In this large prospective study of U.S. men and women, increased physical activity was associated with decreased risk of adenocarcinomas of the upper gastrointestinal tract. The inverse relationship with physical activity was strongest for gastric noncardia adenocarcinoma, but inverse associations were also evident for gastric cardia adenocarcinoma and esophageal adenocarcinoma. No relationship with esophageal squamous cell carcinoma was detected.
Similarly reduced risks were evident in the top four categories of physical activity. This finding suggests that the apparent protection provided by physical activity is reached at a very low threshold (i.e., any exercise versus no exercise is a benefit). Alternatively, noncausal mechanisms, such as residual confounding by a healthy lifestyle or confounding by unmeasured or unknown factors, may be responsible for the findings.
A strength of the present study was the availability of information on tumor histology and anatomic location, which allowed separate investigations of the association between various upper gastrointestinal tract cancer subsites and physical activity. Also, the prospective study design minimized the possibility of differential recall of physical activity by participants with and without upper gastrointestinal tract cancer. Subjects with pre-existing cancer at baseline were excluded from the analyses in order to reduce the influence that malignant disease may have had on physical activity levels at study baseline. In secondary analyses, the potential for bias created by pre-existing but undiagnosed cancer was further curtailed by excluding the first 2 follow-up years and excluding participants with poor health status at entry. The substantial size of the cohort yielded sizeable numbers of esophageal and gastric cancer cases and generated ample statistical power and precision in estimating the dose–response relationship with physical activity.
Previous epidemiologic data concerning the relationship between physical activity and esophageal cancer are inconclusive. One cohort study of recreational physical activity29
showed a relative risk for the combination of oral and total esophageal cancers of 0.46 (95% CI=0.11, 1.90; p
for trend=0.05). Similarly, in one case–control study,17
the OR for esophageal adenocarcinoma was 0.67 (95% CI=0.42, 1.09; p
for trend=0.11) for high versus low levels of occupational physical activity. Another case–control study20
used a mixed-case group of adenocarcinomas of the esophagus and gastric cardia cancers and showed a nonsignificant inverse relationship with recreational activity, but results were not shown. Further, two cohort studies30,31
examined total esophageal cancer rates among mail carriers30
and agricultural workers31
and presented identical relative risk estimates of 0.5 (95% CI=0.3, 0.8) for subjects with high versus low physical activity levels, but individual-level physical activity data were not assessed.
In contrast, one case–control study32
showed an apparent adverse effect of occupational physical activity on total esophageal cancer, reporting an OR of 0.7 (95% CI=0.3, 1.4) for low versus high activity level. Another case–control study18
used a combination of recreational and occupational activity to determine physical activity levels and showed no association with esophageal adenocarcinomas, but the data were not shown.
The association between physical activity and gastric cancer also remains unsettled. Four case–control studies16,17,32,33
and four cohort studies19,29,31,34
found a significant16,17,19,29,31,33
inverse relationship of physical activity to gastric cancer, with relative risk estimates ranging from 0.32 to 0.79. One case-series35
study reported that people with gastric cardia cancer were less likely to be recreationally physically active than people with esophageal cancer (p
=0.031), but it did not show actual risk estimates.
In contrast, two case–control studies20,36
and four cohort studies30,37–39
observed no association between physical activity and gastric cancer, and one early retrospective cohort study using occupational mortality data40
reported a positive relationship between physical activity and gastric cancer but provided no data regarding the statistical significance of the results.
One possible reason for the heterogeneity in findings from previous investigations of physical activity in relation to upper gastrointestinal tract cancers is that analyses were not always carried out according to major histologic type or anatomic location. For example, studies could have missed an inverse association between physical activity and adenocarcinoma of the esophagus if physical activity is truly unrelated to esophageal squamous cell carcinoma but the case definition combined esophageal adenocarcinoma and squamous cell carcinoma. Failure to distinguish between histologic types of esophageal cancer hampers comparisons of risk estimates across studies.
