Published OnlineFirst July 14, 2015; DOI: 10.1158/1055-9965.EPI-15-0301
Review
The Association between Leisure Time Physical Activity and Pancreatic Cancer Risk in Adults: A Systematic Review and Meta-analysis
Cancer Epidemiology, Biomarkers & Prevention
Megan S. Farris1,2, Mohammed H. Mosli2,3, Alison A. McFadden1, Christine M. Friedenreich1,2,4, and Darren R. Brenner1,4
Abstract We conducted a meta-analysis of the association between leisure time physical activity (LTPA) and risk of pancreatic cancer to update previous analyses in light of newly published studies, to examine subgroups of interest and potential sources of heterogeneity. We searched the PubMed and MEDLINE databases for studies until February 2015. Study information was collected using a standardized form to abstract relevant data on study design, number of cases, participant and study characteristics, assessment of LTPA, risk estimates, and adjustments for confounding by two independent abstractors. We used randomeffects models to pool estimates from included studies of lowest versus highest comparison of LTPA. The search identified 26 studies eligible for inclusion into the meta-analysis. The combined summary risk estimate was [relative risk (RR), 0.89; 95% confidence interval (CI), 0.82–0.96]. There was evidence of
heterogeneity across studies (I2 ¼ 22.1%, Pheterogeneity ¼ 0.130). Some of the heterogeneity could be explained by study design, with stronger protective effects observed among case– control studies (RR, 0.69; 95% CI, 0.59–0.81) compared with cohort studies (RR, 0.96; 95% CI, 0.91–1.02). Across study designs, age of population was a source of heterogeneity, with stronger effects observed among younger (75 min/wk of vigorous LTPA; ref. 29). Risk estimates reporting LTPA in quartiles/quintiles showed evidence of risk reduction (RR, 0.80; 95% CI, 0.60–1.06; refs. 6, 9, 11, 37), whereas low versus high (RR, 0.92; 95% CI, 0.82–1.03; refs. 33, 36, 38–40, 43, 45–47) and frequency measures (sessions per week; RR, 0.92; 95% CI, 0.92–1.03; refs. 7, 15, 34, 42) subgroups produced limited evidence of a protective effect. In addition, the sports participation subgroup reported no effect (RR, 0.99; 95% CI, 0.69–1.44; refs. 23, 24, 44). With respect to the duration of activity, lifetime (RR, 0.89; 95% CI, 0.80–0.98; refs. 7, 11, 15, 23–25, 34, 36, 37, 39–42, 44–47) and studies that assessed 2–10 years of activity (RR, 0.62; 95% CI, 0.46–0.84; refs. 9, 18) supported a protective effect; however, past year reporting of LTPA revealed no association (6, 8, 21, 22, 33, 38, 43). Investigating heterogeneity Both study design and median age of the study population were statistically significant sources of heterogeneity across studies (P ¼ 0.001) according to meta-regression. Other study characteristics accounting for heterogeneity across studies were the confounding variables used for adjustment (P ¼ 0.064) and gender (P ¼ 0.054). Effects were also heterogeneous within and across LTPA level characterizations, for example, heterogeneity among risk estimates reporting under the WHO recommendations was moderately high (I2 ¼ 57.4%, Pheterogeneity ¼ 0.016). This heterogeneity may be accounted for by either Stevens and colleagues (8) or Brenner and colleagues (25), as when these studies were removed,
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0.5
1.0 OR/RR
2.0
5.0
10.0
the I2 statistic decreased by 18% and 25%, respectively, and became non-statistically significant. No other studies in the subgroup analysis based on the recommended levels of LTPA as defined by the WHO made any significant difference in the heterogeneity. In addition, for 4 studies that reported risk estimates for LTPA as quartiles or quintiles, there was moderate but non-statistically significant heterogeneity (I2 ¼ 42.8%, Pheterogeneity ¼ 0.137; refs. 6, 9, 11, 37). When Nothlings (6) was removed, the heterogeneity decreased by 42.8%. When Stevens and colleagues (8), Brenner and colleagues (25), and Nothlings (6) were excluded, heterogeneity is substantially reduced in the overall results (I2 ¼ 0.0%, Pheterogeneity ¼ 0.467). Furthermore, within cohort studies and case–control studies, there was very good agreement overall, thus heterogeneity may be indicative of a difference in magnitude of effect between study designs. In addition, 25 studies reporting effects from models with more detailed covariate adjustment supported a statistically significant protective effect (RR, 0.90; 95% CI, 0.82–0.98; refs. 6– 9, 18, 21, 22, 24, 25, 36–43, 45, 47), in comparison to other confounder subgroups. Cohort and case–control specific analyses In cohort studies alone (Table 3), age of the population was also a determinant of differences in effect estimates. Studies with median age of 60 years' subgroups (RR, 1.00; 95% CI, 0.89–1.12; refs. 6, 7, 21, 22, 43–45, 47). We also observed large differences in the effects between the one risk estimate with no covariate adjustment (RR, 1.20; 95% CI, 0.63–2.27; ref. 44) in comparison to the 3 studies with basic covariate adjustment (RR, 0.82; 95% CI, 0.64–1.05; refs. 11, 23, 46) and the 21 studies with more comprehensive
