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Cancer Epidemiology Biomarkers & Prevention 16, 2533, December 1, 2007. doi: 10.1158/1055-9965.EPI-07-0708
© 2007 American Association for Cancer Research
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Review

Obesity and Risk of Colorectal Cancer: A Meta-analysis of 31 Studies with 70,000 Events

Alireza Ansary Moghaddam, Mark Woodward and Rachel Huxley

The George Institute for International Health, Sydney, Australia

Requests for reprints: Rachel Huxley, The George Institute for International Health, P.O. Box M201, Missenden Road, Sydney, NSW 2050 Australia. Phone: 61-2-9657-0358; Fax: 61-2-9657-0301. E-mail: rhuxley{at}thegeorgeinstitute.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Colorectal cancer is the second most common cause of death and illness in developed countries. Previous reviews have suggested that obesity may be associated with 30% to 60% greater risk of colorectal cancer, but little consideration was given to the possible effect of publication bias on the reported association.

Methods: Relevant studies were identified through EMBASE and MEDLINE. Studies were included if they had published quantitative estimates of the association between general obesity [defined here as body mass index (BMI) ≥30 kg/m2] and central obesity (measured using waist circumference) and colorectal cancer. Random-effects meta-analyses were done, involving 70,000 cases of incident colorectal cancer from 31 studies, of which 23 were cohort studies and 8 were case-control studies.

Results: After pooling and correcting for publication bias, the estimated relative risk of colorectal cancer was 1.19 [95% confidence interval (95% CI), 1.11-1.29], comparing obese (BMI ≥30 kg/m2) with normal weight (BMI <25 kg/m2) people; and 1.45 (95% CI, 1.31-1.61), comparing those with the highest, to the lowest, level of central obesity. After correcting for publication bias, the risk of colorectal cancer was 1.41 (95% CI, 1.30-1.54) in men compared with 1.08 (95% CI, 0.98-1.18) for women (Pheterogeneity <0.001). There was evidence of a dose-response relationship between BMI and colorectal cancer: for a 2 kg/m2 increase in BMI, the risk of colorectal cancer increased by 7% (4-10%). For a 2-cm increase in waist circumference, the risk increased by 4% (2-5%).

Conclusions: Obesity has a direct and independent relationship with colorectal cancer, although the strength of the association with general obesity is smaller than previously reported. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2533–47)


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cancers of the colon and rectum (colorectal) constitute a significant proportion of the global burden of cancer morbidity and mortality. This is particularly so in developed countries where these malignancies rank second in terms of both incidence and mortality, compared with fifth in less developed countries (1). Approximately 1 million new cases of colorectal cancer are diagnosed, and more than half a million people die from colorectal cancer each year (1, 2). The wide geographic variation in incidence rates for colorectal cancer, together with observations from migrant studies, suggest that lifestyle risk factors, including diet (3, 4), physical activity (5), obesity (6), and diabetes (7), play a pivotal role in the etiology of the disease (8).

Previous reviews (6, 9-11) have indicated that obesity is associated with 7% to 60% greater risk of colorectal cancer compared with normal weight individuals, with some suggestion that the relationship with obesity is stronger for cancer of the colon compared with rectal cancer. However, no overall quantitative estimate of this difference has previously been reported, possibly due to insufficient data on site-specific associations with obesity to allow reliable estimation. It seems that the excess risk of colorectal cancer may be higher among obese men compared with obese women, but findings of a sex difference have been inconsistently reported (6, 9-11). Moreover, there remains uncertainty regarding whether publication bias may be unduly influencing these estimates of effect as findings from the two most recent overviews provide conflicting results on this issue (10, 11).

Hence, the purpose of this current review is to summarize all of the available data to provide the most reliable estimation of the strength, and nature, of the association between measures of general and central obesity with cancers of the colon and rectum, in both men and women. To minimize the potential for bias, we restricted the review to include only studies that reported incident colon and rectal cancer and which used the same criteria to define overweight and obesity in the study population.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Data Sources
We adhered to the Meta-analysis of Observational Studies in Epidemiology guidelines for the conduct of meta-analysis of observational studies (12). Relevant studies were identified through EMBASE and MEDLINE using a combined text word and MESH heading search strategy with the terms colorectal cancer, colorectal neoplasm, colon cancer, colon neoplasm, rectal cancer, rectal neoplasm, cohort, and case-control studies combined with body mass index (BMI), obesity, and waist circumference. References from identified studies were also scanned to identify any other relevant studies.

