: race (White, Black, other), physical activity (none, light exercise, moderate exercise, heavy exercise, unknown), alcohol use (none, three drinks per week or less, one drink per day, two or more drinks per day, unknown), smoking status (never, current, former, ever smoker but unknown if current, pipe/cigar in men, unknown), educational level (less than high school graduate, high school graduate, some college, college graduate, unknown), parental history of colon cancer (yes, no), fat intake (estimated grams per week for 20 food items divided into tertiles (18
)), vegetable and grain intake (the frequency per week of consuming nine vegetable and grain food items, divided into tertiles (18
)), aspirin use (none, occasional, 115 per month, 16 or more per month, aspirin use but frequency unknown, aspirin use but duration unknown) and, in women, estrogen replacement therapy (never, current, former). Rate ratios reported in the text are those obtained from multivariate analyses.
We assessed whether other risk factors for colon cancer modified the association between BMI and colon cancer mortality by including multiplicative interaction terms between BMI (<25, 2529.99,
30) and each of the above risk factors in separate multivariate models. To assess whether age modified the association, we categorized attained age into four strata (<60 years, 60<70 years, 70<80 years, and
80 years). Statistical significance of the interaction terms was assessed at the p = 0.05 level using the likelihood ratio test.
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RESULTS
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Table 2 shows the age-adjusted percent distribution of BMI categories across levels of other risk factors for colon cancer. At baseline, men and women in the highest BMI categories (BMI
30 or World Health Organization grade 2 or grade 3 overweight) were more likely to be Black, never drinkers, less educated, and less physically active. They also were more likely to report high fat intake, low consumption of vegetables and grains, and more use of aspirin. Men in the BMI
30 category were likely to be former smokers, whereas women were likely to be never smokers. Women with a BMI of
30 were likely to report no estrogen replacement therapy use. Rate ratios from age-adjusted and multivariate survival analyses at each BMI level for men and women are summarized in tables 3 and 4, respectively.
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TABLE 2. Age-adjusted percent distribution of body mass index (weight (kg)/height (m)2) (BMI) categories among levels of colon cancer risk factors, Cancer Prevention Study II, United States, 19821994
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Men
The relation between BMI and colon cancer death rates was stronger in men (table 3) than in women (table 4). In men, the increase in mortality appeared linear across all BMI levels. After controlling for other risk factors, we found significant, positive associations for all levels of BMI greater than 25.0. The strongest association was for the highest category (BMI
32.5) (rate ratio (RR) = 1.90, 95 percent confidence interval (CI): 1.46, 2.47). The linear association continued below the referent BMI level, implying an increase in risk of death with increasing BMI across the entire BMI range examined. When World Health Organization categories were used, the increased risk was observed at BMI 2529.99 (RR = 1.34, 95 percent CI: 1.21, 1.48) and BMI
30 (RR = 1.75, 95 percent CI: 1.49, 2.05).
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TABLE 3. Colon cancer mortality by body mass index level among men, Cancer Prevention Study II, United States, 19821994
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TABLE 4. Colon cancer mortality by body mass index level among women, Cancer Prevention Study II, United States, 19821994
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The association between BMI and colon cancer death rates in men varied significantly (p for interaction = 0.01) by educational level. No increased risk of death was associated with higher BMI levels in men with less than a high school education. The increased risk observed among more educated men appeared to increase slightly with increasing education (among college graduates, RR = 1.53, 95 percent CI: 1.26, 1.84 for BMI 25.029.9; RR = 2.33, 95 percent CI: 1.73, 3.14 for BMI
30). There was no significant effect modification by attained age or any other covariate.
Women
Among women, after adjusting for all other risk factors, we found higher death rates from colon cancer in the three highest categories of BMI (BMI 27.529.9, RR = 1.26, 95 percent CI: 1.03, 1.53; BMI 30.032.4, RR = 1.37, 95 percent CI: 1.09, 1.72; and BMI
32.5, RR = 1.23, 95 percent CI: 0.96, 1.59) (table 4). When we used World Health Organization-recommended BMI categories, women in the highest category (BMI
30) had a significantly increased risk of colon cancer mortality (RR = 1.25, 95 percent CI: 1.06, 1.46).
Alcohol intake significantly modified (p for interaction = 0.01) the association between BMI and colon cancer mortality in women. Among women reporting one drink per day and women reporting two or more drinks per day, high BMI of
30 was associated with a greater than twofold increased risk (RR = 2.49, 95 percent CI: 1.53, 4.03 and RR = 2.28, 95 percent CI: 1.48, 3.52, respectively), whereas no significant increase was noted in heavy women who did not drink or drank less than daily. There was no significant effect modification by attained age or any other covariate.
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DISCUSSION
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These prospective mortality data support the hypothesis that BMI is an independent risk factor for colon cancer death in both sexes but that the relation is stronger and more linear in men than in women. Our findings in men are consistent with those of several other studies (4















21
) that have reported an increase in risk from the lowest to highest BMI levels. Other studies have also found a weak association between BMI and colon cancer in women and increased risk only at the highest levels of BMI (4
, 10
, 12
, 14
, 16