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Table 2. Overall and stratified analyses of studies adjusted study effects for physical activity and pancreatic cancer risk Overall/stratified Total number Number Pooled RR analysis of studies of cases (95% CI) I2, % Overall 33 6664 0.89 (0.82–0.96) 22.1% Gender Combined 10 3003 0.79 (0.68–0.91) 31.2% Male 13 1936 0.95 (0.80–1.13) 32.3% Female 10 1539 0.92 (0.82–1.03) 0.0% Study design Cohort 25 4515 0.96 (0.91–1.02) 0.0% Case–control 8 1963 0.69 (0.59–0.81) 0.0% Population-based 6 937 0.74 (0.61–0.91) 0.0% Hospital-based 2 1026 0.63 (0.50–0.80) 0.0% Confounding adjustment No adjustment 3 535 0.84 (0.60–1.17) 19.8% Basic modela 4 533 0.82 (0.66–1.02) 0.0% a Basic model with smoking 1 291 0.78 (0.51–1.20) Otherb 25 5119 0.90 (0.82–0.98) 31.9% Location United States 11 2398 0.92 (0.80–1.05) 27.5% Canada 3 405 0.72 (0.52–1.00) 5.6% Europe 11 2448 0.84 (0.73–0.96) 34.2% Asia 8 1227 0.95 (0.80–1.13) 6.4% Median age at baseline/recruitment, y 60 11 2573 1.00 (0.89–1.12) 15.6% Median year of data collection Before 2000 31 5573 0.90 (0.84–0.97) 2.4% After 2000 2 1091 0.80 (0.50–1.28) 89.3% Incidence vs. mortality Incidence 28 6158 0.88 (0.81–0.96) 24.8% Mortality 5 506 0.96 (0.69–1.32) 22.8% Assessment of outcome Pathology reports 1 93 0.90 (0.54–1.50) ICD codes 12 2372 0.91 (0.79–1.05) 36.5% Cancer registry 8 1274 0.88 (0.76–1.02) 0.0% Multiple methods 10 2785 0.85 (0.72–1.02) 41.1% Subjective measures 2 140 0.83 (0.59–1.16) 0.0% Reporting period of physical activity Lifetime 20 4347 0.89 (0.80–0.98) 24.8% Past year 9 1749 0.98 (0.90–1.06) 0.0% 2–10 y 4 568 0.62 (0.46–0.84) 0.0% Type/intensity of physical activity WHO recommendations 9 2265 0.85 (0.69–1.05) 57.4% Quartiles/quintiles 5 838 0.80 (0.60–1.06) 42.8% Low vs. high (subjective) 11 2100 0.92 (0.82–1.03) 0.3% Frequency (times) 5 1192 0.92 (0.82–1.03) 0.0% Sports participation 3 269 0.99 (0.69–1.44) 0.0%
Pheterogeneity 0.130
P across subgroups
0.159 0.150 0.721
0.054
0.537 0.783 0.715 0.812
0.001
0.287 0.828
0.064
0.353
0.065 0.182 0.347 0.125 0.38
0.976
0.932 0.795 0.296
0.001
0.428 0.002
0.828
0.117 0.269
0.642
0.099 0.629 0.084 0.571
0.408
0.152 0.611 0.819
0.305
0.016 0.137 0.438 0.604 0.558
0.514
a
Age, sex, and site. Combination of basic, smoking, and/or other lifestyle/health factors.
b
covariate adjustment (RR, 0.97; 95% CI, 0.91–1.03; refs. 6– 8, 21, 22, 24, 36–43, 45, 47). In case–control studies (Table 4), there was sufficient agreement between all subgroup analyses including study characteristics, assessment of LTPA, and pancreatic cancer, accounting for little to no difference in effects. Investigating publication bias To determine whether publication bias was present, a funnel plot was produced and visually assessed for asymmetry and verified by the Begg test. On the funnel plot, there were "missing" small studies (large value for 1/se) showing a harmful effect (positive b). This visual finding was not supported by the Begg test (P ¼ 0.889); therefore, publication bias is not present in this meta-analysis.
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Discussion The results of this meta-analysis support a protective association between LTPA and pancreatic cancer risk, with a risk reduction of 9% in cohort studies, 31% in case–control studies, and despite heterogeneity, 11% overall. Although the magnitude of the association is not as high as for other physical activity and cancer site associations (15–17), this result may be attributable to several limitations of the present study, including heterogeneity between included studies, inconsistent measurements of LTPA, insufficient adjustment for confounding, and other methodologic limitations related to the conduct of studies regarding pancreatic cancer. LTPA is associated with reduced risk of several cancers, the observational epidemiologic evidence is classified as "convincing" for colon and breast cancer, "probable" for prostate
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Physical Activity and Pancreatic Cancer Risk: Meta-analysis
Table 3. Stratified analyses of cohort studies adjusted study effects for LTPA and pancreatic cancer risk Overall/stratified Total number Number Pooled RR analysis of studies of cases (95% CI) I2, % Gender Combined 7 1977 0.90 (0.81–1.00) 0.0% Male 10 1379 0.96 (0.85–1.10) 0.0% Female 8 1159 0.97 (0.79–1.19) 43.1% Confounding adjustment No adjustment 1 242 1.20 (0.63–2.27) Basic modela 3 292 0.82 (0.64–1.05) 0.0% Basic model with smokinga 0 0 b Other 21 3981 0.97 (0.91–1.03) 0.0% Location United States 8 1866 0.96 (0.82–1.13) 34.0% Europe 10 1622 0.95 (0.88–1.03) 0.0% Asia 7 1027 1.01 (0.85–1.20) 0.0% Median age at baseline/recruitment, y 60 11 2573 1.00 (0.89–1.12) 15.6% Median year of data collection Before 2000 24 4250 0.94 (0.87–1.01) 0.0% After 2000 1 265 1.00 (0.91–1.10) Incidence vs. mortality Incidence 20 4009 0.96 (0.91–1.02) 0.0% Mortality 5 506 0.96 (0.69–1.32) 22.8% Assessment of outcome Pathology reports 0 0 ICD codes 9 1874 0.98 (0.88–1.10) 14.0% Cancer registry 5 542 0.96 (0.80–1.15) 0.0% Multiple methods 9 1959 0.92 (0.80–1.05) 9.9% Subjective measures 2 140 0.83 (0.59–1.16) 0.0% Reporting period of physical activity Lifetime 16 2937 0.95 (0.87–1.03) 0.4% Past year 8 1508 0.98 (0.90–1.07) 0.0% 2–10 y 1 70 0.60 (0.28–1.30) Type/intensity of physical activity WHO recommendations 6 1127 0.99 (0.91–1.08) 0.0% Quartiles/quintiles 4 652 0.84 (0.61–1.15) 48.5% Low vs. high (subjective) 9 1568 0.93 (0.81–1.07) 13.0% Frequency (times) 3 899 0.94 (0.84–1.06) 0.0% Sports participation 3 269 0.99 (0.69–1.44) 0.0%
Pheterogeneity 0.583 0.940 0.091
P across subgroups 0.156
0.427 0.644 0.472 0.157 0.581 0.654
0.646
0.825 0.931 0.296
0.062
0.549
0.285
0.558 0.269
0.795
0.317 0.680 0.352 0.571
0.200
0.447 0.556
0.750
0.457 0.121 0.326 0.903 0.558
0.518
a
Age, sex, and site. Combination of basic, smoking, and/or other lifestyle/health factors.