Statistical Methods
Studies were included if they had published quantitative estimates and SEs (or some other measure of variability) of the association between general obesity (defined here as BMI ≥30 kg/m2) or central obesity (measured using waist circumference) and colorectal cancer by April 2007. Studies were excluded if they provided only an estimate of effect, with no means by which to calculate the SE, or if the estimates were not, at least, age adjusted. Studies also excluded if reporting mortality from colorectal cancer. Information from the studies was extracted independently by two authors (A.A.M. and R.H.). Pooled estimates of relative risks (RR) were obtained using either hazard ratios (for cohort studies) or odds ratios (for case-control studies) by means of a random-effects approach. Studies were weighted according to an estimate of their "statistical size," defined as the inverse of the variance of the log RR (13). Heterogeneity was estimated using the I2 statistic and tested using the Q statistic (13).

Pooled RRs for general obesity were estimated continuously (per 2-unit increment in BMI) and using a binary measure [comparing obese individuals (BMI ≥30 kg/m2) with those in the reference range of BMI (<25 kg/m2)]. The RR and 95% confidence intervals (95% CI) per 2 units higher BMI were derived by multiplying both the estimated log RR and its SE by 2.

In addition, estimates from those studies that used the same three BMI categories were pooled separately to examine any dose-response effect; normal weight, BMI 18.5 to 24.9 kg/m2; overweight, BMI 25 to 29.9 kg/m2; and obese, BMI ≥30 kg/m2. The results for the association between waist circumference and colorectal cancer risk are described continuously (per 2-cm increase in waist circumference), and by comparing risk in the highest with those in lowest category of waist circumference as defined in each qualifying study (there was no consistent categorization of central obesity across studies). Possible sources of heterogeneity were investigated by comparing the results for colon and rectal cancer, sex groups, study designs, and whether the study adjusted for risk factors, including cigarette smoking, alcohol consumption, physical activity, diabetes, and dietary variables.

Publication bias was investigated through funnel plots and tested using Egger's test (13, 14). Funnel plots are plots of the exposure estimated from individual studies against a measure of study size, and are so called because the precision in the estimation of the underlying exposure increases as the sample size of studies increases. If bias is absent, results from small studies will scatter relatively widely compared with larger studies, all around the same average. Corrections for publication bias were made using the trim-and-fill procedure, which essentially corrects the funnel plot by imputing where the missing studies would be most likely to fall, should they have been recorded (13). All analyses were done using STATA, version 10.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The search identified 2,055 studies, of which 565 were potentially relevant (Fig. 1 ). A total of 79 reports from 23 cohort studies (15-40) and eight case-control studies (41-48), with information on a total of 70,906 individuals with colorectal cancer (~66% colon; 49% female) were eligible for inclusion in these analyses. The summary characteristics of included studies are shown online (Tables 1 , 2 –3 ). Most of the study populations were from Western populations: North America (n = 19), Europe (n = 7), and Australia (n = 2). The remaining three studies were from Asia.


Figure 1
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  		Figure 1. Flowchart of the literature search.

 

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  		Table 1. Cohort studies reporting on the association between general obesity and risk of colorectal cancer

 

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  		Table 2. Case-control studies reporting on the association between obesity and risk of colorectal cancer

 

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  		Table 3. Cohort studies reporting on the association between central obesity and risk of colorectal cancer

 
General Obesity and Risk of Colorectal Cancer
A total of 26 studies, with information on 69,619 events, reported on the association between general obesity and colorectal cancer, with some studies reporting both sex-specific and site-specific associations. Hence, the overall number of reported associations exceeded the number of contributing studies. The pooled estimate indicated that individuals with a BMI ≥30 kg/m2 had a 40% greater risk of colorectal cancer compared with individuals with a BMI <25 kg/m2 (RR, 1.40; 95% CI, 1.31-1.51). There was evidence of significant heterogeneity across studies (P < 0.001) that was not explained by differences in study design; the summary estimate for the association between obesity and colorectal cancer from case-control studies was nonsignificantly higher than that obtained from cohort studies: RR 1.50 (95% CI, 1.31-1.72) versus RR 1.35 (95% CI, 1.24-1.46; Pheterogeneity = 0.19; Fig. 2 ).


