Physical Activity and Risk of Esophageal Cancer
Physical Activity and Risk of Esophageal Cancer
From 422 unique studies identified using the search strategy, 9 studies met the inclusion criteria. These studies reported on the association between physical activity and 1,871 cases of esophageal cancer among 1,381,844 patients. During the peer review process, with an updated search till May 1, 2014, an additional hospital case–control study from India was identified with 704 cases of ESCC. No relevant RCTs were identified. The coefficient of agreement between the two reviewers for study selection was excellent (Cohen's κ = 0.82). Six studies on dietary or socioeconomic risk factors for cancer mentioned assessing physical activity as a covariate but did not specifically measure or report association between physical activity and esophageal cancer per se; four of these studies were published more than 15 years ago and hence, data was not accessible; additional data could not be obtained from contacting authors of two recent studies and hence, these were excluded. Two studies did not have an appropriate control group. In a Dutch cohort, de Jonge and colleagues compared the mean physical activity levels in patients with EAC, ESCC and gastric cardia adenocarcinoma, but there was no referent population to allow calculation of a risk estimate. The same group compared differences in physical activity levels in patients with BE with and without EAC and did not observe any significant differences, but an estimate of EAC risk among the most physically active to the least physically active was not possible. One study reported the association between physical activity and mortality from esophageal cancer, and was excluded.
Baseline Characteristics. The characteristics of these studies are shown in Table 1. The earliest cohort study recruited patients starting in 1978 and latest completed recruitment in 2007, with mean reported follow-up ranging from 6 to 18.8 years. Seven studies were performed in the Western population (5 in North America, 2 in Europe) and two studies were performed in Asian population. Four studies were performed exclusively in men. In three studies, recreational (with or without household) physical activity was the only measured domain; in three studies, only occupational physical activity was inferred based on the job-title. Physical activity was assessed using self-administered questionnaire in most of the studies, and was based on a combination of intensity, duration and frequency of recreational physical activity. Of the nine studies, three reported exclusively on risk of EAC, and one reported exclusively on the risk of ESCC; four studies reported on risk of esophageal cancer with no separate information on risk by histological-subtype.
Quality Assessment. Four observational studies (all cohort studies) were at low-risk of bias based on study design, exposure ascertainment and adjusting for key confounding variables, and were deemed to be of high quality (Table 2). The included studies variably accounted for other potential confounders: smoking (8/9), obesity (7/9), alcohol use (5/9) and family history of esophageal cancer (3/9); none of the studies adjusted for gastroesophageal reflux symptoms. Socioeconomic status, which appears to have inverse association with physical activity was accounted for in 5/9 studies. For outcome ascertainment, most studies relied on record linkage through the cancer registry (with or without review of death certificates and pathology databases), or review of medical records. In all these studies, a temporal relation between exposure and outcomes was established – physical activity preceded esophageal cancer by at least 1 year, and usually longer periods.
Overall Risk of Esophageal Cancer. Of the nine studies identified, four reported a statistically significant inverse association between overall physical activity and esophageal cancer risk. On meta-analysis, risk of esophageal cancer was 29% lower among the most physically active people as compared with the least physically active people (OR, 0.71; 95% CI, 0.57–0.89) (Figure 2). There was moderate heterogeneity observed across studies (I = 47%).
(Enlarge Image)
Figure 2.
Physical activity and risk of esophageal cancer.
Risk of Esophageal Adenocarcinoma. Of the four studies identified, two reported a statistically significant inverse association between physical activity and EAC risk. On meta-analysis, risk of EAC was 32% lower among the most physically active people as compared with the least physically active people (OR, 0.68; 95% CI, 0.55–0.85) (Figure 3). There was minimal heterogeneity observed across studies (I = 0%).
(Enlarge Image)
Figure 3.
Physical activity and risk of esophageal adenocarcinoma.
Risk of Esophageal Squamous Cell Carcinoma. Only two studies reported the association between physical activity and risk of ESCC. One of them, performed in Iran, observed a strong inverse association, whereas the other, performed in the United States, reported a null association. During the peer review process, another low quality, case–control study published after data of search was identified. This study performed in India reported a 5-fold higher risk of ESCC in patients with the highest level of occupational physical activity. On meta-analysis, there was no association between physical activity and risk of ESCC (OR, 1.10; 95% CI, 0.21–5.64), albeit with considerable heterogeneity (I = 95%).