b
cancer, and "possible" for endometrial and lung cancers (48, 49). There are several hypothesized biologic mechanisms whereby this reduction of risk may occur, including lowering of insulin levels, reduction of abdominal fat mass, elevated tolerance to oxidative stress through induction of antioxidant gene expression, and increased levels of various antitumor defenses (34, 49, 50). Specifically important for pancreatic cancer, LTPA improves insulin resistance through lowering fasting insulin and C-peptide levels and increasing insulin stimulated synthesis of glycogen in muscles (51, 52). As insulin resistance, hyperinsulinemia, and hyperglycemia have been hypothesized to play an important etiologic role in pancreatic carcinogenesis (53, 54), it is plausible that LTPA may exert protective effects through modulation of these pathways. Age is recognized a nonmodifiable risk factor for pancreatic cancer (55). Estimates from studies in this meta-analysis differed significantly in terms of median age of the study population. A significant protective effect was found in studies including participants of a younger median age (60 years. This finding
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is particularly of interest in the cohort studies, in which across subgroups, the strongest significant protective effects were observed among younger populations. This result suggests the impact of LTPA with pancreatic cancer risk reduction may be age-dependent and will dilute as age increases. In a rat model of pancreatic cancer, when compared with sedentary controls, aerobic LTPA inhibited pancreatic carcinogenesis when LTPA was implemented at 6 weeks of age but promoted pancreatic carcinogenesis when implemented at 13 weeks of age, suggesting that the effect of LTPA on pancreatic carcinogenesis may vary with age (56). There is also evidence that increased duration of some exposures, such as adiposity (57) and smoking (58), may result in increased pancreatic cancer risk. This risk accumulation may diminish the apparent protective effect of LTPA in older populations. Noncausal explanations for the protective association between LTPA and pancreatic cancer risk should also be considered. Adjustment for confounding variables was limited; other modifiable factors were not accounted for in all of these studies and therefore, residual confounding may be present. A significant
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Table 4. Stratified analyses of case–control studies adjusted study effects for LTPA and pancreatic cancer risk Overall/stratified Total number Number Pooled RR analysis of studies of cases (95% CI) I2, % Gender Combined 3 1212 0.63 (0.51–0.79) 0.0% Male 3 557 0.73 (0.55–0.98) 0.0% Female 2 380 0.83 (0.58–1.19) 0.0% Selection of controls Population-based 6 1123 0.74 (0.61–0.91) 0.0% Hospital-based 2 1026 0.63 (0.50–0.80) 0.0% Confounding adjustment No adjustment 2 293 0.75 (0.54–1.04) 0.0% Basic modela 1 241 0.84 (0.54–1.30) 1 291 0.78 (0.51–1.20) Basic model with smokinga Otherb 4 1324 0.62 (0.50–0.77) 0.0% Location United States 3 718 0.76 (0.58–1.00) 0.0% Canada 3 405 0.72 (0.52–1.00) 5.6% Europe 1 826 0.62 (0.46–0.83) Asia 1 200 0.66 (0.43–1.01) Median age at baseline/recruitment, y 60 0 0 Median year of data collection Before 2000 7 1323 0.73 (0.60–0.88) 0.0% After 2000 1 826 0.62 (0.46–0.83) Incidence vs. mortality Incidence 8 2149 0.69 (0.59–0.81) 0.0% Mortality 0 0 Assessment of outcome Pathology reports 1 93 0.90 (0.54–1.50) ICD codes 3 498 0.62 (0.45–0.87) 0.0% Cancer registry 3 732 0.75 (0.59–0.97) 0.0% Multiple methods 1 826 0.62 (0.46–0.83) Subjective measures 0 0 Reporting period of physical activity Lifetime 4 1410 0.69 (0.57–0.84) 0.0% Past year 1 241 0.84 (0.54–1.30) 2–10 y 3 498 0.62 (0.45–0.87) 0.0% Type/intensity of physical activity WHO recommendations 3 1138 0.62 (0.49–0.79) 0.0% Quartiles/quintiles 1 186 0.62 (0.35–1.09) Low vs. high (subjective) 2 532 0.81 (0.60–1.10) 0.0% Frequency (times) 2 293 0.75 (0.54–1.04) 0.0% Sports participation 0 0
Pheterogeneity
P across subgroups
0.970 0.343 0.903
0.234
0.715 0.812
0.353
0.361
0.249
0.821 0.699 0.347
0.680
0.632 0.813
0.268
0.783
0.400
0.783
0.632 0.728
0.473
0.592
0.727
0.632 0.632
0.260
0.813 0.361
a
Age, sex, and site. Combination of basic, smoking, and/or other lifestyle/health factors.