Figure 2
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  		Figure 2. RRs and 95% CIs for colorectal cancer comparing obese (BMI ≥30 kg/m2) with nonobese individuals (BMI <25 kg/m2). Black square, point estimate (with area proportional to statistical "information"); horizontal line, 95% CI for observed effect in each study. Diamond, pooled estimate and 95% CI for meta-analysis. C, colon; R, rectum; CR, colorectal. *, these studies defined obesity as BMI >28 kg/m2.

 
Subsequent analyses were restricted to cohort studies for which there was evidence of heterogeneity across cohort studies (P < 0.001). Furthermore, as shown in the funnel plot (Fig. 3 ), there was evidence of publication bias (P = 0.003) and the trim-and-fill analysis indicated that the true estimate of effect for the association between obesity and colorectal cancer may be closer to 20%: RR 1.19 (95% CI, 1.11-1.29).


Figure 3
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  		Figure 3. Funnel plot with 95% pseudo–confidence limits for the data from Fig. 2.

 
Some of the observed heterogeneity in study estimates was explained by differences in the magnitude of the association of obesity with site-specific cancers. The pooled estimate of the association between obesity and colon cancer was significantly higher than that of the association between obesity and cancer of the rectum: RR 1.44 (95% CI, 1.28-1.63) versus RR 1.21 (95% CI, 1.10-1.34; Pheterogeneity = 0.04; Fig. 4 ). However, after correcting for the presence of publication bias, this difference was reduced and became nonsignificant: the RR was 1.24 (95% CI, 1.11-1.39) for colon cancer and 1.13 (95% CI, 1.02-1.25) for rectal cancer (Pheterogeneity = 0.23).


Figure 4
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  		Figure 4. Subgroup analyses of general obesity and colorectal cancer for the data from Fig. 2. Conventions as in Fig. 2.

 
Sex differences in the strength of the association between obesity and colorectal cancer were also a source of heterogeneity. The risk of colorectal cancer was RR 1.46 (95% CI, 1.36-1.56) in obese men compared with RR 1.15 (95% CI, 1.06-1.24) for obese women (Pheterogeneity < 0.001; Fig. 4). The sex difference was apparent for both cancers of the colon (P = 0.003) and rectum (P < 0.001). Restricting the analysis to only those 10 studies that reported separate estimates for men and women gave similar findings: RR 1.44 (95% CI, 1.32-1.58) in men compared with 1.09 (95% CI, 1.01-1.17) in women (Pdifference < 0.001). There was, again, evidence of publication bias in studies that published sex-specific results: After correction for publication bias, the sex difference was RR 1.41 (95% CI, 1.30-1.54) versus RR 1.08 (95% CI, 0.98-1.18; Pheterogeneity < 0.001).

The ability to adjust for potential confounders, such as high-fat diets, alcohol consumption, diets low in fiber and low levels of physical activity, differed between studies, and hence may have contributed to between-study variation. Comparison of the summary estimate from the 32 reports that had adjusted for at least one of the above variables with that from the 19 reports that did not adjust for any of these variables indicated that adjustment for diet and physical activity did not attenuate the association: RR 1.30 (95% CI, 1.16-1.45) versus 1.38 (95% CI, 1.25-1.53; Pheterogeneity = 0.44; Fig. 4). Restricting the analysis to those three studies that reported both unadjusted and adjusted estimates yielded similar results (P = 0.98). After correcting for publication bias, the difference between the unadjusted and adjusted remained unchanged: RR 1.18 (95% CI, 1.06-1.31) versus RR 1.25 (95% CI, 1.12-1.41), respectively (Pheterogeneity = 0.47).

