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Physical Activity and Risk of Lung Cancer: A Meta-analysis

Zhong, Shanliang MA; Ma, Tengfei MA; Chen, Lin MA; Chen, Weixian PhD; Lv, Mengmeng MA; Zhang, Xiaohui MA; Zhao, Jianhua MA

Clinical Journal of Sport Medicine: May 2016 - Volume 26 - Issue 3 - p 173–181
doi: 10.1097/JSM.0000000000000219
General Review

Objective: Previous studies concerning the association between physical activity (PA) and risk of lung cancer yielded mixed results. We investigated the association by performing a meta-analysis.

Data Sources: Relevant studies were identified by searching PubMed and EMBASE to January 2014. Twelve cohort studies and 6 case–control studies involving 2 468 470 participants and 26 453 cases of lung cancer were selected for meta-analysis.

Main Results: We calculated the summary relative risk (RR) and 95% confidence intervals (CIs) using random-effects models. The analyses showed that individuals who participated in any amount of PA had an RR of 0.79 (95% CI, 0.73-0.86) for risk of lung cancer. Those who participated in high PA (vs low PA) had an RR of 0.75 (95% CI, 0.68-0.84). Stratifying by study design (case–control and cohort studies), smoking status (current, former, and never smokers), and gender, similar inverse associations were found for all the subgroups except for never smokers subgroup.

Conclusions: Pooled results from observational studies support a protective effect of PA against lung cancer.

Supplemental Digital Content is Available in the Text.

*Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China;

Teaching and Research Office of General Surgery, Xuzhou Medical College, Xuzhou, China; and

Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.

Corresponding Author: Jianhua Zhao, MA, Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing 210009, China (seuzsl@163.com).

Supported by the National Natural Science Foundation of China (81272470).

The authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.cjsportmed.com).

Received March 01, 2014

Accepted March 09, 2015

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INTRODUCTION

Lung cancer, one of the most common types of cancer, is the leading cause of cancer-related death in the worldwide and one of the most incurable cancers due to late presentation, disease relapse, and low rate of curative therapy.1 In addition to the role of smoking, indoor radon, household coal smoke, prior lung disease, and genetic susceptibility in the etiology of lung cancers, increasing evidence implicates physical inactivity as a risk factor.2 Because especially leisure-time physical activity (PA) is usually associated with a generally healthier lifestyle, the independent role of PA in the etiology of cancer may be difficult to demonstrate. A number of epidemiologic studies have sought to establish a relationship between PA and risk of lung cancer in the past 3 decades but with varying results. Two latest meta-analyses3,4 have explored the association between PA and risk of lung cancer. The first one,3 including the results of 14 cohort studies, found an overall relative risk (RR) of 0.77 [95% confidence interval (CI), 0.73-0.81] for high level of PA and 0.87 (95% CI, 0.83-0.90) for medium level of PA, when compared with the reference group with low level of PA. However, the 14 cohort studies have included 3 studies5–7 whose subjects were overlapped in another 3 included studies,8–10 thereby contributing to a bias. The second one4 has only explored the association in smokers. Therefore, we systematically conducted a meta-analysis by combining all available data of studies to derive a more precise estimation of this association.

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METHODS

Literature Search

We searched PubMed and EMBASE for studies in humans of the association between PA and risk of lung cancer. The search strategy used the terms “exercise,” “physical activity,” “motor activity,” “lung cancer,” and “risk.” The latest date of this search was January 2014. Reference lists from relevant review articles were examined manually to further identify potentially relevant studies. All searches were conducted independently by 2 reviewers; differences were checked by the 2 and resolved by discussion. When more than one of the same patient population was included in several publications, only the most recent or largest population was used in this meta-analysis.

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Inclusion Criteria

The following inclusion criteria were used in selecting literature for further meta-analysis: (1) the exposure of interest was PA; (2) the outcomes of interest were lung cancer; (3) the type of study was cohort or case–control; and (4) the RR and 95% CIs were reported (or information to calculate them).

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Data Extraction

Two investigators extracted the data independently. Discrepancies were adjudicated by the third investigator until consensus was achieved on every item. The following information was abstracted from each included articles: the name of the first author, year of publication, country origin, follow-up period, sample size, PA measurements, the RRs and corresponding 95% CIs, and confounders adjusted for in multivariate analysis, respectively. For studies that provided more than one RR, the RRs from multivariate models with the most completed adjustment for confounding factors were abstracted for analyses.

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Assessment of Methodological Quality

The methodological quality of the included studies was independently evaluated by 2 investigators using the Newcastle–Ottawa Scale (NOS).11 Each study was assessed based on 3 broad perspectives: selection, comparability, and exposure with a score ranging from 0 to 9. A score of 7 or greater indicated that 1 study was of high quality. Discrepancies were adjudicated through discussion and re-evaluation of the methodology of the study in question.