b
difference in adjustment for confounders was found between studies. Smoking was often adjusted for, but other unhealthy behaviors associated with smoking, such as alcohol consumption, poor diet, family history of cancer, or presence of other chronic conditions, were not consistently included as confounders, which have been shown to be probable risk factors for pancreatic cancer (26, 57, 58). It is possible that those who participate in LTPA are also likely to make other healthy lifestyle choices and vice versa. The observed protective effect, therefore, may be attributable to these factors, as opposed to LTPA itself. It is also possible that confounding factors may mask the "real" association, therefore leading to an underestimation of the protective effects of LTPA. In support of this possibility, those studies adjusting for a higher number of potential confounders observed significant results. Future studies should consistently involve a comprehensive list of covariate information to isolate this relation further and reduce the chance of spurious or attenuated associations. Through careful
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methodologic considerations, the issues of residual confounding, reverse causation, and selection bias may subside. However, because of the nature of the studies included in this review, these concerns are still present. The issue of reverse causality where the potential for subclinical disease prior to study recruitment may exist resulting in study participants not feeling well and therefore, not exercising, should be considered. More definitive methods for identifying pancreatic cancer cases through screening programs and early diagnosis would reduce the concern of reverse causality. Moreover, because of the nature of case–control studies, selection bias may be present. Controls who choose to participate in research studies tend to be more healthy, have a different distribution of LTPA and, therefore, may cause an overinflation in the risk estimate. This meta-analysis was strengthened by the large number of studies included, allowing for extensive subgroup analysis to characterize various subgroups of interest and examine potential
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Physical Activity and Pancreatic Cancer Risk: Meta-analysis
sources of heterogeneity. Furthermore, the subgroup analysis by characterization of LTPA was a considerable strength in this study; the WHO recommendations may be incorporated in the development of future studies assessing this relation. The implications of these results are strengthened regarding LTPA as an easily targeted modifiable behavior change from a public health perspective in comparison to overall physical activity and other types of physical activity examined in past meta-analyses (19, 20, 26). Furthermore, from a methodologic perspective, many studies do not include any or adequate measures of occupational, household- and transportation-related activity, therefore, there is an increased potential for publication bias or gaps in this literature when examining total physical activity in comparison to LTPA. In the analysis stratified by study design, we observed significant differences in results between case–control and cohort studies. The magnitude of effect in the majority of case–control studies was generally lower in comparison to cohort studies. This likely is related to the more detailed assessments of LTPA that is often done and possible in case–control studies and would have decreased some measurement error associated with these assessments. All included studies measured LTPA through subjective measures and, therefore, may be subject to misclassification of LTPA. Misclassification may be exacerbated by differential recall, as case–control studies are more prone to recall bias (59). Consequently, risk estimates obtained from self-reported questionnaires may be attenuated (60). LTPA is inherently difficult to measure because it includes many unstructured activities that occur in different contexts. To examine the relation and reduce measurement bias in LTPA reporting more accurately, we performed subgroup analyses identifying characteristics of LTPA by intensity. However, we were limited in this analysis by the LTPA assessments used in these studies and, consequently, a need exists in future studies to include more accurate reports of LTPA through the use of objective measurements such as with activity monitors or supervised LTPA. A second concern in our meta-analysis is that the primary analysis compared lowest versus highest LTPA to assess the risk of pancreatic cancer. In making this comparison, the assumption was that the relationship between LTPA and pancreatic cancer risk is relatively uniform and appropriate for this meta-analysis. However, some studies' highest measure of LTPA may be equivalent to other studies' middle measure of LTPA, in which case an underestimate of the association may occur. This limitation underscores the importance for future studies to conform to a uniform method of reporting LTPA, for example, through use of the guidelines made by the WHO Global Recommendations for Physical Activity and Health (29). In so doing, comparability between studies would be improved that would permit better assessments across
populations. Although we found a non-statistically significant risk reduction among the 9 studies reporting LTPA corresponding to WHO recommendations (8, 18, 21, 22, 25, 41), this finding may be attributable to the moderately high heterogeneity among these studies. An important risk reduction may be present in these studies that could be more fully assessed with a pooled analysis that would apply a common definition for LTPA across studies. Such an analysis would still be limited by the original methods used for assessing LTPA and the heterogeneity across studies could not be fully resolved. A pooled analysis could also address some of the issues that arise when comparing populations that have underlying differences in levels of LTPA. To address the concerns, in part, we used random-effects models to combine the risk estimates. This approach made the assumption that the true effect is being sampled from a distribution of effects. Therefore, this method accounts statistically, to some extent, for differences in measurements and definitions of LTPA. In conclusion, the current data suggest a statistically significant association between LTPA and pancreatic cancer risk. While the effects are comparatively small (11% risk reduction), this finding may be attributable to several limiting factors of the present study and to the fact that the protective effect of LTPA may depend on age. There is substantial evidence in other cancer sites for the beneficial effect of LTPA on cancer risk, and biological plausibility also exists for an effect of LTPA in pancreatic cancer etiology. To incorporate the benefits of LTPA in potentially reducing the risk of pancreatic cancer, future research should focus on more accurate measures of LTPA, such as supervised LTPA and activity monitors.
Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
Acknowledgments The authors thank Marcus Vaska for his support in generating a search strategy. The authors would like to thank Dr. Doreen Rabi and Dr. Derek Roberts for their contributions to the development of the study protocol and guidance with the drafting of the manuscript.
Grant Support C.M. Friedenreich was supported by Alberta Innovates Health Solutions Health Senior Scholar Award and Alberta Cancer Foundation Weekend to End Women's Cancers Breast Cancer Chair. 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 March 20, 2015; revised June 3, 2015; accepted July 9, 2015; published OnlineFirst July 14, 2015.
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The Association between Leisure Time Physical Activity and Pancreatic Cancer Risk in Adults: A Systematic Review and Meta-analysis Megan S. Farris, Mohammed H. Mosli, Alison A. McFadden, et al. Cancer Epidemiol Biomarkers Prev 2015;24:1462-1473. Published OnlineFirst July 14, 2015.
