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Cancer Epidemiology Biomarkers & Prevention Vol. 14, 2082-2086, September 2005
© 2005 American Association for Cancer Research

The Association of Physical Activity and Body Mass Index with the Risk of Large Bowel Polyps

Kristin Wallace2, John A. Baron1,2, Margaret R. Karagas2, Bernard F. Cole2, Tim Byers4, Michael A. Beach3, Loretta H. Pearson2, Carol A. Burke5, William B. Silverman6 and Robert S. Sandler7

Departments of 1 Medicine, 2 Community and Family Medicine, and 3 Anesthesia, Dartmouth Hitchcock Medical Center, Lebanon, New Hamsphire; 4 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado; 5 Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio; 6 Department of Medicine, University of Iowa, Iowa City, Iowa; and 7 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: John A. Baron, Professor of Medicine, and of Community and Family Medicine, Suite 300, 46 Centerra Parkway, Lebanon, NH 03756. Phone: 603-650-3456; Fax: 603-650-3473. E-mail: john.a.baron{at}dartmouth.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 BMI and Polyp Risk
 Discussion
 References
 
Purpose and Method: Several studies have suggested that physical inactivity and obesity increase the risk for colorectal neoplasia. In this study, we investigated the association of physical activity and body mass index (BMI) with the risk of different types of large bowel polyps. We did an observational analysis nested within a randomized double-blind placebo-controlled chemoprevention trial among patients with one or more recently resected histologically confirmed colorectal adenoma. Nine hundred thirty patients were randomized to calcium (1,200 mg/d, as carbonate) or placebo. Follow-up colonoscopies were conducted approximately 1 and 4 years after the qualifying examination. At study entry, we obtained each subject's current body weight and height, which we used to calculate BMI. After the second study colonoscopy, we asked subjects questions about their leisure time physical activity. Seven hundred eighty-seven subjects completed at least part of the physical activity questionnaire.

Results: We found no association between measures of physical activity or BMI and tubular adenomas or hyperplastic polyps. However, among men, there were strong inverse associations observed between physical activity and advanced neoplastic polyps. Compared with men whose total daily energy expenditure was in the lowest tertile, those in the highest tertile had a risk ratio of 0.35 (95% confidence interval, 17-0.72); there was no similar reduction observed among women (risk ratio, 1.21; 95% confidence interval, 0.36-4.03; P for interaction = 0.04).

Data Interpretations: We found a significant inverse relationship between several measures of physical activity and risk of advanced colorectal neoplasms, particularly among men. No associations were found between BMI and hyperplastic polyps, tubular adenomas, or advanced neoplastic polyps.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 BMI and Polyp Risk
 Discussion
 References
 
Physical activity is strongly associated with a reduction in the risk of large bowel cancer (1, 2), whereas obesity has been linked to an increase in risk (3-5). A recent comprehensive review estimated that high levels of physical activity reduced the risk of colon or colorectal cancer by 40% to 50% (1) independently of body size. Conversely, high body mass index (BMI) levels have been associated with as much as a 2-fold increase in risk of colorectal cancer and with stronger associations observed in men (4, 5).

Numerous studies have also examined the association of physical activity with colorectal adenomas—precursors to most colorectal cancers (6, 7). Many of these have reported strong to moderate effects for at least some measures of activity (3, 8-16), although a few reported only weak associations or no relation at all (17-21). Results from a number of studies suggest that the inverse association between physical activity may be stronger for subgroups of adenomas such as those that are large or severely dysplastic (3, 13, 16, 20).

Increasing BMI levels have been associated with a higher risk of adenoma in many (3, 13, 16, 18, 20, 22-28), but not all, investigations (10, 17, 29). Several have observed an increased risk of large (13, 18, 20, 22, 24, 26) or advanced adenomas (large size, presence of villous histology, or severe dysplasia) with higher BMI (16, 23).

However, data from large prospective studies are sparse, and virtually all the data refer to prevalent adenomas found at screening exams. To further evaluate these associations, we did an observational analysis nested within a large multicenter, double-blind, placebo-controlled trial of the effect of calcium supplementation on the recurrence of large bowel adenomas.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 BMI and Polyp Risk
 Discussion
 References
 
Our analysis is based on data from the Calcium Polyp Prevention Study, a randomized double-blind placebo controlled trial testing the effect of calcium carbonate supplementation (1,200 mg/d) on the recurrence of colorectal adenomas (30). We reviewed data on 2,918 apparently eligible subjects. We were unable to contact 223; 1,066 declined to participate; 510 were found to be ineligible; and 1 did not enroll for unknown reasons. After written consent had been obtained, the remaining 1,118 subjects began a 3-month placebo run-in period to assess their adherence to the study regimen. At the end of the run-in period, 930 subjects had taken at least 80% of their prescribed tablets, wished to continue the study, and were considered appropriate for randomization. Study participants were recruited at six clinical centers in the United States; each had a history of at least one histologically confirmed colorectal adenoma excised within the 3 months before entry and was shown to have no remaining polyps in the entire large bowel after complete colonoscopic examination.