An additional potential explanation for the inconsistencies in findings from previous studies of physical activity in relation to upper gastrointestinal tract cancers is imprecision related to the measurement of physical activity. It appears that investigations using more refined physical activity instruments tended to uncover inverse relationships of physical activity with gastric cancer, whereas studies using rather crude assessments were less likely to detect an association. For example, four16,17,19,29
of the five16,17,19,29,33
studies that detected a significant inverse relationship between physical activity and gastric cancer provided detailed response options regarding the frequency, intensity, and duration of activity.
In contrast, detailed physical activity information was collected in only two37,39
of the nine20,30–32,34,36–39
studies that reported nonsignificant findings for gastric cancer. Of the remaining seven20,30–32,34,36,38
nonsignificant studies, three studies30,31,34
lacked an individual-level measure of physical activity because they were based on a comparison of groups of subjects with high versus low occupational activity, an approach that may have lacked precision; two studies32,36
used cancers potentially related to physical activity as controls (e.g., liver and esophageal cancers), which may have introduced selection bias; one study38
used college sports as an activity measure, which may not have encompassed the etiologically relevant time period of exposure; and one study20
cannot be evaluated because it provided no information on the method of physical activity assessment. Inconsistent findings of previous investigations on physical activity and upper gastrointestinal tract cancers are not due to differences in study design (case–control versus cohort studies), sample size (large versus small numbers of cases), or type of physical activity studied (recreational versus occupational activity).
A potential limitation of the present study is related to the physical activity assessment,41
which was self-reported as opposed to objectively measured, included only one measure at baseline, did not encompass activities of light intensity, and did not include the duration of physical activity. However, the physical activity tool was characterized by a reasonable level of detail because it requested information on the frequency of activities performed each week that reached or exceeded a certain threshold of intensity (i.e., increases in breathing or heart rate or working up a sweat) and activity duration (i.e., 20 minutes). In addition, because the data concerning physical activity were gathered before the diagnosis of cancer, any imprecision or misclassification of physical activity would tend to indicate a weaker rather than a stronger relationship between physical activity and upper gastrointestinal cancer.
The present study lacked data on antacid use (as a surrogate measure of GERD) in the full cohort, but antacid use had virtually no impact on the relationship of physical activity to upper gastrointestinal tract cancer in the subset of participants for whom information on antacid use was available. Residual confounding by GERD remains possible because antacid use represents a weak proxy measure of GERD and antacid use data used here were based on a rather crude binary response variable.
Another limitation of the study is the lack of control for confounding by H. pylori
infection. Although there is no evidence for an association between physical activity and H. pylori
physical activity tends to be positively correlated with SES, a variable that is inversely related to H. pylori
infection. Thus, uncontrolled confounding by H. pylori
infection could have caused a spurious apparent protective effect of physical activity on risk for gastric cancer in this data, even though estimates were controlled for education level as a surrogate measure of SES.
Increased physical activity may decrease the risk of upper gastrointestinal tract adenocarcinomas by preventing chronic inflammation. For example, endurance-trained athletes and subjects who regularly exercise exhibit decreased resting levels of inflammatory cytokines and C-reactive protein compared with habitually sedentary individuals.43–46
Chronic inflammation plays a critical role in the etiology of esophageal and gastric adenocarcinomas,47–49
and nonsteroidal anti-inflammatory drugs are associated with decreased risk of gastric noncardia adenocarcinoma.50
Physical activity improves insulin sensitivity and lowers circulating insulin,51
thereby enhancing insulin-like growth factor (IGF) binding protein-1, which reduces bioavailable IGF-1.52,53
IGF-1 stimulates cell proliferation and inhibits apoptosis in gastric cancer,54,55
and suppressed levels of IGF-1 increase expression of p53, a protein that is involved in DNA repair, cell cycle arrest, and apoptosis.56
Physical activity may also decrease circulating leptin57,58
independent of BMI,59,60
although whether physical activity specifically reduces gastric leptin secretion or its expression in gastric tumor cells is unknown.
In conclusion, these prospective data suggest that increased physical activity plays a role in the prevention of upper gastrointestinal tract adenocarcinomas. No association was seen with esophageal squamous cell carcinoma. Further research is required to evaluate these findings in other populations and to elucidate possible biological mechanisms involved.