Resistance Training to Reduce Chemotoxicity in Colon Cancer

摘要 身体中脂肪量（FM）和肌肉量（MM）的比例可能对以下方面具有重要意义： 结肠癌（CC）患者化疗的校准。化疗剂量目前基于 体表面积（BSA），其来源于关于身高和体重的信息。体重或体重 特别是在癌症患者中，体重指数（BMI）不是FM或MM的准确测量。 预测FM或MM，BSA给药可能导致剂量不足（这可能影响癌症特异性和总体 生存）或过量（导致剂量限制性毒性[DLT]，定义为化疗毒性， 需要随后减少或停止救生治疗）。结果表明，这些 低MM或肌肉减少症患者的DLT风险高于正常MM患者。DLT影响剂量强度 并且可能损害化疗的功效。我们建议检查随机临床试验的效果， 在化疗期间进行的基于家庭的阻力训练（RT）与DLT的等待名单对照的试验。 参与者将是来自北方Kaiser Permanente的180名新诊断的II期和III期CC患者 加州（KPNC）、宾夕法尼亚州立大学癌症研究所（PSCI）和达纳法伯癌症研究所（DFCI）。的 干预将在化疗的前6周开始开始，并持续到化疗结束。 治疗具体来说，我们将研究组间差异的阻力训练与重量清单 控制剂量强度和3级和4级毒性以及MM的变化和炎症的变化 标记。由于大约40-45%的新诊断的CC患者在诊断时患有肌肉减少症，我们将 研究运动对低MM患者的益处是否大于正常MM患者。我们将 还检查特异性炎症标志物（如CRP、IL-6和TNF-RII）作为基线的潜在生物标志物 MM，并确定它们如何响应RT而变化。 化疗特异性药物清除率，我们将研究RT诱导的机体组成变化的影响 5-FU和奥沙利铂的药代动力学（PK）。如果RT有助于减少DLT和MM以及炎症 标记物可以识别那些最有可能从定制的运动指南中受益的患者，然后评估 这些参数可用于帮助瞄准高风险患者。由于DLT是一个常见的问题， 大量新诊断的CC患者未检测到肌肉减少症，其中许多人可能需要 由于低MM导致的剂量减少，本研究有可能对临床护理产生重大影响，并改善 结肠癌的预后。

ABSTRACT The proportions of fat mass (FM) and muscle mass (MM) in the body may have important implications for calibration of chemotherapy in patients with colon cancer (CC). Chemotherapy dosing is currently based on body surface area (BSA), which is derived from information on height and weight. Body weight or Body Mass Index (BMI), especially among cancer patients, is not an accurate measure of FM or MM. Given this inability to predict FM or MM, dosing by BSA may lead to underdosing (which may impact cancer-specific and overall survival) or overdosing (leading to dose-limiting toxicity [DLT] defined as toxicity from chemotherapy that requires subsequent reductions in or discontinuation of life-saving treatment). Results have shown that those with low MM, or sarcopenia, have a higher risk of DLT than those with normal MM. DLT impacts dose intensity and may compromise efficacy of chemotherapy. We propose to examine the effects of a randomized clinical trial conducted during chemotherapy of home based resistance training (RT) versus a waitlist control on DLT. Participants will be 180 newly diagnosed Stage II and III CC patients from Kaiser Permanente of Northern California (KPNC), the Penn State Cancer Institute (PSCI), and the Dana Farber Cancer Institute (DFCI). The intervention will begin during the first 6 weeks of chemotherapy and continue through the completion of treatment. Specifically, we will examine between group differences for resistance training versus weight list control for dose intensity and grade 3 and 4 toxicities as well as changes in MM and changes in inflammatory markers. Since approximately 40-45% of newly diagnosed CC patients have sarcopenia at diagnosis, we will examine if the benefits of exercise are greater for those who have low MM compared to normal MM. We will also examine specific inflammatory markers (e.g. CRP, IL-6 and TNF-RII) as potential biomarkers of baseline MM, and determine how they change in response to RT. To determine effects of change of MM on chemotherapy-specific drug clearance, we will examine the impact of RT induced body composition changes on the pharmacokinetics (PK) of 5-FU and oxaliplatin. If RT helps to reduce DLT and MM and inflammatory markers can identify those patients most-likely to benefit from tailored exercise guidelines, then assessment of these parameters can be used to help target high risk patients. Given that DLT is a common problem and there are large numbers of newly diagnosed CC patients with undetected sarcopenia, many of whom may require dose reductions due to low MM, this study has the potential to have a large impact on clinical care and improve prognosis of colon cancer.