Two follow-up colonoscopies were planned for each subject after randomization: approximately 1 and 4 years after the qualifying exam. Interim examinations were discouraged unless clinically necessary. At each study exam, the endoscopist recorded the size and location of all mucosal lesions using standard clinical technique. Each colorectal lesion was examined histologically by our study pathologist as well as by a pathologist at the local clinical centers. The study pathologist categorized each mucosal lesion as neoplastic or nonneoplastic, and graded neoplasms with regard to histologic type and degree of dysplasia using standard pathologic technique (31). In cases of disagreement, the study pathologist's diagnosis was accepted.

At study enrollment, subjects completed a questionnaire addressing basic demographic characteristics, medical history, and lifestyle habits including a food frequency questionnaire (32). Subjects also reported their current body weight and height at baseline, and completed a validated food frequency questionnaire (32). At study completion, we administered an end-of-treatment questionnaire soon after the subject had stopped taking study medication. The study completion questionnaire included the validated physical activity questions designed for the Harvard Alumni Health Study (33). Using this instrument, participants were asked how many city blocks or miles they regularly walked each day, the usual pace of walking, and the number of flights of stairs climbed at work or at home each day. They also were asked, at least once a week, "Do you engage in any regular activity similar to brisk walking, jogging, aerobics, bicycling long enough to work up a sweat, get your heart thumping, and get out of breath?" For positive responses, we inquired about the number of times per week the activity was engaged in, and the type of activity. We assessed total energy expenditure using a modified version of the instrument used in the Stanford Five-City Project (34) which addressed the amount of time participants spent in the following activities on a usual weekday and on weekends: sleeping or reclining, light activities (e.g., desk work, janitorial work, walking for pleasure, bowling, fishing), moderate activities (e.g., delivering mail, truck driving, raking the lawn, sweeping and mopping, volleyball, brisk walking), hard activities (e.g., heavy carpentry, construction work, scrubbing floors, tennis (doubles), karate and very hard activities (e.g., heavy manual work, carrying heavy loads such as bricks or lumber, jogging, soccer, singles tennis). Both questionnaires have been validated across a broad range of populations (35-39).

Statistical Analysis
The main risk period of the study was the interval after the first follow-up exam (~1 year after the qualifying colonoscopy) up to and including the second surveillance colonoscopy (~4 years after the qualifying examination). Histologic lesions were classified into three categories: hyperplastic polyps, tubular adenomas, or "advanced neoplasms," which we defined as tubulovillous or villous adenomas (≥25% villous component), large adenomas (≥1 cm), those with severe dysplasia (carcinoma in situ), or invasive cancer. Polyps were also classified by location: proximal (i.e., the cecum, ascending colon, hepatic flexure, and transverse colon) or distal (i.e., splenetic flexure, descending colon, sigmoid colon, and the rectum).

To assess the association between type of colorectal polyp and indices of physical activity, we did generalized linear regression analyses to compute risk ratios (RR) and 95% confidence intervals (95% CI) while adjusting for age, sex, clinical center, time since first study exam, treatment assignment, and BMI measured at baseline. We also assessed models including smoking status and total caloric intake, but neither of these covariates substantially changed the physical activity RRs and so were not included in the final models. In the generalized linear regression analysis, we used a logarithm linkage function with a binomial distribution.

Blocks walked were analyzed as above and below the median. We analyzed flights of stairs climbed per day in tertiles. Usual walking pace was analyzed in two categories: <3 or ≥3 mph, which correspond to "casual or strolling/average or normal" and "fairly brisk or brisk." As an additional measure of vigorous activity, we analyzed whether a subject reported working up a sweat at least once per week.

