Physical activity and risk of colon adenoma: a meta-analysis

Background: Little evidence is available on the relation of physical activity with colon adenomas, a colon cancer precursor. Methods: We conducted a systematic literature review and meta-analysis of published studies (in English) through April 2010, examining physical activity or exercise and risk or prevalence of colon adenoma or polyp. Random effects models were used to estimate relative risks (RRs) and corresponding confidence intervals (CIs). A total of 20 studies were identified that examined the association and provided RRs and corresponding 95% CIs. Results: A significant inverse association between physical activity and colon adenomas was found with an overall RR of 0.84 (CI: 0.77–0.92). The association was similar in men (RR=0.81, CI: 0.67–0.98) and women (RR=0.87, CI: 0.74–1.02). The association appeared slightly stronger in large/advanced polyps (RR=0.70, CI: 0.56–0.88). Conclusion: This study confirms previous reports of a significant inverse association of physical activity and colon adenoma, and suggests that physical activity can have an important role in colon cancer prevention.

Convincing evidence exists for a causal, inverse association between physical activity and risk of colon cancer (International Agency for Research on Cancer WHO, 2002; World Cancer Research Fund/American Institute for Cancer Research, 2007b;Wolin et al, 2009). This association is plausibly supported by several biological mechanisms, including decreased inflammation, decreased insulin-like growth factor levels, reduced hyperinsulinemia and modulated immune function (Wolin et al, 2009). Fewer data are available with respect to physical activity and colon adenomas, the precursor lesion detected and removed during sigmoidoscopy or colonoscopy. Although numerous studies have examined this association, no comprehensive meta-analysis is available. A limited meta-analysis by the World Cancer Research Fund included three studies, and estimated physical activity was associated with a statistically significant 15% reduction in colon polyp risk (World Cancer Research Fund/American Institute for Cancer Research, 2007a). Estimation of the risk reduction associated with the physical activity is important for public health because lifestyle is associated with a decreased risk of colon cancer, even among those who have undergone colon cancer screening (Wei et al, 2009). Furthermore, evidence on smoking has suggested that risk may vary for colon polyps versus colon cancer (Botteri et al, 2008). We therefore conducted a meta-analysis to estimate the summary relative risk (RR) of colon polyps associated with physical activity.

MATERIALS AND METHODS
We searched the literature using PubMed, CINAHL and Scopus for all studies on physical activity or exercise and colon polyps through April 2010. We employed the terms exercise and physical activity in combination with colon polyps using the terms colon polyp, colon adenoma, colorectal polyp, colorectal adenoma and adenomatous polyps. We also utilised a previous review of the data (Samad et al, 2005;Lee and Oguma, 2006;World Cancer Research Fund/American Institute for Cancer Research, 2007a) and manual searches of the reference lists of identified manuscripts. We included recurrent, incident and prevalent cases of colon polyps. We did not limit studies by type of physical activity or study sample demographics.
Our search yielded 89 potential articles. We excluded reviews, non-human studies, editorials/comments/letters to the editor, studies without colon polyps as an outcome, studies where physical activity was only included as a covariate (and thus no measure of association was presented), and where no metric for effect estimate precision (P-value, s.e., confidence interval (CI)) was provided. Combined with searches from the reference sections of manuscripts and previous reviews, this yielded 20 manuscripts. From each manuscript, we abstracted the sample size (including number of cases), gender, years of follow-up or type of control sample, case definition, physical activity domain, adenoma detection method, sample definition criteria and results. We also abstracted the variables that each study used in its most adjusted analysis. Data extraction was performed by a single investigator (KYW). Where studies included more than one type of physical activity without a summary measure, we included only leisure time physical activity, which is the major modifiable component of energy.
Previous meta-analyses have suggested that results for adenomatous polyps need to be presented separately from hyperplastic or malignant polyps. (Botteri et al, 2008) Although we did not restrict our analysis to studies where data was limited to adenomatous polyps, we did consider those results separately. Specifically, we excluded results for hyperplastic polyps where feasible. We also identified studies considered to be the 'best approach' using criteria similar to those used in a previous metaanalysis (Botteri et al, 2008), namely, studies that met all of the following: (1) limited the outcome to only adenomatous polyps; (2) all individuals received a full colonoscopy; and (3) the study population excluded anyone with inherited colorectal cancer syndromes, inflammatory bowel disease, a history of colon polyps or cancer, or a previous colon resection.