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Review
The Association between Leisure Time Physical Activity and Pancreatic Cancer Risk in Adults: A Systematic Review and Meta-analysis
Cancer Epidemiology, Biomarkers & Prevention
Megan S. Farris1,2, Mohammed H. Mosli2,3, Alison A. McFadden1, Christine M. Friedenreich1,2,4, and Darren R. Brenner1,4
Abstract We conducted a meta-analysis of the association between leisure time physical activity (LTPA) and risk of pancreatic cancer to update previous analyses in light of newly published studies, to examine subgroups of interest and potential sources of heterogeneity. We searched the PubMed and MEDLINE databases for studies until February 2015. Study information was collected using a standardized form to abstract relevant data on study design, number of cases, participant and study characteristics, assessment of LTPA, risk estimates, and adjustments for confounding by two independent abstractors. We used randomeffects models to pool estimates from included studies of lowest versus highest comparison of LTPA. The search identified 26 studies eligible for inclusion into the meta-analysis. The combined summary risk estimate was [relative risk (RR), 0.89; 95% confidence interval (CI), 0.82–0.96]. There was evidence of
heterogeneity across studies (I2 ¼ 22.1%, Pheterogeneity ¼ 0.130). Some of the heterogeneity could be explained by study design, with stronger protective effects observed among case– control studies (RR, 0.69; 95% CI, 0.59–0.81) compared with cohort studies (RR, 0.96; 95% CI, 0.91–1.02). Across study designs, age of population was a source of heterogeneity, with stronger effects observed among younger (75 min/wk of vigorous LTPA; ref. 29). Risk estimates reporting LTPA in quartiles/quintiles showed evidence of risk reduction (RR, 0.80; 95% CI, 0.60–1.06; refs. 6, 9, 11, 37), whereas low versus high (RR, 0.92; 95% CI, 0.82–1.03; refs. 33, 36, 38–40, 43, 45–47) and frequency measures (sessions per week; RR, 0.92; 95% CI, 0.92–1.03; refs. 7, 15, 34, 42) subgroups produced limited evidence of a protective effect. In addition, the sports participation subgroup reported no effect (RR, 0.99; 95% CI, 0.69–1.44; refs. 23, 24, 44). With respect to the duration of activity, lifetime (RR, 0.89; 95% CI, 0.80–0.98; refs. 7, 11, 15, 23–25, 34, 36, 37, 39–42, 44–47) and studies that assessed 2–10 years of activity (RR, 0.62; 95% CI, 0.46–0.84; refs. 9, 18) supported a protective effect; however, past year reporting of LTPA revealed no association (6, 8, 21, 22, 33, 38, 43). Investigating heterogeneity Both study design and median age of the study population were statistically significant sources of heterogeneity across studies (P ¼ 0.001) according to meta-regression. Other study characteristics accounting for heterogeneity across studies were the confounding variables used for adjustment (P ¼ 0.064) and gender (P ¼ 0.054). Effects were also heterogeneous within and across LTPA level characterizations, for example, heterogeneity among risk estimates reporting under the WHO recommendations was moderately high (I2 ¼ 57.4%, Pheterogeneity ¼ 0.016). This heterogeneity may be accounted for by either Stevens and colleagues (8) or Brenner and colleagues (25), as when these studies were removed,
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0.5
1.0 OR/RR
2.0
5.0
10.0
the I2 statistic decreased by 18% and 25%, respectively, and became non-statistically significant. No other studies in the subgroup analysis based on the recommended levels of LTPA as defined by the WHO made any significant difference in the heterogeneity. In addition, for 4 studies that reported risk estimates for LTPA as quartiles or quintiles, there was moderate but non-statistically significant heterogeneity (I2 ¼ 42.8%, Pheterogeneity ¼ 0.137; refs. 6, 9, 11, 37). When Nothlings (6) was removed, the heterogeneity decreased by 42.8%. When Stevens and colleagues (8), Brenner and colleagues (25), and Nothlings (6) were excluded, heterogeneity is substantially reduced in the overall results (I2 ¼ 0.0%, Pheterogeneity ¼ 0.467). Furthermore, within cohort studies and case–control studies, there was very good agreement overall, thus heterogeneity may be indicative of a difference in magnitude of effect between study designs. In addition, 25 studies reporting effects from models with more detailed covariate adjustment supported a statistically significant protective effect (RR, 0.90; 95% CI, 0.82–0.98; refs. 6– 9, 18, 21, 22, 24, 25, 36–43, 45, 47), in comparison to other confounder subgroups. Cohort and case–control specific analyses In cohort studies alone (Table 3), age of the population was also a determinant of differences in effect estimates. Studies with median age of 60 years' subgroups (RR, 1.00; 95% CI, 0.89–1.12; refs. 6, 7, 21, 22, 43–45, 47). We also observed large differences in the effects between the one risk estimate with no covariate adjustment (RR, 1.20; 95% CI, 0.63–2.27; ref. 44) in comparison to the 3 studies with basic covariate adjustment (RR, 0.82; 95% CI, 0.64–1.05; refs. 11, 23, 46) and the 21 studies with more comprehensive
