Adaptive Randomization of Aerobic Exercise During Chemotherapy in Colon Cancer

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PROJECT SUMMARY/ABSTRACT Patients with colon cancer who require chemotherapy dose reductions and treatment delays are twice as likely to experience disease recurrence and death than patients who complete their full chemotherapy dose on time. Up to 60% of patients develop toxicities of sufficient severity to require chemotherapy dose reductions or treatment delays. We hypothesize that aerobic exercise improves chemotherapy relative dose intensity and reduces patient-reported chemotherapy toxicities by improving the calibration of chemotherapy through changes in body composition and altering immune function. In response to RFA-CA-21-031, we will conduct a Bayesian, multi-stage, response-adaptive, dose-ranging trial of aerobic exercise. Participants will be 219 stage II-III colon cancer survivors recruited from three diverse socioeconomic, racial, and geographic regions (Baton Rouge, LA; Boston, MA; Oakland, CA). The first 80 participants are randomized to 1 of 5 groups equally: moderate-intensity aerobic exercise at 75 min/wk, 150 min/wk, 225 min/wk, 300 min/wk, or attention control (stretching). This is followed by adaptive randomization in which subsequent participants are assigned to an exercise group in a ratio proportional to the probability that the specific exercise group improves chemotherapy dose intensity and is feasible. Exercise is chemotherapy-periodized with more and less demanding weeks to accommodate cyclical variations in patient-reported symptoms. Aim 1 will evaluate the dose-response effects of moderate-intensity aerobic exercise compared with attention control on chemotherapy relative dose intensity (primary endpoint). Aim 2 will determine the effect of moderate-intensity aerobic exercise compared with control on gastrointestinal and peripheral neuropathy symptoms assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE (key secondary endpoint)]. Aim 3 will determine the effect of moderate-intensity aerobic exercise compared with control on whole-body tissue distribution (total body fat mass and lean mass) measured using dual-energy x-ray absorptiometry. Aim 4 will determine the effect of moderate-intensity aerobic exercise compared with control on changes in neutrophil counts, phenotypes, and functions (biomarkers of neutrophil effector functions including elastase, citrullinated Histone H3, and myeloperoxidase and direct measures of chemotaxis and oxidative burst). This study will leverage a transdisciplinary team's synergies to identify an exercise prescription that is patient-centered and proven to have a high probability of clinical benefit. This study will directly inform clinical practice guidelines that recognize exercise as an essential supportive care intervention for chemotherapy and establish exercise training as obligatory for delivering high-quality, evidence-based care to colon cancer survivors.