As a measure of total energy expenditure on daily activities, we summed the weekday and weekend MET-hours (metabolic equivalent unit) spent engaged in sleep (1 MET), light activities (1.5 METs), moderate activities (4 METs), hard activities (6 METs), and very hard activities (10 METs). The MET value is defined as the ratio of the metabolic rate associated with a given activity to the resting rate. Because resting metabolic rate is ~1 kcal/kg body weight/h, the energy expended per week on each activity or sport can be estimated by multiplying its MET score by the hours spent per week on that activity. The MET values assigned to each category of energy expenditure were the same as those used in the modified Stanford Five-City Project (34). In the analyses, we divided energy expenditure (MET-hours per week) into tertiles.

BMI was divided into three categories using the standard established by WHO: normal (<25 kg/m2), overweight (25 to <29.9 kg/m2), and obese (BMI ≥ 30 kg/m2; ref. 40). We had too few subjects (n = 6) in the category of "underweight" (<18.5 kg/m2), so these subjects were included in the normal weight group.

We tested for the presence of interactions between calcium treatment and physical activity, calcium treatment and BMI, gender and physical activity, and gender and BMI using product terms in our generalized linear models. P values for linear trends were derived from appropriate orthogonal linear contrasts. All statistical tests were done using Wald tests. Analyses including all lesions found after randomization were similar to those for the main risk period, and are not presented.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
BMI and Polyp Risk
 Discussion
 References
 
The mean age of study participants was 60.9 ± 8.9 years; 72% were men (Table 1). Average height and weight were 172.6 ± 9.2 cm and 81.9 ± 14.8 kg, respectively. Forty-four percent of subjects were categorized as "overweight" (n = 347) whereas 25% of subjects were "obese" (n = 196). Subject response to the physical activity questions ranged from a high of 787 (95% of the 832 who completed the study), among subjects who reported whether or not they worked up a sweat, to a low of 736 (88%) for pace of walking. There were no substantial or statistically significant differences in the baseline characteristics between the 930 subjects who were randomized and those who completed the exercise portion of the study (data not shown).


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  		Table 1. Baseline characteristics of the participants in the Calcium Polyp Prevention Study that completed at least a portion of exit questionnaire (n = 787)

 
Exercise and Polyp Risk
Overall, 787 subjects answered at least one physical activity question on the exit study questionnaire. Of these 787 subjects, 156 had at least one hyperplastic polyp, 236 had at least one tubular adenoma, and 70 had at least one advanced adenoma.

All measures of physical activity were unrelated to a risk of tubular adenomas. There were also no consistent associations with hyperplastic polyps (Table 2). There were no material differences in these relative risks between men and women (data not shown).


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  		Table 2. Association of physical activity measures and risk of hyperplastic polyps and tubular adenomas

 
For advanced lesions, RRs differed substantially between men and women for three of the five physical activity measures (Table 3). Among women, only stairs climbed per day was inversely associated with risk of advanced adenomas. In contrast, among men, pace of walking, stairs climbed per day, and total energy expended on daily activities were all associated with a reduction in the risk of advanced neoplastic polyps. We found similar associations for proximal or distal colorectal polyps in all analyses (data not shown).


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  		Table 3. Association of physical activity measures and risk of advanced large bowel polyps for women and men

 

   BMI and Polyp Risk
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 BMI and Polyp Risk
Discussion
 References
 
We observed no association between categories of BMI and risk of any type of polyp (Table 4). Compared with normal weighed patients, the RR (95% CI) for hyperplastic polyps among obese subjects was 0.89 (0.62-1.27). For tubular adenomas, the RR was 1.07 (0.82-1.40) and for advanced neoplastic polyps it was 1.07 (0.62-1.86). There were no statistically significant interactions between treatment group and BMI or physical activity on risk of any type of polyp, nor were there any between BMI and physical activity. We observed no differences in the associations of BMI with polyp risk in the proximal or distal colorectum (data not shown).


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  		Table 4. Association of BMI and risk of colorectal polyps

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 BMI and Polyp Risk
 Discussion
References
 
In this large clinical study, we found that physical activity was associated with a reduced risk of advanced colorectal adenomas (but not tubular adenomas) primarily among men. Activity was unrelated to risk of hyperplastic polyps. BMI was not clearly related to any type of polyp.