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Table 2. Overall and stratified analyses of studies adjusted study effects for physical activity and pancreatic cancer risk Overall/stratified Total number Number Pooled RR analysis of studies of cases (95% CI) I2, % Overall 33 6664 0.89 (0.82–0.96) 22.1% Gender Combined 10 3003 0.79 (0.68–0.91) 31.2% Male 13 1936 0.95 (0.80–1.13) 32.3% Female 10 1539 0.92 (0.82–1.03) 0.0% Study design Cohort 25 4515 0.96 (0.91–1.02) 0.0% Case–control 8 1963 0.69 (0.59–0.81) 0.0% Population-based 6 937 0.74 (0.61–0.91) 0.0% Hospital-based 2 1026 0.63 (0.50–0.80) 0.0% Confounding adjustment No adjustment 3 535 0.84 (0.60–1.17) 19.8% Basic modela 4 533 0.82 (0.66–1.02) 0.0% a Basic model with smoking 1 291 0.78 (0.51–1.20) Otherb 25 5119 0.90 (0.82–0.98) 31.9% Location United States 11 2398 0.92 (0.80–1.05) 27.5% Canada 3 405 0.72 (0.52–1.00) 5.6% Europe 11 2448 0.84 (0.73–0.96) 34.2% Asia 8 1227 0.95 (0.80–1.13) 6.4% Median age at baseline/recruitment, y 60 11 2573 1.00 (0.89–1.12) 15.6% Median year of data collection Before 2000 31 5573 0.90 (0.84–0.97) 2.4% After 2000 2 1091 0.80 (0.50–1.28) 89.3% Incidence vs. mortality Incidence 28 6158 0.88 (0.81–0.96) 24.8% Mortality 5 506 0.96 (0.69–1.32) 22.8% Assessment of outcome Pathology reports 1 93 0.90 (0.54–1.50) ICD codes 12 2372 0.91 (0.79–1.05) 36.5% Cancer registry 8 1274 0.88 (0.76–1.02) 0.0% Multiple methods 10 2785 0.85 (0.72–1.02) 41.1% Subjective measures 2 140 0.83 (0.59–1.16) 0.0% Reporting period of physical activity Lifetime 20 4347 0.89 (0.80–0.98) 24.8% Past year 9 1749 0.98 (0.90–1.06) 0.0% 2–10 y 4 568 0.62 (0.46–0.84) 0.0% Type/intensity of physical activity WHO recommendations 9 2265 0.85 (0.69–1.05) 57.4% Quartiles/quintiles 5 838 0.80 (0.60–1.06) 42.8% Low vs. high (subjective) 11 2100 0.92 (0.82–1.03) 0.3% Frequency (times) 5 1192 0.92 (0.82–1.03) 0.0% Sports participation 3 269 0.99 (0.69–1.44) 0.0%
Pheterogeneity 0.130
P across subgroups
0.159 0.150 0.721
0.054
0.537 0.783 0.715 0.812
0.001
0.287 0.828
0.064
0.353
0.065 0.182 0.347 0.125 0.38
0.976
0.932 0.795 0.296
0.001
0.428 0.002
0.828
0.117 0.269
0.642
0.099 0.629 0.084 0.571
0.408
0.152 0.611 0.819
0.305
0.016 0.137 0.438 0.604 0.558
0.514
a
Age, sex, and site. Combination of basic, smoking, and/or other lifestyle/health factors.
b
covariate adjustment (RR, 0.97; 95% CI, 0.91–1.03; refs. 6– 8, 21, 22, 24, 36–43, 45, 47). In case–control studies (Table 4), there was sufficient agreement between all subgroup analyses including study characteristics, assessment of LTPA, and pancreatic cancer, accounting for little to no difference in effects. Investigating publication bias To determine whether publication bias was present, a funnel plot was produced and visually assessed for asymmetry and verified by the Begg test. On the funnel plot, there were "missing" small studies (large value for 1/se) showing a harmful effect (positive b). This visual finding was not supported by the Begg test (P ¼ 0.889); therefore, publication bias is not present in this meta-analysis.
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Discussion The results of this meta-analysis support a protective association between LTPA and pancreatic cancer risk, with a risk reduction of 9% in cohort studies, 31% in case–control studies, and despite heterogeneity, 11% overall. Although the magnitude of the association is not as high as for other physical activity and cancer site associations (15–17), this result may be attributable to several limitations of the present study, including heterogeneity between included studies, inconsistent measurements of LTPA, insufficient adjustment for confounding, and other methodologic limitations related to the conduct of studies regarding pancreatic cancer. LTPA is associated with reduced risk of several cancers, the observational epidemiologic evidence is classified as "convincing" for colon and breast cancer, "probable" for prostate
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Physical Activity and Pancreatic Cancer Risk: Meta-analysis
Table 3. Stratified analyses of cohort studies adjusted study effects for LTPA and pancreatic cancer risk Overall/stratified Total number Number Pooled RR analysis of studies of cases (95% CI) I2, % Gender Combined 7 1977 0.90 (0.81–1.00) 0.0% Male 10 1379 0.96 (0.85–1.10) 0.0% Female 8 1159 0.97 (0.79–1.19) 43.1% Confounding adjustment No adjustment 1 242 1.20 (0.63–2.27) Basic modela 3 292 0.82 (0.64–1.05) 0.0% Basic model with smokinga 0 0 b Other 21 3981 0.97 (0.91–1.03) 0.0% Location United States 8 1866 0.96 (0.82–1.13) 34.0% Europe 10 1622 0.95 (0.88–1.03) 0.0% Asia 7 1027 1.01 (0.85–1.20) 0.0% Median age at baseline/recruitment, y 60 11 2573 1.00 (0.89–1.12) 15.6% Median year of data collection Before 2000 24 4250 0.94 (0.87–1.01) 0.0% After 2000 1 265 1.00 (0.91–1.10) Incidence vs. mortality Incidence 20 4009 0.96 (0.91–1.02) 0.0% Mortality 5 506 0.96 (0.69–1.32) 22.8% Assessment of outcome Pathology reports 0 0 ICD codes 9 1874 0.98 (0.88–1.10) 14.0% Cancer registry 5 542 0.96 (0.80–1.15) 0.0% Multiple methods 9 1959 0.92 (0.80–1.05) 9.9% Subjective measures 2 140 0.83 (0.59–1.16) 0.0% Reporting period of physical activity Lifetime 16 2937 0.95 (0.87–1.03) 0.4% Past year 8 1508 0.98 (0.90–1.07) 0.0% 2–10 y 1 70 0.60 (0.28–1.30) Type/intensity of physical activity WHO recommendations 6 1127 0.99 (0.91–1.08) 0.0% Quartiles/quintiles 4 652 0.84 (0.61–1.15) 48.5% Low vs. high (subjective) 9 1568 0.93 (0.81–1.07) 13.0% Frequency (times) 3 899 0.94 (0.84–1.06) 0.0% Sports participation 3 269 0.99 (0.69–1.44) 0.0%
Pheterogeneity 0.583 0.940 0.091
P across subgroups 0.156
0.427 0.644 0.472 0.157 0.581 0.654
0.646
0.825 0.931 0.296
0.062
0.549
0.285
0.558 0.269
0.795
0.317 0.680 0.352 0.571
0.200
0.447 0.556
0.750
0.457 0.121 0.326 0.903 0.558
0.518
a
Age, sex, and site. Combination of basic, smoking, and/or other lifestyle/health factors.