Subgroup Analysis. On sub-group analysis, the association between physical activity and risk of esophageal cancer was stable across case–control and cohort studies, and across Western and Asian population (Table 3). On analysis by domain of physical activity, recreational physical activity, the potentially modifiable component of physical activity, was associated with a decreased risk of esophageal cancer (OR, 0.79; 95% CI, 0.67–0.93; I = 0%).
Dose–Response Relationship. A non-significant trend towards an inverse dose response relationship between physical activity and esophageal cancer risk was observed. Using the least active group as reference, people in the middle tertile or 2 quartile of physical activity had a non-statistically significant 12% lower risk of esophageal cancer (5 studies; OR, 0.88; 95% CI, 0.70–1.10; I = 19%). In comparison, the most physically active people (highest tertile of physical activity or 4 quartile) had a 24% lower risk of esophageal cancer (5 studies; OR, 0.76; 95% CI, 0.60–0.97; I = 0%).
High-quality Studies. On restricting analysis to the four high-quality studies, we observed that physical activity is associated with a 16% lower risk of esophageal cancer, though this association did not reach pre-specified statistical significance (OR, 0.84; 95% CI, 0.71–1.00; p = 0.05). The results were consistent across studies (I = 0%).
Sensitivity Analysis. To assess whether any one study had a dominant effect on the summary OR, each study was excluded and its effect on the main summary estimate was evaluated. While no study significantly affected the summary estimate, exclusion of the study by Etemadi and colleagues on the association between physical activity and risk of ESCC resulted in resolution of the previously observed marked heterogeneity in the analysis. The favorable and strong effect sizes observed in this single study were causing heterogeneity in the strength, but not the direction, of overall association. On analysis after excluding this study, the summary estimate remained significant (OR, 0.76; 95% CI, 0.64–0.89) and minimal heterogeneity was observed in the analysis (I = 15%).
Given the small number of studies identified in our analysis, statistical tests for assessing publications bias were not performed.
Results
Study Flow
From 422 unique studies identified using the search strategy, 9 studies met the inclusion criteria. These studies reported on the association between physical activity and 1,871 cases of esophageal cancer among 1,381,844 patients. During the peer review process, with an updated search till May 1, 2014, an additional hospital case–control study from India was identified with 704 cases of ESCC. No relevant RCTs were identified. The coefficient of agreement between the two reviewers for study selection was excellent (Cohen's κ = 0.82). Six studies on dietary or socioeconomic risk factors for cancer mentioned assessing physical activity as a covariate but did not specifically measure or report association between physical activity and esophageal cancer per se; four of these studies were published more than 15 years ago and hence, data was not accessible; additional data could not be obtained from contacting authors of two recent studies and hence, these were excluded. Two studies did not have an appropriate control group. In a Dutch cohort, de Jonge and colleagues compared the mean physical activity levels in patients with EAC, ESCC and gastric cardia adenocarcinoma, but there was no referent population to allow calculation of a risk estimate. The same group compared differences in physical activity levels in patients with BE with and without EAC and did not observe any significant differences, but an estimate of EAC risk among the most physically active to the least physically active was not possible. One study reported the association between physical activity and mortality from esophageal cancer, and was excluded.
Characteristics and Quality of Included Studies
Baseline Characteristics. The characteristics of these studies are shown in Table 1. The earliest cohort study recruited patients starting in 1978 and latest completed recruitment in 2007, with mean reported follow-up ranging from 6 to 18.8 years. Seven studies were performed in the Western population (5 in North America, 2 in Europe) and two studies were performed in Asian population. Four studies were performed exclusively in men. In three studies, recreational (with or without household) physical activity was the only measured domain; in three studies, only occupational physical activity was inferred based on the job-title. Physical activity was assessed using self-administered questionnaire in most of the studies, and was based on a combination of intensity, duration and frequency of recreational physical activity. Of the nine studies, three reported exclusively on risk of EAC, and one reported exclusively on the risk of ESCC; four studies reported on risk of esophageal cancer with no separate information on risk by histological-subtype.