26
). While the reasons for the gender difference seen in these studies are not completely understood, one hypothesis is that the greater tendency for abdominal or central adiposity in men (in contrast to the tendency for peripheral fat deposition in women) may be important. If central adiposity is indeed more important in colon carcinogenesis than generalized or peripheral obesity (4
, 9
, 24
, 26
), then BMI may simply be a more accurate indicator of central adiposity in men than in women. Consequently, the weaker effect seen in women may reflect greater misclassification of the relevant exposure.
Recently, Giovannucci (31
) outlined a mechanism by which elevated BMI may influence colon cancer risk and suggested that altered glucose-insulin dynamics may be involved. Prolonged elevated insulin levels (hyperinsulinemia) resulting from increased insulin resistance and glycemic load may increase colon cancer risk by acting as a tumor growth promoter or mitogen. Since central obesity is correlated with insulin resistance and hyperinsulinemia, the finding of a stronger association in men in our study, along with the observation that muscle tissue in women is more sensitive to insulin than that in men (32
), would support the hyperinsulinemia hypothesis.
Another potential explanation for the weaker association between BMI and colon cancer mortality in women may be the possible protective effects of estrogen. Observational studies report an inverse association between estrogen replacement therapy in postmenopausal women and colorectal polyps (33
), colon cancer incidence (34
), and mortality (35
). Conversion of androgens to estrogens by adipose tissue is the primary source of extraglandular estrogen production in postmenopausal women, and circulating estrogen levels increase with age and obesity (36

39
). If estrogen production by adipose tissue protects against colon cancer in women, why not in men? Estrogen levels increase with obesity in both sexes (40
). Estrogen supplementation in males has been shown to increase insulin resistance rather than improve insulin sensitivity (41
), and the estradiol/testosterone ratio is positively associated with plasma glucose and insulin levels (42
). Assuming a role of hyperinsulinemia in colon carcinogenesis, elevated estrogen levels as a consequence of obesity in males may lead to a relative estrogen/testosterone imbalance, followed by increased insulin resistance and hyperinsulinemia, and an increase in colon cancer risk. Leptin and insulin-like growth factor-1 are additional hormones that may participate in the pathway between obesity and the incidence or dissemination of colon cancer (
, 44
). A specific role for these hormones in colon cancer risk deserves further investigation in populations where hormone levels have been measured.
Interactions between BMI and physical activity in younger women (17
) and between BMI and family history in younger men and women (4
) have been reported for colon cancer risk. We did not observe significant interaction by these variables in our data. However, we did find significant effect modification by alcohol intake of the association between BMI and colon cancer mortality in women. While not significant, this interaction was also suggested in men. High alcohol consumption is a probable independent risk factor for cancers of the colon and rectum (45
). Several mechanisms for its action have been advanced, including induction of microsomal enzymes that convert procarcinogens to more active forms (46
), inhibition of DNA repair (47
), and an indirect effect operating through depletion of several beneficial nutrients, including folate and methionine (48


52
). It seems biologically plausible that alcohol consumption also may modify the effect of other exposures on colon cancer.
The finding of significant interaction by educational level in men is hard to explain. This may reflect chance or inadequate control for factors associated with lower education such as increased physical activity. Though we included a physical activity covariate in multivariate analyses, the limited information available may not have provided adequate control.
Strengths of our study include its prospective design, similar analytical methods for men and women, ability to control for a large number of other risk factors, exclusion of latent disease, and large size. Limitations include reliance on mortality rather than incidence data, lack of colon cancer subsite data, lack of anthropometric measurements, lack of screening data, and reliance on single, self-reported measurements for BMI determination.
Because of our reliance on mortality data, our results reflect the potential effect of body mass index on colon cancer incidence, survival, or both. In addition, we have no information on colon cancer screening, a factor that is likely to influence survival. If lean individuals are more likely to get screened, they would be expected to have more diagnosed colon polyps and fewer invasive cancers. However, a recently published study of incident colon polyps in a subgroup of this cohort offers little support for such a screening bias (53
). In that study, a modest but positive association was seen between increasing body mass index and risk of self-reported incident colon polyps (53
).
Finally, study participants are, on average, more educated and affluent than the US population as a whole, and they are less likely to be of non-White race. While these differences may influence comparisons of absolute rates of disease or exposure between this population and that of the United States, they are unlikely to compromise internal validity.
The findings of our study add to the current literature suggesting that obesity increases the risk of colon cancer mortality and that the effect is considerably greater in men. Future research may focus on the role of sex hormones in explaining the different association seen in men and women, with attention to the effects of estrogen, leptin, and insulin-like growth factors.
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NOTES
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Reprint requests to Dr. Eugenia E. Calle, Department of Epidemiology and Surveillance Research, American Cancer Society, 1599 Clifton Road, N.E., Atlanta, GA 30329-4251 (e-mail: jcalle{at}cancer.org).
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Received for publication June 24, 1999.
Accepted for publication February 4, 2000.