Data analysis
Meta-analysis of random effects was used to allow for the heterogeneity of results across studies. (Mosteller and Colditz, 1996) Data were processed in SAS, and the analyses were performed using R-package 'meta' (SAS Institute Inc., Cary, NC, USA). A summary forest plot was generated in Stata (StataCorp LP, College Station, TX, USA). As most studies reported RRs or odds ratios (ORs) and their associated 95 percent CIs, we used these data as summary statistics for each study. First, we derived the s.e. of log (RR or OR) using the 95 percent CI, with the expression: (log (upper limit) -log (lower limit))/2*1.96. These s.es were used as weights for summary effect estimates in the meta-analysis. We visually examined publication bias using Funnel plots, and employed the rank correlation method to formally test for bias. (Begg and Mazumdar, 1994) Where studies reported results separately for men and women, we included both estimates when reporting the overall association. To evaluate the potential effects of limiting results to only adenomatous polyps, we conducted exploratory analysis in the subset of those studies. We also included results separately for large/advanced adenoma, if the data were presented as such in the original manuscript. We also conducted exploratory analyses limited to those studies defined as the 'best approach'. To test sub-analysis differences (large vs all adenomas; best approach vs all studies), we partitioned 'total heterogeneity' into between-group and within-group heterogeneity, and used the 'between-group' heterogeneity index as the test statistic against w 2 distribution with 1 degree of freedom. (Cooper and Hedges, 1994).
There was a tendency for the effect of physical activity to be restricted to large or advanced adenomas and not low grade ones. Similarly, physical activity was associated with large (41 cm) (RR ¼ 0.63, 95% CI: 0.36 -1.10), but not with small adenomas in a sample of US male health professionals (Giovannucci et al, 1995). In a cohort of US female nurses, a significant overall risk reduction (RR ¼ 0.58, 95% CI: 0.40 -0.86) was reported, which was also stronger for larger than smaller adenomas (Giovannucci et al, 1996). Our meta-analysis found the effect was stronger, though not significantly so (P ¼ 0.16), for large or advanced (RR ¼ 0.70, 95% CI: 0.56 -0.88) adenomas than for the overall effect. In analyses limited to the 18 studies where results for adenomatous polyps were separated from all polyps (i.e., hyperplastic, malignant polyps), the meta-analysis estimate for the association between physical activity and risk of polyps was largely unchanged (RR ¼ 0.83, 95% CI: 0.73 -0.93). In analysis limited to the six studies (Kono et al, 1991;Sandler et al, 1995;Colbert et al, 2002;Lieberman et al, 2003;Tiemersma et al, 2003;Hauret et al, 2004) defined as the 'best approach,' the effect estimate was similar to that for all studies (RR ¼ 0.87, 95% CI: 0.73 -1.05), though not statistically significant.

DISCUSSION
Previous, though limited, reviews have indicated physical activity is associated with a significant reduction in colon polyp risk. (World Cancer Research Fund/American Institute for Cancer Research, 2007a) Our comprehensive meta-analysis supports this conclusion, showing a significant 16% risk reduction when comparing the most to the least active. Risk reductions were similar for men and women, and held when limited to studies designated as the best approach. We found the association was notably stronger when analyses were limited to advanced or large polyps, with a risk reduction of 35%. I-V overall (I 2 = 46.2%, P = 0.005) Shinchi et al, 1994Tiemersma et al, 2003Larsen et al, 2006D+L overall Rosenberg et al, 2006Neugut, 1996Kahn et al, 1998Hauret et al, 2004Tiemersma et al, 2003Kono et al, 1991Kono et al, 1999Wallace et al, 2005Lubin et al, 1997Neugut, 1996Label Lieberman et al, 2003Enger et al, 1997Sandler, 1995Little et al, 1993Boutron-Ruault et al, 2001Boutron-Ruault et al, 2001Giovannucci et al, 1996Colbert et al, 2002Kahn et al, 1998Hermann et al, 2009Wallace et al, 2005Sandler, 1995Larsen et al, 2006Giovannucci et al, 1995   These results support the previously documented role of physical activity in colon cancer prevention (International Agency for Research on Cancer WHO, 2002; World Cancer Research Fund/ American Institute for Cancer Research, 2007a and2007b;Wolin et al, 2009). Earlier reports that failed to find an association between physical activity and colon polyps had suggested that physical activity may be more important in the adenoma to carcinoma sequence than in adenoma development (Colbert et al, 2002). Our meta-analysis, combined with the above-mentioned data demonstrating physical activity's role in colon cancer prevention, suggests that physical activity has a role across the carcinogenic process. Several mechanisms have been proposed for such effects, including enhanced immune function, decreased inflammation, reduced insulin levels and insulin resistance, and higher vitamin D levels (Wolin et al, 2009). Hyperinsulinemia has also been directly related to colon polyp risk (Wei et al, 2006). This comprehensive meta-analysis provides support for an inverse association between physical activity and colon polyps, and also for the role of physical activity in colon cancer carcinogenesis. Physical activity may reduce the risk of colon polyps by 15% and may provide a substantially larger reduction in risk of large and advanced polyps.