b
cancer, and "possible" for endometrial and lung cancers (48, 49). There are several hypothesized biologic mechanisms whereby this reduction of risk may occur, including lowering of insulin levels, reduction of abdominal fat mass, elevated tolerance to oxidative stress through induction of antioxidant gene expression, and increased levels of various antitumor defenses (34, 49, 50). Specifically important for pancreatic cancer, LTPA improves insulin resistance through lowering fasting insulin and C-peptide levels and increasing insulin stimulated synthesis of glycogen in muscles (51, 52). As insulin resistance, hyperinsulinemia, and hyperglycemia have been hypothesized to play an important etiologic role in pancreatic carcinogenesis (53, 54), it is plausible that LTPA may exert protective effects through modulation of these pathways. Age is recognized a nonmodifiable risk factor for pancreatic cancer (55). Estimates from studies in this meta-analysis differed significantly in terms of median age of the study population. A significant protective effect was found in studies including participants of a younger median age (60 years. This finding
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is particularly of interest in the cohort studies, in which across subgroups, the strongest significant protective effects were observed among younger populations. This result suggests the impact of LTPA with pancreatic cancer risk reduction may be age-dependent and will dilute as age increases. In a rat model of pancreatic cancer, when compared with sedentary controls, aerobic LTPA inhibited pancreatic carcinogenesis when LTPA was implemented at 6 weeks of age but promoted pancreatic carcinogenesis when implemented at 13 weeks of age, suggesting that the effect of LTPA on pancreatic carcinogenesis may vary with age (56). There is also evidence that increased duration of some exposures, such as adiposity (57) and smoking (58), may result in increased pancreatic cancer risk. This risk accumulation may diminish the apparent protective effect of LTPA in older populations. Noncausal explanations for the protective association between LTPA and pancreatic cancer risk should also be considered. Adjustment for confounding variables was limited; other modifiable factors were not accounted for in all of these studies and therefore, residual confounding may be present. A significant
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Table 4. Stratified analyses of case–control studies adjusted study effects for LTPA and pancreatic cancer risk Overall/stratified Total number Number Pooled RR analysis of studies of cases (95% CI) I2, % Gender Combined 3 1212 0.63 (0.51–0.79) 0.0% Male 3 557 0.73 (0.55–0.98) 0.0% Female 2 380 0.83 (0.58–1.19) 0.0% Selection of controls Population-based 6 1123 0.74 (0.61–0.91) 0.0% Hospital-based 2 1026 0.63 (0.50–0.80) 0.0% Confounding adjustment No adjustment 2 293 0.75 (0.54–1.04) 0.0% Basic modela 1 241 0.84 (0.54–1.30) 1 291 0.78 (0.51–1.20) Basic model with smokinga Otherb 4 1324 0.62 (0.50–0.77) 0.0% Location United States 3 718 0.76 (0.58–1.00) 0.0% Canada 3 405 0.72 (0.52–1.00) 5.6% Europe 1 826 0.62 (0.46–0.83) Asia 1 200 0.66 (0.43–1.01) Median age at baseline/recruitment, y 60 0 0 Median year of data collection Before 2000 7 1323 0.73 (0.60–0.88) 0.0% After 2000 1 826 0.62 (0.46–0.83) Incidence vs. mortality Incidence 8 2149 0.69 (0.59–0.81) 0.0% Mortality 0 0 Assessment of outcome Pathology reports 1 93 0.90 (0.54–1.50) ICD codes 3 498 0.62 (0.45–0.87) 0.0% Cancer registry 3 732 0.75 (0.59–0.97) 0.0% Multiple methods 1 826 0.62 (0.46–0.83) Subjective measures 0 0 Reporting period of physical activity Lifetime 4 1410 0.69 (0.57–0.84) 0.0% Past year 1 241 0.84 (0.54–1.30) 2–10 y 3 498 0.62 (0.45–0.87) 0.0% Type/intensity of physical activity WHO recommendations 3 1138 0.62 (0.49–0.79) 0.0% Quartiles/quintiles 1 186 0.62 (0.35–1.09) Low vs. high (subjective) 2 532 0.81 (0.60–1.10) 0.0% Frequency (times) 2 293 0.75 (0.54–1.04) 0.0% Sports participation 0 0
Pheterogeneity
P across subgroups
0.970 0.343 0.903
0.234
0.715 0.812
0.353
0.361
0.249
0.821 0.699 0.347
0.680
0.632 0.813
0.268
0.783
0.400
0.783
0.632 0.728
0.473
0.592
0.727
0.632 0.632
0.260
0.813 0.361
a
Age, sex, and site. Combination of basic, smoking, and/or other lifestyle/health factors.