Quality Assessment. Four observational studies (all cohort studies) were at low-risk of bias based on study design, exposure ascertainment and adjusting for key confounding variables, and were deemed to be of high quality (Table 2). The included studies variably accounted for other potential confounders: smoking (8/9), obesity (7/9), alcohol use (5/9) and family history of esophageal cancer (3/9); none of the studies adjusted for gastroesophageal reflux symptoms. Socioeconomic status, which appears to have inverse association with physical activity was accounted for in 5/9 studies. For outcome ascertainment, most studies relied on record linkage through the cancer registry (with or without review of death certificates and pathology databases), or review of medical records. In all these studies, a temporal relation between exposure and outcomes was established – physical activity preceded esophageal cancer by at least 1 year, and usually longer periods.
Physical Activity and Risk of Esophageal Cancer
Overall Risk of Esophageal Cancer. Of the nine studies identified, four reported a statistically significant inverse association between overall physical activity and esophageal cancer risk. On meta-analysis, risk of esophageal cancer was 29% lower among the most physically active people as compared with the least physically active people (OR, 0.71; 95% CI, 0.57–0.89) (Figure 2). There was moderate heterogeneity observed across studies (I = 47%).
(Enlarge Image)
Figure 2.
Physical activity and risk of esophageal cancer.
Risk of Esophageal Adenocarcinoma. Of the four studies identified, two reported a statistically significant inverse association between physical activity and EAC risk. On meta-analysis, risk of EAC was 32% lower among the most physically active people as compared with the least physically active people (OR, 0.68; 95% CI, 0.55–0.85) (Figure 3). There was minimal heterogeneity observed across studies (I = 0%).
(Enlarge Image)
Figure 3.
Physical activity and risk of esophageal adenocarcinoma.
Risk of Esophageal Squamous Cell Carcinoma. Only two studies reported the association between physical activity and risk of ESCC. One of them, performed in Iran, observed a strong inverse association, whereas the other, performed in the United States, reported a null association. During the peer review process, another low quality, case–control study published after data of search was identified. This study performed in India reported a 5-fold higher risk of ESCC in patients with the highest level of occupational physical activity. On meta-analysis, there was no association between physical activity and risk of ESCC (OR, 1.10; 95% CI, 0.21–5.64), albeit with considerable heterogeneity (I = 95%).
Subgroup and Sensitivity Analyses
Subgroup Analysis. On sub-group analysis, the association between physical activity and risk of esophageal cancer was stable across case–control and cohort studies, and across Western and Asian population (Table 3). On analysis by domain of physical activity, recreational physical activity, the potentially modifiable component of physical activity, was associated with a decreased risk of esophageal cancer (OR, 0.79; 95% CI, 0.67–0.93; I = 0%).
Dose–Response Relationship. A non-significant trend towards an inverse dose response relationship between physical activity and esophageal cancer risk was observed. Using the least active group as reference, people in the middle tertile or 2 quartile of physical activity had a non-statistically significant 12% lower risk of esophageal cancer (5 studies; OR, 0.88; 95% CI, 0.70–1.10; I = 19%). In comparison, the most physically active people (highest tertile of physical activity or 4 quartile) had a 24% lower risk of esophageal cancer (5 studies; OR, 0.76; 95% CI, 0.60–0.97; I = 0%).
High-quality Studies. On restricting analysis to the four high-quality studies, we observed that physical activity is associated with a 16% lower risk of esophageal cancer, though this association did not reach pre-specified statistical significance (OR, 0.84; 95% CI, 0.71–1.00; p = 0.05). The results were consistent across studies (I = 0%).
Sensitivity Analysis. To assess whether any one study had a dominant effect on the summary OR, each study was excluded and its effect on the main summary estimate was evaluated. While no study significantly affected the summary estimate, exclusion of the study by Etemadi and colleagues on the association between physical activity and risk of ESCC resulted in resolution of the previously observed marked heterogeneity in the analysis. The favorable and strong effect sizes observed in this single study were causing heterogeneity in the strength, but not the direction, of overall association. On analysis after excluding this study, the summary estimate remained significant (OR, 0.76; 95% CI, 0.64–0.89) and minimal heterogeneity was observed in the analysis (I = 15%).
Given the small number of studies identified in our analysis, statistical tests for assessing publications bias were not performed.
Source...