A Pan-Cancer Target Trial Emulation of Exercise and Distant Disease-Free Recurrence

BACKGROUND: We leveraged observational data to conduct a target trial emulation (TTE) framework evaluating the association of exercise on distant disease-free survival (DDFS) in a pan-cancer cohort. METHODS: To emulate a randomized controlled trial (RCT), a "historical" exercise assessment (Th) identified non-exercising (<10 metabolic equivalent of task-hours per week [MET-h/week]) patients. Repeat assessment 9-15 months later (T0) was used to classify patients into an exercise group (≥10 MET-h/week: increased exercise from Th) and a control group (up to 10 MET-h/week: minimal increase in exercise from Th). Kaplan-Meier methods and Cox proportional hazards models from the T0 assessment were used to estimate hazard ratios (HRs) for the exercise versus control group on DDFS and overall survival (OS). RESULTS: A total of 3,022 patients were classified into the exercise group and 1,183 into the control group. With 5.2 years (IQR 2.7, 7.0 years) median follow-up from T0, the 5-year DDFS was 95% (95% CI, 93-96) in the exercise group and 92% (95% CI, 91-94) in the control group. Compared with the control group, the adjusted HR for the exercise group was 0.80 (95% CI, 0.59-1.09, p=0.20) for DDFS and 0.78 (95% CI, 0.55-1.11, p=0.20) for OS. CONCLUSIONS: In this pan-cancer TTE, we estimated a potential 20-30% improvement in DDFS in the exercise group compared to control. IMPACT: These data add to a growing body of evidence supporting further development of exercise as a therapeutic-intent strategy in primary solid tumors.