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Statistical Methods

All statistical analyses were performed with Stata software (version 12; Stata Corporation, College Station, Texas), and all tests were 2 sided. If a study provided separate OR or RR estimates for men and women, we treated them as 2 different studies.8,12,13 The natural logarithm of the RR from each study was combined to estimate a summary of RR for PA and risk of lung cancer using the DerSimonian and Laird random-effects model14 that accounts for both within- and between-study variation. For each study, low-level PA represented the reference category, high-level PA represented the highest category, moderate-level PA represented in-between, and moderate-high level of PA represented both low- and moderate-level PA. First, we compared high level of PA with low PA. Second, estimates comparing the moderate level of PA to low PA were calculated. Third, estimates were also calculated for moderate to high level of PA. For studies not report a risk estimate for moderate PA or moderate to high level of PA, a summary estimate was calculated using reported risk estimate for each PA category. Statistical heterogeneity among studies was assessed with the Q and I 2 statistics15; and P < 0.1 was considered significant.16 Meta-regression17 was conducted to further explore the heterogeneity quantitatively for among the studies. Sensitivity analyses were performed to reflect the influence of the individual data on the summary RRs. Publication bias was evaluated using the Begg and Egger test.18

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RESULTS

Characteristics of the Studies

Figure 1 outlines the search strategy used to obtain relevant literature. A total of 1182 titles and abstracts were identified and screened, and 30 studies were reviewed in detail. Three articles without data about the association between PA and risk of lung cancer were excluded.19–21 One meeting abstract was also excluded.22 We further excluded 10 duplicate studies,2,5–7,23–28 one23 of which, however, was included in the subgroup analysis by smoking status. Finally, 12 cohort studies8–10,12,13,29–35 and 6 case–control studies36–41 involving 2 468 470 participants and 26 453 cases of lung cancer were selected for meta-analysis. The characteristics of the included studies are shown in Table.

FIGURE 1

FIGURE 1

TABLE-a Characteristics of Studies Included in the Meta-analysis

TABLE-a Characteristics of Studies Included in the Meta-analysis

TABLE-b Characteristics of Studies Included in the Meta-analysis

TABLE-b Characteristics of Studies Included in the Meta-analysis

TABLE-c Characteristics of Studies Included in the Meta-analysis

TABLE-c Characteristics of Studies Included in the Meta-analysis

We assessed the methodological quality of studies included in the final analyses (see Table, Supplemental Digital Content 1, http://links.lww.com/JSM/A72, which presents the methodological quality of case–control studies; see Table, Supplemental Digital Content 2, http://links.lww.com/JSM/A73, which presents the methodological quality of cohort studies). The NOS results showed that the average score was 6.3 (range, 5-8) for case–control studies and 7.8 (range, 6-9) for cohort studies, indicating that the methodological quality of studies was generally good.

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Evidence Synthesis

Risk estimates for moderate-high versus low PA are shown in Figure 2A. A statistically significant inverse association between PA and lung cancer was observed in overall analysis (RR, 0.79; 95% CI, 0.73-0.86). In subgroup analysis by study design, a significantly decreased risk of lung cancer was found in both case–control studies (RR, 0.61; 95% CI, 0.50-0.73) and cohort studies (RR, 0.88; 95% CI, 0.83-0.92).

FIGURE 2

FIGURE 2

The pooled RRs of lung cancer for the moderate PA versus low PA are presented in Figure 2B. Compared with low level of PA, the summary RR of moderate-level PA was 0.87 (95% CI, 0.84-0.90) for all studies, 0.70 (95% CI, 0.48-1.01) for case–control studies, and 0.88 (95% CI, 0.86-0.91) for cohort studies.

Figure 2C presents the estimated RRs for high PA versus low PA. Overall, there was a statistically significant reduction in lung cancer risk among high PA individuals (RR, 0.75; 95% CI, 0.68-0.84). When stratified by study design, RRs of case–control studies and cohort studies were 0.59 (95% CI, 0.50-0.70) and 0.85 (95% CI, 0.78-0.93), respectively. In the subgroup analysis by smoking status, a significantly decreased risk of lung cancer was found in current smokers (RR, 0.76; 95% CI, 0.67-0.86) and former smokers (RR, 0.77; 95% CI, 0.69-0.85) with high-level PA. However, no association between high level of PA and lung cancer risk was found for never smokers (RR, 0.75; 95% CI, 0.50-1.12) (Figure 3). Stratifying by gender, the results indicated that high-level PA was associated with reduced risk of lung cancer in both men (RR, 0.82; 95% CI, 0.74-0.91) and women (RR, 0.73; 95% CI, 0.63-0.86), with a slightly more beneficial effect among females with high level of PA (Figure 4).

