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

老年结直肠癌患者的肌减少和化疗毒性机制：M

• 批准号: 10463649
• 负责人: Grant R Williams
• 金额: $ 20.69万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463649
• 关键词: Address; Adult; Age; Aging; Biological Products; Body Composition; Body Surface Area; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Cessation of life; Clinical; Clinical Trials Design; Colorectal Cancer; Community Clinical Oncology Program; Community Networks; Coupled; DNA Damage; Development; Development Plans; Diagnosis; Disease; Dose; Drug Kinetics; Elderly; Ethnic Origin; Evaluation; Fluorouracil; Foundations; Future; GDF8 gene; Genetic; Genetic Variation; Goals; Height; Homeostasis; Hospitalization; Image; Incidence; Individual; Inferior; Inflammation; Intervention; Intervention Trial; Life; Link; Longitudinal cohort study; Longitudinal prospective study; Malignant Neoplasms; Malnutrition; Measurement; Measures; Mediating; Mediation; Mentors; Mentorship; Methods; Molecular Epidemiology; Muscular Atrophy; Nature; Newly Diagnosed; Obesity; Outcome; Patients; Process; Prospective Studies; Race; Research; Risk; Role; Site; Skeletal Muscle; Subgroup; Time; Toxic effect; Toxicity due to chemotherapy; Training; Treatment outcome; Treatment-related toxicity; Weight; X-Ray Computed Tomography; abdominal CT; adverse outcome; age related; base; cancer diagnosis; career; career development; catalyst; chemotherapy; colorectal cancer treatment; combat; experience; genetic variant; high risk; improved; improved outcome; insight; inter-individual variation; irinotecan; lean body mass; metastatic colorectal; muscle form; nutrition; older patient; oxaliplatin; patient subsets; personalized intervention; personalized medicine; programs; prospective; recruit; reduced muscle mass; repaired; response; sex; skeletal muscle wasting; systemic inflammatory response; telomere; tool; treatment optimization

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.

摘要 结直肠癌（CRC）是美国第二大常见的癌症死亡原因， 诊断发生在老年人（≥ 65岁）。患有CRC的老年人接受严格治疗的风险增加- 相关毒性和其他不良后果。在老年人中明显的异质老化过程 使CRC的治疗复杂化并导致结果的显著变化。了解可变性 在老年CRC患者中，化疗毒性对于个性化治疗和改善结果是必要的。 低肌肉质量，称为肌减少症，在老年人中非常普遍。骨骼肌质量的损失 早在生命的第4个十年就明显，并随着年龄的增长呈线性增长。在CRC中，低肌肉质量 与化疗相关毒性增加和生存率降低有关。迄今为止的大多数研究 CRC中的肌减少是回顾性的，未能全面评估肌减少，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，委员会认为， 传统的通过体表面积（BSA）的化疗剂量忽略了身体组成的可变性 在成年癌症患者中得到证实。由于肌减少症经常导致较低的瘦体重（LBM）， BSA，肌减少症患者接受的化疗有效剂量相对于其LBM更高，可能导致 化学毒性增加。迫切需要对老年CRC患者的肌减少症进行前瞻性评估， 更好地了解肌减少症与不良结局的相关性，并制定精确和个性化的 干预措施，以改善结果。我们前瞻性纵向研究的中心目标是更好地了解 老年转移性结直肠癌患者的肌减少症及其与化疗毒性和总生存率的关系 我们将利用计算机断层扫描（CT）成像的常规临床应用来评估肌肉质量， 基线，并评估化疗治疗期间随时间推移的轨迹。此外，我们还将探讨 端粒稳态、DNA损伤反应/修复（DDR）、炎症和肌肉生长抑制素的遗传变异 以及奥沙利铂的药代动力学（PK）改变（在患者亚组中），以探索其介导的 肌减少症与3-5级化学毒性之间的关联。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、身体组成方法、PK测量/解释和分子生物学 流行病学我的研究结果将为未来的研究提供信息，包括开发化学毒性预测工具 针对老年CRC患者的干预性试验，对抗肌减少症的干预性试验，以及 在肌萎缩症患者中采用LBM以增加化疗剂量的替代给药策略， 以避免不必要的毒性，同时维持和/或改善功效。我提议的研究 我的经验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，专注于改善老年CRC患者的预后。

项目成果

Medicare and patient spending among beneficiaries diagnosed with chronic myelogenous leukemia.

诊断患有慢性粒细胞白血病的受益人的医疗保险和患者支出。

• DOI: 10.1002/cncr.32137
• 发表时间: 2019
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Kenzik,KellyM;Bhatia,Ravi;Williams,GrantR;Bhatia,Smita
• 通讯作者: Bhatia,Smita

Association of malnutrition with geriatric assessment impairments and health-related quality of life among older adults with gastrointestinal malignancies.

胃肠道恶性肿瘤的老年人的营养不良与老年评估障碍和与健康相关的生活质量的关联。

• DOI: 10.1002/cncr.33122
• 发表时间: 2020-12-01
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Williams GR;Al-Obaidi M;Dai C;Mir N;Challa SA;Daniel M;Patel H;Barlow B;Young-Smith C;Gbolahan O;Paluri R;Bhatia S;Giri S
• 通讯作者: Giri S

Sarcopenia & aging in cancer.

肌肉减少症和癌症衰老。

• DOI: 10.1016/j.jgo.2018.10.009
• 发表时间: 2019-05
• 期刊: Journal of geriatric oncology
• 影响因子: 3
• 作者: Williams GR;Rier HN;McDonald A;Shachar SS
• 通讯作者: Shachar SS

Geriatric Assessment Predictors of 1-Year Mortality in Older Adults With GI Malignancies: A Survival Tree Analysis.

患有胃肠道恶性肿瘤的老年人一年死亡率的老年评估预测因素：生存树分析。

• DOI: 10.1200/cci.22.00065
• 发表时间: 2022
• 期刊: JCO clinical cancer informatics
• 影响因子: 4.2
• 作者: Williams,GrantR;Dai,Chen;Giri,Smith;Al-Obaidi,Mustafa;Harmon,Christian;Kenzik,KellyM;McDonald,Andrew;Gbolahan,Olumide;Outlaw,Darryl;Khushman,Moh'd;Richman,Joshua;Bhatia,Smita
• 通讯作者: Bhatia,Smita

Pain among older adults with gastrointestinal malignancies- results from the cancer and aging resilience evaluation (CARE) Registry.

患有胃肠道恶性肿瘤的老年人的疼痛——来自癌症和衰老恢复力评估（CARE）登记处的结果。

• DOI: 10.1007/s00520-022-07398-4
• 发表时间: 2022
• 期刊: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
• 作者: Al-Obaidi,Mustafa;Kosmicki,Sarah;Harmon,Christian;Lobbous,Mina;Outlaw,Darryl;Khushman,Moh'd;McGwin,Gerald;Bhatia,Smita;Giri,Smith;Williams,GrantR
• 通讯作者: Williams,GrantR