A large-scale cohort study tracking 231,067 health professionals for up to 32 years found that consistently meeting physical activity guidelines at moderate levels—approximately 16.9 metabolic equivalent of task hours per week (about 5 hours of brisk walking or 2 hours of running per week)—provided optimal protection against digestive system cancers. No additional benefit was observed from substantially higher activity levels.
The researchers documented 6,538 incident digestive system cancers (DSCs) and 3,791 DSC deaths across 3 prospective cohorts: the Health Professionals Follow-Up Study (1988 to 2020), Nurses' Health Study (1988 to 2021), and Nurses' Health Study II (1991 to 2021). For brevity, metabolic equivalent of task hours are referred to as MET-hours.
Primary Findings
Traditional dose-response analysis using restricted cubic spline models suggested optimal DSC risk reduction occurred at approximately 50 MET-hours per week (evidence of nonlinearity for incidence and mortality). However, this finding proved misleading. When the researchers incorporated long-term consistency into their analysis, they discovered that the apparent benefit of reaching 50 MET-hours/week was actually driven by the study participants who were more likely to consistently meet activity guidelines over time, rather than the higher volume itself providing additional protection.
In joint analyses examining both physical activity volume and consistency in meeting guidelines (7.5 or more MET-hours per week), study participants who consistently met guidelines at moderate levels (median, 16.9 MET-hours per week; 100% consistency) demonstrated substantial DSC risk reduction compared with those who had minimal activity and low consistency. Participants who performed much higher amounts consistently (median, 38.5 MET-hours per week) showed no further benefit. Additionally, participants with high activity volume (median, 30.7 MET-hours per week) but low consistency did not demonstrate lower risk.
Higher total leisure-time physical activity levels demonstrated inverse associations with both DSC risk and mortality. Comparing participants with 45 or more vs fewer than 3 MET-hours per week, the researchers found that the multivariable-adjusted hazard ratio was 0.83 for incident DSC and 0.72 for fatal DSC. The inverse associations remained evident for both digestive tract cancers and digestive accessory organ cancers (ie, pancreas, gallbladder, liver) when comparing the highest and lowest activity categories. Individual cancer subsites consistently showed inverse associations for both risk and mortality, including in oral, esophageal, colonic, pancreatic, gallbladder, and hepatic cancers.
Following additional adjustment for body mass index, hazard ratios attenuated but remained statistically significant for total DSC risk and fatal DSC, suggesting physical activity protects against digestive cancers both through weight control and through independent biological mechanisms. After BMI adjustment, digestive tract cancer associations lost statistical significance, while associations for accessory organ cancers remained robust and suggested that physical activity may protect against these cancers through pathways that are independent of weight management. The E-value for the observed association was 1.74 for DSC risk and 2.12 for DSC mortality, indicating that an unmeasured confounder would need to be associated with both exposure and outcome by a relative risk of 1.74-fold or 2.12-fold, respectively, above measured confounders to fully explain the estimates.
Sensitivity Analyses
Results remained consistent when longer lag times (4, 8, and 12 years) were applied, when oral and throat cancers were excluded from the DSC definition, and across stratified analyses by age, sex, body mass index, smoking status, and diet quality. Marginal structural models with stabilized inverse probability weighting produced similar inverse associations. In joint analyses with a multicomponent healthy lifestyle score, participants in the healthiest lifestyle category had similarly low risk regardless of activity level, suggesting lifestyle clustering did not explain the main findings. The overall proportion of completed physical activity questionnaires relative to eligible cycles was 82% in the Health Professionals Follow-Up Study, 92% in the Nurses' Health Study, and 82% in Nurses' Health Study II.
Practical Implications
In accompanying editorial, Jasmine Yee, PhD, Haryana M. Dhillon, PhD, and Janette L. Vardy, MD, PhD, of The University of Sydney in Sydney, New South Wales, Australia, noted that the optimal dose of 17 MET-hours weekly can be achieved through various practical combinations: brisk walking for 60 minutes on 4 days per week, jogging for 25 minutes on 5 days per week, or a hybrid approach such as jogging for 20 minutes on 3 days combined with 45 minutes of brisk walking on 3 other days.
Drs. Yee, Dhillon, and Vardy also offered a more realistic and achievable goal for those who are unable to achieve 17 MET-hours weekly due to comorbidities or other barriers: reaching approximately 8 to 9 MET-hours with at least 71% consistency still provides meaningful benefit, they wrote.
Several important questions remain unanswered, they added. The relative contribution of moderate-intensity vs vigorous-intensity aerobic activity in risk reduction has not been established, nor has the potential role of resistance training—recommended twice weekly in current guidelines—in reducing digestive cancer risk and mortality. The editorial also highlights a gap between evidence and practice. Despite well-established benefits of physical activity, the majority of people are not meeting current guidelines. Drs. Yee, Dhillon, and Vardy referenced the recent CHALLENGE trial, which demonstrated that simply advising people to exercise is insufficient—rather, they explained, facilitating physical activity requires a multifaceted approach that incorporates behavioral change theories, structured programs supported by exercise specialists, and environmental modifications such as walkable urban spaces and accessible facilities.
Study Design, Population, and Baseline Characteristics
Physical activity was assessed through validated questionnaires at baseline and updated biennially for the Health Professionals Follow-Up Study and every 2 to 4 years for the Nurses' Health Studies. Consistency was calculated as the percentage of follow-up years that met the recommended level of 7.5 or more MET-hours per week. Analyses used cumulative averages with a 2-year lag; for mortality analyses, activity updates were stopped after DSC diagnosis to limit reverse causation. Baseline-only analyses were closer to null than repeated-measures analyses, which showed the importance of long-term patterns. Multivariable models adjusted for age, calendar year, cohort, race, family history of cancer, cigarette smoking status and pack-years, alcohol intake, total calories, Alternative Healthy Eating Index score, calcium intake, aspirin use, multivitamin use, endoscopy screening, and postmenopausal hormone use for women.
The final analysis included 44,860 men and 186,207 women who were free from cancer and cardiovascular disease at baseline. The cohorts consisted primarily of White health professionals (94% to 96% across activity categories). The median age at baseline was 43 years. Participants with higher physical activity levels demonstrated more favorable health profiles, including lower mean body mass index (24.3 for 45 or more MET-hours per week vs 27.2 for less than 3 MET-hours per week), lower smoking rates (7% current smokers vs 14%), and healthier dietary patterns as measured by mean Alternative Healthy Eating Index scores (51 vs 43).
Disclosures: The Health Professionals Follow-Up Study is supported by grant number NCI U01 CA167552. The Nurses' Health Study is supported by grant numbers NCI UM1 CA186107 and P01 CA87969. The Nurses' Health Study II is supported by grant numbers NCI U01 CA176726 and U01 HL145386. Edward L. Giovannucci, MD, ScD, of the Department of Nutrition at Harvard School of Public Health, is funded as an American Cancer Society Clinical Research Professor.
The authors declared having no competing interests.
Source: JAMA Oncology, Editorial