Several investigations have studied the size or histologic characteristics of adenomas in relation to physical activity, with mixed results. Both prospective (3, 13) and case-control (15, 18, 20, 27) studies have reported stronger inverse associations between physical activity and large adenomas as opposed to small adenomas. Others, however, have reported similar reductions in risk for both large and small polyps (19, 27). A recent pooled case-control analysis reported a 60% reduction in risk of severely dysplastic polyps with greater physical activity (>2 hours/wk) and the association, as in our study, was detected only among men (16). In the only previous prospective study to examine adenoma recurrence, no association was observed between moderate or vigorous activity physical activity and risk of large or histologically advanced neoplasms (21), but the study included few subjects who engaged in vigorous activity. Why physical activity may be more clearly associated with advanced colorectal neoplasms than earlier adenomas is not known, yet analogous findings have been reported in animal experiments (41, 42).

A positive association between BMI and risk of colorectal adenomas has been found in several (3, 13, 18, 20, 22-27), but not all (10, 17, 29), investigations. Higher BMI levels have been more strongly associated with advanced lesions than with nonadvanced, tubular adenomas (13, 20, 22, 24, 26). In a prospective study in which large bowel adenomas were observed over a 3-year period, the authors reported a positive association between obesity and adenoma growth (43). There are several possible explanations for the differences in our results and others. First, because our BMI analysis was prospective and we studied incident adenomas, we can be more certain that the risk factor preceded the outcome. All but a few of the cited studies are case-control. Second, the thresholds for obesity or high BMI in the previous studies were often much lower than those proposed by WHO, the measures we used. Third, we were likely underpowered to fully examine the distal adenomas that were the focus of most of the previous studies, especially for advanced adenomas. Fourth, we examined incident adenomas and all of the previous investigations examined prevalent adenomas, and it is possible that risk factors differ for incident and prevalent lesions. Finally, one cannot totally discount the possibility of measurement error of BMI in our study, which could have biased our results toward the null (44).

Relatively few studies have evaluated the relationship between physical activity and risk of hyperplastic polyps. As in our study, these have generally found no significant association (45, 46). In one report, however, there was a nonsignificant 50% lower risk in the highest quartile of activity compared with the lowest (45), and in three studies a positive relationship has been observed between increasing BMI levels and hyperplastic polyps (28, 45, 46). In one of these, the association was confined to men (46). Although the mechanism(s) by which physical activity protects against colorectal neoplasia has not been elucidated, several have been proposed, including decreased stool transit time, lower bile acid secretion, and enhanced immune function (47). Still others have suggested that a sedentary lifestyle and obesity may lead to increases in insulin levels, which may increase mucosal cell proliferation (48). Further, several inflammatory markers, such as C-reactive protein and interleukin 6, have been associated with obesity (49-51) and inversely correlated with higher levels of physical activity (52, 53). A recent study reported that high C-reactive protein levels were associated with an increased risk of incident colorectal cancer (54).

Our study has several important advantages, including a questionnaire that assessed both occupational and leisure time activities, virtually complete follow-up, and uniform histologic review of all large bowel lesions. However, our analysis also has important limitations. Physical activity levels were measured concurrently with the final study exam, making a prospective analysis impossible. Thus, it is conceivable that activity levels could have changed in the 3-year period between the initial cleaning exam and the time physical activity was assessed. There have been, however, several studies to suggest that there is fairly reliable recall of previous physical activity (55-58). Additionally, we believe that with respect to our study, there were likely few changes in activity levels between the first study exam and time of follow-up exam because of the short time interval between them (generally <3 years). If anything, this misclassification would have resulted in a conservative bias. Because activity levels were assessed concurrently with the final study exam, there is some slight possibility of recall bias; however, very few subjects (if any) would have been aware of the results of their study exam other than the presence/absence of some type of polyp. In addition, we had limited statistical power to examine the association of physical activity and different types of advanced polyps, particularly among women. Additionally, all of our patients had a history of previous adenomas, and this population may differ from the general population at risk for adenomas or cancer. Furthermore, measurement error associated with the assessment of physical activity and/or BMI could have biased the results toward the null. Finally, as with any observational analysis, there could have been confounding factors that we did not control for, which could have influenced the results.

Despite these limitations, our results suggest that it is important to stratify adenomas not only according to size and degree of dysplasia but also by histology when considering associations with lifestyle factors. This is especially true in polyp prevention trials in which a short follow-up time generates few severely dysplastic or large polyps but a larger number of tubulovillous adenomas. Our analysis of histologic type of polyps suggests that the occurrence of these advanced adenomas is reduced by a higher level of physical activity in men and that obesity is not related to risk.


   Footnotes
 
Grant support: NIH grants CA37287, CA23108, and CA46927-11.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/24/04; revised 5/19/05; accepted 6/28/05.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 BMI and Polyp Risk
 Discussion
 References
 

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