Dose-Response Relationship between Overall Obesity and Risk of Colorectal Cancer
A total of nine studies reported on the dose-response association between BMI and colorectal cancer risk using BMI categories representing normal weight, overweight, and obesity. Pooling the estimates within these three categories showed evidence of a dose-response relationship between excess weight and the risk of colorectal cancer in both men and women, with some suggestion that the association was stronger for cancer of the colon compared with the rectum, particularly among men (Table 4 ). However, after correcting for publication bias, the dose-response relationships, particularly for colon cancer, were weakened such that there was no clear difference in the strength of the association between obesity and cancers of the colon and rectum (Table 4). Overall, 11 studies reported an estimate of the RR for colorectal cancer per unit increase in BMI. Pooling these data indicated that for every 2 kg/m2 increment in BMI (equivalent to ~5 kg extra weight), the risk of colorectal cancer increased by 7% (95% CI, 4-10%). Correction for publication bias reduced this association by 1% (RR, 1.06; 95%CI, 1.03-1.09).


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  		Table 4. Dose-response association between general obesity and colorectal cancer before and after correction for publication bias (reference group is BMI <25 kg/m2; normal weight)

 
Central Obesity and Risk of Colorectal Cancer
Overall, 8 of the 23 cohort studies reported on the association between waist circumference and subsequent risk of colorectal cancer. Although there was a lack of uniformity across the studies in how central obesity was defined, with studies using quartiles, quintiles or highest versus lowest category of waist circumference (e.g., ≥102 versus <94 cm; or ≥88 versus <80 cm), the estimates of effect were relatively consistent across the studies (Pheterogeneity = 0.80; Fig. 5 ). The pooled estimate indicated that individuals in the highest category of waist circumference had ~50% greater risk compared with individuals in the lowest category (RR, 50%; 95% CI, 35-67%; Fig. 5). There was some evidence of publication bias (P = 0.001) but the results from the trim-and-fill analysis did not materially reduce the summary estimate of effect (RR, 1.45; 95% CI, 1.31-1.61). Two studies additionally reported on the continuous relationship between waist circumference and colorectal cancer; for every 2-cm increment in waist circumference, the risk of colorectal cancer increased by 4% (95% CI, 2-5%). Correction for publication bias did not have an effect on this association.


Figure 5
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  		Figure 5. RR and 95% CI for colorectal cancer comparing highest versus lowest category of waist circumference. Conventions as in Fig. 2.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The findings from this meta-analysis, which includes information on 70,000 cases of colorectal cancer, indicate that obesity has a direct, and independent, relationship with colorectal cancer, although the magnitude of the association is smaller than previously estimated. Based on these data, individuals with a BMI ≥30 kg/m2 have an ~20% greater risk of developing colorectal cancer compared with those considered to be of normal weight (BMI <25 kg/m2). However, the association between BMI, a measure of general obesity, and risk of colorectal cancer seems to be continuous down to low levels of BMI. For every 2 kg/m2 increase in BMI, the risk of developing colorectal cancer increased by 7%. Similarly, a 2-cm increase in waist circumference, a measure of central obesity, was associated with a 4% greater risk of colorectal cancer. These estimates are smaller, but compatible, with those reported by Larsson and colleagues in a previous review (11).

In agreement with some previous reports (6, 15, 17-25, 30), there was an indication that the carcinogenic effects of excess weight differed according to cancer site, being greater for cancer of the colon compared with that of the rectum. The data also indicated a sex difference in the strength of the association, such that the risk of developing colorectal cancer is 30% higher in obese men compared with obese women.

The mechanisms that might underlie the association between excess weight and cancers of the colon and rectum remain unclear. It has been speculated that obesity serves as a surrogate marker of the cumulative effect of a chronic imbalance in dietary intake and physical activity over the life course. Experimental studies (49-52) have shown that severe caloric restriction has a protective effect against the development of several site-specific tumors, including colon cancer. There is also good evidence that physical activity is protective against colon/colorectal cancer (5, 53). A recent review (53) of the epidemiologic evidence (n = 46) reported that the average reduction in risk of colon cancer across studies was 40% to 50% among the most physically active group compared with the least active, which was independent of diet, BMI, and other potential confounders.

