Adaptive Randomization of Aerobic Exercise During Chemotherapy in Colon Cancer

项目摘要/摘要 需要减少化疗剂量和延迟治疗的结肠癌患者的可能性是前者的两倍 与按时完成全部化疗剂量的患者相比，患者更容易经历疾病复发和死亡。 高达60%的患者出现足够严重的毒性，需要减少化疗剂量或 治疗延误。我们假设有氧运动提高了化疗的相对剂量强度和 通过以下方式改进化疗校准，减少患者报告的化疗毒性 身体成分的变化和免疫功能的改变。为响应RFA-CA-21-031，我们将进行 贝叶斯，多阶段，反应适应，剂量范围的有氧运动试验。参赛者年龄为219岁 II-III结肠癌幸存者从三个不同的社会经济、种族和地理区域招募(巴顿 洛杉矶鲁日；马萨诸塞州波士顿；加利福尼亚州奥克兰)。前80名参与者被随机分为5组： 75分钟/周、150分钟/周、225分钟/周、300分钟/周的中等强度有氧运动或注意力控制 (拉伸)。这之后是自适应随机化，其中后续参与者被分配到 与特定运动组改善化疗的概率成正比的运动组 剂量强度大，是可行的。锻炼是化疗--以更多和更少的周为周期 适应患者报告症状的周期性变化。目标1将评估剂量-反应效应 中等强度有氧运动与注意控制对化疗相对剂量强度的影响 (主端点)。目标2将确定中等强度有氧运动的效果与 使用患者评估胃肠道和周围神经病症状的控制-报道 不良事件通用术语标准的结果版本[PRO-CTCAE(主要次要 端点)]。目标3将确定中等强度有氧运动与对照组相比对 用双能x线测量全身组织分布(全身脂肪质量和瘦肉质量) 吸光度测定法。目标4将确定中等强度有氧运动与对照的效果 中性粒细胞计数、表型和功能的变化(中性粒细胞效应器功能的生物标志物 包括弹性蛋白酶、瓜氨酸组蛋白H3和髓过氧化物酶，以及直接测定趋化和 氧化爆发)。这项研究将利用跨学科团队的协同效应来确定一项练习 以患者为中心，并被证明有很大可能临床受益的处方。这项研究将 直接告知临床实践指南，承认运动是一种基本的支持性护理干预 并将运动训练作为提供高质量循证护理的必备条件 结肠癌幸存者。

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.