b
difference in adjustment for confounders was found between studies. Smoking was often adjusted for, but other unhealthy behaviors associated with smoking, such as alcohol consumption, poor diet, family history of cancer, or presence of other chronic conditions, were not consistently included as confounders, which have been shown to be probable risk factors for pancreatic cancer (26, 57, 58). It is possible that those who participate in LTPA are also likely to make other healthy lifestyle choices and vice versa. The observed protective effect, therefore, may be attributable to these factors, as opposed to LTPA itself. It is also possible that confounding factors may mask the "real" association, therefore leading to an underestimation of the protective effects of LTPA. In support of this possibility, those studies adjusting for a higher number of potential confounders observed significant results. Future studies should consistently involve a comprehensive list of covariate information to isolate this relation further and reduce the chance of spurious or attenuated associations. Through careful
1470 Cancer Epidemiol Biomarkers Prev; 24(10) October 2015
methodologic considerations, the issues of residual confounding, reverse causation, and selection bias may subside. However, because of the nature of the studies included in this review, these concerns are still present. The issue of reverse causality where the potential for subclinical disease prior to study recruitment may exist resulting in study participants not feeling well and therefore, not exercising, should be considered. More definitive methods for identifying pancreatic cancer cases through screening programs and early diagnosis would reduce the concern of reverse causality. Moreover, because of the nature of case–control studies, selection bias may be present. Controls who choose to participate in research studies tend to be more healthy, have a different distribution of LTPA and, therefore, may cause an overinflation in the risk estimate. This meta-analysis was strengthened by the large number of studies included, allowing for extensive subgroup analysis to characterize various subgroups of interest and examine potential
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sources of heterogeneity. Furthermore, the subgroup analysis by characterization of LTPA was a considerable strength in this study; the WHO recommendations may be incorporated in the development of future studies assessing this relation. The implications of these results are strengthened regarding LTPA as an easily targeted modifiable behavior change from a public health perspective in comparison to overall physical activity and other types of physical activity examined in past meta-analyses (19, 20, 26). Furthermore, from a methodologic perspective, many studies do not include any or adequate measures of occupational, household- and transportation-related activity, therefore, there is an increased potential for publication bias or gaps in this literature when examining total physical activity in comparison to LTPA. In the analysis stratified by study design, we observed significant differences in results between case–control and cohort studies. The magnitude of effect in the majority of case–control studies was generally lower in comparison to cohort studies. This likely is related to the more detailed assessments of LTPA that is often done and possible in case–control studies and would have decreased some measurement error associated with these assessments. All included studies measured LTPA through subjective measures and, therefore, may be subject to misclassification of LTPA. Misclassification may be exacerbated by differential recall, as case–control studies are more prone to recall bias (59). Consequently, risk estimates obtained from self-reported questionnaires may be attenuated (60). LTPA is inherently difficult to measure because it includes many unstructured activities that occur in different contexts. To examine the relation and reduce measurement bias in LTPA reporting more accurately, we performed subgroup analyses identifying characteristics of LTPA by intensity. However, we were limited in this analysis by the LTPA assessments used in these studies and, consequently, a need exists in future studies to include more accurate reports of LTPA through the use of objective measurements such as with activity monitors or supervised LTPA. A second concern in our meta-analysis is that the primary analysis compared lowest versus highest LTPA to assess the risk of pancreatic cancer. In making this comparison, the assumption was that the relationship between LTPA and pancreatic cancer risk is relatively uniform and appropriate for this meta-analysis. However, some studies' highest measure of LTPA may be equivalent to other studies' middle measure of LTPA, in which case an underestimate of the association may occur. This limitation underscores the importance for future studies to conform to a uniform method of reporting LTPA, for example, through use of the guidelines made by the WHO Global Recommendations for Physical Activity and Health (29). In so doing, comparability between studies would be improved that would permit better assessments across
populations. Although we found a non-statistically significant risk reduction among the 9 studies reporting LTPA corresponding to WHO recommendations (8, 18, 21, 22, 25, 41), this finding may be attributable to the moderately high heterogeneity among these studies. An important risk reduction may be present in these studies that could be more fully assessed with a pooled analysis that would apply a common definition for LTPA across studies. Such an analysis would still be limited by the original methods used for assessing LTPA and the heterogeneity across studies could not be fully resolved. A pooled analysis could also address some of the issues that arise when comparing populations that have underlying differences in levels of LTPA. To address the concerns, in part, we used random-effects models to combine the risk estimates. This approach made the assumption that the true effect is being sampled from a distribution of effects. Therefore, this method accounts statistically, to some extent, for differences in measurements and definitions of LTPA. In conclusion, the current data suggest a statistically significant association between LTPA and pancreatic cancer risk. While the effects are comparatively small (11% risk reduction), this finding may be attributable to several limiting factors of the present study and to the fact that the protective effect of LTPA may depend on age. There is substantial evidence in other cancer sites for the beneficial effect of LTPA on cancer risk, and biological plausibility also exists for an effect of LTPA in pancreatic cancer etiology. To incorporate the benefits of LTPA in potentially reducing the risk of pancreatic cancer, future research should focus on more accurate measures of LTPA, such as supervised LTPA and activity monitors.
Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
Acknowledgments The authors thank Marcus Vaska for his support in generating a search strategy. The authors would like to thank Dr. Doreen Rabi and Dr. Derek Roberts for their contributions to the development of the study protocol and guidance with the drafting of the manuscript.
Grant Support C.M. Friedenreich was supported by Alberta Innovates Health Solutions Health Senior Scholar Award and Alberta Cancer Foundation Weekend to End Women's Cancers Breast Cancer Chair. 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 March 20, 2015; revised June 3, 2015; accepted July 9, 2015; published OnlineFirst July 14, 2015.
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The Association between Leisure Time Physical Activity and Pancreatic Cancer Risk in Adults: A Systematic Review and Meta-analysis Megan S. Farris, Mohammed H. Mosli, Alison A. McFadden, et al. Cancer Epidemiol Biomarkers Prev 2015;24:1462-1473. Published OnlineFirst July 14, 2015.
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