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

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Sensitivity Analysis and Publication Bias

From the results of the leave-one-out sensitivity analysis, the summary RRs were not materially altered (data not shown). We explored the source of heterogeneity by gender, study design, smoking status, geographic area (Asia, America, and Europe), sample size (continuous variables), and study quality (continuous variables) with subgroup analysis and meta-regression. However, the results revealed that none of them contributed to the source of heterogeneity (the analysis was based on the comparison of high PA vs low PA) (data not shown).

Begg's and Egger's test were used to assess the publication bias of included studies. We found no evidence of publication bias in the overall meta-analysis for the moderate-high, moderate, and high PA versus low PA (Begg test: P = 0.24, P = 0.50, and P = 0.52, respectively; Egger test: P > 0.05, P = 0.27, and P = 0.06, respectively).

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DISCUSSION

This meta-analysis investigated the association between PA and risk of lung cancer on the basis of previously published research involving 2 468 470 participants and 26 453 cases of lung cancer. The summary results, as derived from 12 cohort studies and 6 case–control studies, indicated that PA was associated with reduced risk of lung cancer.

The effect of PA within different subgroups of the population defined by smoking status was examined in several studies. The results suggested that both current smokers and former smokers experienced benefits with PA. However, no association was found between PA and lung cancer among never smokers. It has been suggested that the etiology of lung cancer among never smokers is distinct from that among smokers,42 thereby bring about a different result. PA increases pulmonary ventilation and perfusion, which in turn reduces concentration of carcinogenic agents, including tobacco-specific nitrosamines, in the airways and the subsequent risk of lung cancer.43,44 PA has also been shown to attenuate smoking-related lung function decline.45 This mechanism may be operative even after smoking cessation, contributing to similarity effect of PA on lung cancer risk among current and former smokers.

In the subgroup analyses by gender, we observed a slightly greater risk reduction of lung cancer afforded by PA among women than men; however, no significant difference was detected between the 2 RRs using z test (z = 1.22, P = 0.22).46 When stratified by study design, both case–control studies and cohort studies showed a significant inverse association between PA and risk of lung cancer. However, the case–control studies showed a considerably stronger PA-lung cancer association as shown in Figures 2A, C. We noted that there were 3 case–control studies37–39 with smallest sample size that was <500, and the 3 studies showed an extremely significant relationship between PA and risk of lung cancer. Given a small sample size, effect size estimates tend to overestimate the effect in the population.47 This problem may be exacerbated by a publication bias toward the publication of statistically significant results.

One issue should be taken into consideration when interpreting our results. Because especially leisure-time PA is usually associated with a generally healthier lifestyle, the specific role of PA in the etiology of cancer may be difficult to elucidate.48 Fruit and vegetable intake has consistently been associated with a protection of the lung cancer risk.41 Nine studies8,10,12,29–32,37,40 did adjust for possible confounding from diet, but there could still be residual confounding or effect modification from diet in our meta-analysis risk estimates.

Although the depth and breadth of epidemiologic literature on PA and cancer prevention is rich, the biologic mechanisms that are associated with the observed decreases in cancer risk are less abundant, and thus less well understood. Several mechanisms have been postulated to explain the inverse association between PA and risk of lung cancer. One potential mechanism involves PA-associated reduction in inflammation.49 Inflammation has been proposed to promote carcinogenesis in a wide spectrum of cancers, including lung, through its effects on cell proliferation, survival, and migration.31 Another potential mechanism may be via the effects of PA on obesity. Obesity is associated with insulin resistance and high blood insulin levels, which are related to increased risk of lung cancer.50,51 In addition, adipose tissue is the primary source of endogenous estrogens that can promote the growth of lung cancer cells, thus increase lung cancer risk.52 PA is also suggested to enhance immune function, and thus to have preventive action against cancer. It is hypothesized that regular moderate exercise can improve the number and function of natural killer cells that are able to attack most types of cancer and participate in tumor suppression.53

The potential limitations of our study should be considered when interpreting the results. First, there was significant heterogeneity among the included studies. However, we failed to find convincing explanations for the significant heterogeneity by subgroup analysis and meta-regression. We noted that most studies did not measure PA reliably and did not consider the history or intensity of PA. In addition, there was no uniform measurement among the included studies. This may at least partially explain the significant heterogeneity among the studies. Second, the possibility of bias and confounding cannot be excluded for all observational studies. Third, although many of the studies had adjusted for important risk factors, unmeasured factors related to PA may also have influenced results of individual studies.

In conclusion, our data suggest that PA is associated with decreased risk of lung cancer based on the findings of 18 studies. Because PA is a relatively convenient, easy, and affordable risk modifier, our findings have implications for preventing lung cancer.

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Keywords:

physical activity; exercise; lung; cancer; incidence

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