Myopenia and Mechanisms of Chemotherapy Toxicity in Older Adults with Colorectal Cancer: The M&M Study

摘要 结直肠癌(CRC)是美国癌症死亡的第二大常见原因，大多数 诊断发生在老年人中(≥65Y)。患有结直肠癌的老年人接受严重治疗的风险增加- 相关毒性和其他不良后果。老年人明显的异质性衰老过程 使结直肠癌的治疗复杂化，并导致预后的显著差异。了解可变性 在化疗中，对患有结直肠癌的老年人来说，毒性是个性化治疗和改善结果所必需的。 肌肉质量低，称为肌减少症，在老年人中非常普遍。骨骼肌质量的损失是 早在生命的第四个十年就很明显，并随着年龄的增长呈线性增长。在结直肠癌中，肌肉质量低 与化疗相关的毒性增加和生存率下降有关。迄今为止，大多数研究都是关于 结直肠癌的肌松减症是有回顾性的，未能全面评估肌松减症，因此限制了 我们对与不良后果增加相关的潜在机制的理解。此外， 按体表面积(BSA)进行传统的化疗剂量忽略了身体成分的变异性 在患有癌症的成年人身上也有表现。由于肌松减症通常会导致相对于 BSA，肌萎缩症患者接受比他们的LBM更高的有效化疗剂量，可能导致 化学毒性增加。对患有结直肠癌的老年患者进行前瞻性评估是非常必要的 更好地了解肌减少症与不良后果的关联，并制定精确和个性化的 旨在改善结果的干预措施。我们前瞻性纵向研究的中心目标是更好地理解 转移性结直肠癌老年患者的肌松减症及其与化疗毒性和总存活率的关系。 我们将利用常规临床使用的计算机断层扫描(CT)成像来评估肌肉质量 在化疗治疗期间，基线和评估随时间推移的轨迹。此外，我们还将探索 端粒稳态、DNA损伤反应/修复(DDR)、炎症和肌肉生长抑素的遗传变异 以及奥沙利铂的药代动力学改变(PKs)(在一组患者中)，以探索它们对 肌松减症与3-5级化疗毒性之间的关系。这项研究将进一步促进我的长期 目标是优化老年癌症患者的治疗，并提供临床试验设计方面的额外培训， 高级定量分析、身体成分方法、PK测量/解释和分子 流行病学。我的研究结果将为未来的研究提供参考，包括化学毒性预测工具的开发 针对患有CRC的老年人，对抗肌减少症的介入试验，以及潜在的 肌萎缩症患者合并LBM以增加化疗剂量的替代剂量策略 在维持和/或提高疗效的同时，避免不必要的毒性。我提议的研究 经验，再加上我的职业发展计划和指导，将为我提供必要的催化剂 发展独立的研究事业，专注于改善患有结直肠癌的老年人的结果。

Abstract Colorectal Cancer (CRC) is the 2nd most common cause of cancer death in the US with the majority of diagnoses occurring in older adults (≥65y). Older adults with CRC are at increased risk for severe treatment- related toxicities and other adverse outcomes. The heterogeneous aging process evident in older adults complicates the treatment of CRC and results in significant variability in outcomes. Understanding the variability in chemotherapy toxicity in older adults with CRC is necessary to personalize treatments and improve outcomes. Low muscle mass, known as myopenia, is highly prevalent in older adults. Losses in skeletal muscle mass are apparent as early as the 4th decade of life and progress linearly with increasing age. In CRC, low muscle mass is associated with increased chemotherapy-related toxicities and decreased survival. Most studies to date on myopenia in CRC have been retrospective and have failed to comprehensively assess myopenia, thus limiting our understanding of the underlying mechanisms associated with increased adverse outcomes. Furthermore, conventional chemotherapy dosing by body surface area (BSA) ignores the variability in body composition demonstrated in adults with cancer. As myopenia frequently results in lower lean body mass (LBM) relative to BSA, myopenic patients receive higher effective doses of chemotherapy relative to their LBM, likely resulting in increased chemotoxicity. Prospective evaluation of myopenia in older adults with CRC is critically needed to better understand the association of myopenia with adverse outcomes and to develop precise and personalized interventions to improve outcomes. The central goal of our prospective longitudinal study is to better understand myopenia and its association with chemotherapy toxicity and overall survival in older adults with metastatic CRC. We will leverage the routine clinical use of Computed Tomography (CT) imaging to assess muscle mass at baseline and evaluate trajectories over time during treatment with chemotherapy. In addition, we will explore genetic variation in telomere homeostasis, DNA damage response/repair (DDR), inflammation, and myostatin as well as altered pharmacokinetics (PKs) of oxaliplatin (in a subset of patients) to explore their mediation of the association between myopenia and grades 3-5 chemotoxicity. This study will further promote my long-term goal of optimizing the treatment of older adults with cancer and provide additional training in clinical trial design, advanced quantitative analysis, body composition methods, PK measurement/interpretation, and molecular epidemiology. My results will inform future studies including the development of chemotoxicity prediction tools specific to older adults with CRC, interventional trials combating myopenia, and the potential development of alternative dosing strategies in myopenic patients that incorporate LBM to augment chemotherapy dosing in order avoid unnecessary toxicities while maintaining and/or improving efficacy. My proposed research experience coupled with my career development plan and mentorship will provide the necessary catalyst for me to develop an independent research career focused on improving the outcomes of older adults with CRC.