Dietary components may confound the association between obesity and colorectal cancer (54). A recent meta-analysis (55) of 15 cohort studies (~8,000 events) suggested that the highest versus the lowest intake categories of red and processed meat were significantly associated with 28% and 21% increased risk of colorectal cancer, respectively. Likewise, a large prospective study (56) reported that high intake of red and processed meat (>160 g/d compared with <20 g/d) increased the risk of colorectal cancer by 35% with evidence of a dose-response relationship (Ptrend = 0.03).

In the current analyses, we attempted to disentangle the effects of diet and physical activity from obesity, by comparing studies that had adjusted for some measure of diet and physical activity with unadjusted studies. The relationship between obesity and subsequent risk of colorectal cancer, however, was similar irrespective of the level of adjustment, supporting a direct effect of obesity on risk. Recently, there has been speculation as to a possible etiologic role of insulin resistance or, hyperinsulinemia, in colorectal cancer (57, 58), a hypothesis that has received some support from studies demonstrating a positive association between glucose levels and diabetes with the malignancy (7). Further, diabetes has been reported to elevate the risk of other site-specific cancers [e.g., pancreas (59), breast (60), and bladder (61) by ~50%]. Given that the data did not permit exploration of the effect of diabetes on colorectal cancer risk, we are unable to exclude the possibility that the association between obesity and colorectal cancer is not explained by diabetic status.

The observed sex difference in the strength of the association between obesity with cancers of the colon and rectum may be related, in part, to differences in hormonal levels (in particular, estrogen) in women. Some, but not all, studies (31, 44, 62) have reported that the positive association between obesity and the risk of colorectal cancer is apparent in premenopausal but not in postmenopausal women. Slattery and colleagues (44) reported a positive association between high BMI and risk of colon cancer for premenopausal and women who used hormone replacement therapy, but no association among postmenopausal women. In contrast, the European Prospective Investigation into Cancer and Nutrition study (20) reported the largely opposing finding that, in postmenopausal women, waist circumference is weakly associated with the risk of colon cancer only among non–hormone replacement therapy users.

An inherent limitation of meta-analysis, particularly of observational studies, is the presence of publication bias that might artificially inflate the magnitude of any reported association. Our findings suggest that previous reports of around 50% greater risk of colorectal cancer associated with obesity may have substantially overestimated the true strength of the underlying relationship. This finding is in contrast to previous reviews that reported no evidence of publication bias (10, 11), or in the case of one review, only found evidence of it in the association between colon cancer and BMI in women (11). Differences in the study inclusion criteria and methods of analysis between previous reviews and the current meta-analysis may account in part for the discrepant findings. After correcting for the presence of publication bias in the current analyses, the magnitude of the association between obesity and colorectal cancer was approximately halved, from 40% to 20%. Moreover, because we were unable to adjust for potential confounders (e.g., physical activity, alcohol, diet) at the level of the individual, even this reduced estimate of the size of the association might be an overestimate. Finally, as the individual studies used different methods to verify colorectal cancers, the lack of standardization could have had some unpredictable effect on the results. This, as well as the considerable variation in the sets of variables used for adjustment, is reflected in the high degree of heterogeneity between studies of BMI and colorectal cancer, which adds a note of caution to the interpretation of the pooled estimate of association found here in any specific situation.

The global prevalence of obesity is currently estimated to be 300 million, a figure that is expected to increase to 700 million by 2015 (63, 64). Assuming that obesity increases the risk of colorectal cancer by 20%, then each year ~10,000 cases of colorectal cancer worldwide are due to severe excess weight, a figure that is likely to increase to >25,000 by 2015. As these estimates do not take into account the vast number of individuals who are overweight, then these figures are likely to substantially underestimate the true global burden of colorectal cancer that is attributable to excess weight.


   Acknowledgments
 
We thank Dr. Federica Barzi for comments on earlier versions of the manuscript.

Received 8/ 2/07; revised 10/ 2/07; accepted 10/ 9/07.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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