PHARMACOLOGY OF ANTICANCER DRUGS IN ADVANCED AGE

老年抗癌药物的药理学

• 批准号: 6292090
• 负责人: DEREK RAGHAVAN
• 金额: $ 41.79万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-20 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6292090
• 关键词: age difference; antineoplastics; bladder neoplasm; breast neoplasms; clinical research; colorectal neoplasms; comorbidity; cooperative study; drug screening /evaluation; functional ability; gemcitabine; geriatrics; human old age (65+); human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; paclitaxel; pharmacokinetics; questionnaires; uracil analog

Despite the fact that the most rapidly growing segment of the community is the population aged 70 years and older, which is also characterized by the highest overall incidence of cancer, little is known about the detailed pharmacology of cytotoxic agents in this population group. This reflects previous political imperatives, and the conservatism of patients or the medical profession, causing older aged patients to be markedly under-represented in clinical trials. This proposal, from the Women and Special Populations, Genitourinary, Breast and Gastrointestinal Committees of the Southwest Oncology Group, represents the first step in the development of a new paradigm for assessing (a) the feasibility of accrual; (b)the efficacy, toxicity and pharmacology of cytotoxic compounds among patients aged 70 years and older; (c) the feasibility of using standardized self-report measures of comorbidity and functional status in the context of multicenter clinical trials for elderly patients with cancer; (d) at a preliminary level, patterns of expression of key metabolic enzymes in the metabolism of, and resistance to, cytotoxic agents. Fully ambulatory patients in this age group, with metastatic breast cancer, bladder cancer or colorectal malignancy (three of the most common malignancies in this age group) will be treated in a series of standard Phase II trials with docetaxel, gemcitabine-paclitaxel, and uracil-ftorafur [UFT], respectively. The eligibility criteria will be simplified as much as possible to encourage facility of recruitment. In this initial study, elderly patients who are medically fit, apart from the presence of cancer, will be selected, to allow pharmacological and clinical assessment of anticancer therapy that is not confounded by life-threatening undercurrent disease. For each tumor type, 60 cases will be treated. In addition to standard Phase II assessment of efficacy and toxicity, patient-completed questionnaires; will be used as a tool for the assessment of comorbidity and will be used to assess whether the elderly are able successfully to complete such questionnaires, and to identify the extent of previously undiagnosed undercurrent medical disorders, depression, and the level of functional status. Pharmacokinetic measurements will be obtained to establish AUC, half 1ives and clearance values in this elderly population. In addition, we will measure gene expression of deoxycytidine kinase and deaminase (assessing the metabolism of gemcitabine), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) (reflecting metabolism and resistance of flucropyrimidines), and mutations of beta-tubulin (a potential mechanism of resistance to the taxanes) to study the feasibility of assessing age-related genomic regulation of cytotoxic drug metabolism in Phase Il-III clinical trials. A smaller comparison group of patients aged less than 60 years (with the same cancers) will be treated identically to provide pharmacokinetic data and to validate our pharmacokinetic assays against the published literature. This will allow our pharmacokinetic data from the elderly to be set into context. Comparisons between the elderly populations and the limited younger cohorts will not be possible due to the limited case numbers appropriate for the Phase II design of each trial, but the feasibility of data acquisition will be tested and exploration of any obvious correlations between pharmacokinetic characteristics versus efficacy/toxicity will be attempted, but will only be hypothesis-generating in intent.

尽管事实上社区中增长最快的部分是 70 岁及以上人口，其特点是最高 癌症的总体发病率，详细的药理学知之甚少 该人群中细胞毒性药物的数量。这反映了之前的政治 势在必行，以及患者或医学界的保守主义， 导致老年患者在临床中的代表性明显不足 试验。 这项提案来自妇女和特殊人群、泌尿生殖、乳腺 和西南肿瘤学组胃肠委员会，代表 开发新的评估范式的第一步 应计的可行性； (b) 功效、毒性和药理学 70 岁及以上患者的细胞毒性化合物； (三) 使用标准化的合并症自我报告措施的可行性 老年人多中心临床试验背景下的功能状态 癌症患者； (d) 在初步层面上，表达模式 细胞毒性代谢和抵抗中的关键代谢酶 代理。该年龄段的完全卧床患者，患有转移性乳房 癌症、膀胱癌或结直肠恶性肿瘤（三种最常见的癌症） 该年龄段的恶性肿瘤）将通过一系列标准阶段进行治疗 使用多西他赛、吉西他滨-紫杉醇和尿嘧啶-ftorafur [UFT] 进行的 II 项试验， 分别。资格标准将尽可能简化 鼓励招聘便利化。在这项初步研究中，老年患者 除患有癌症外，身体健康的人将被选中， 允许对抗癌治疗进行药理学和临床评估 不会被危及生命的暗流疾病所困扰。对于每种肿瘤类型， 将治疗60例。除了标准的第二阶段评估之外 疗效和毒性，患者填写的问卷；将被用作 评估合并症的工具，将用于评估是否 老年人能够成功地完成此类调查问卷，并确定 先前未诊断的潜在医疗疾病的程度， 抑郁症和功能状态水平。药代动力学测量 将获得以确定 AUC、half 1ives 和清除值 老年人口。此外，我们还将测量基因表达 脱氧胞苷激酶和脱氨酶（评估吉西他滨的代谢）， 胸苷酸合酶 (TS) 和二氢嘧啶脱氢酶 (DPD) （反映氟嘧啶的代谢和耐药性），以及突变 β-微管蛋白（紫杉烷类抗药性的潜在机制）来研究 评估细胞毒性药物与年龄相关的基因组调控的可行性 II-III期临床试验中的代谢。较小的对照组 年龄小于 60 岁的患者（患有相同癌症）将接受治疗 同样提供药代动力学数据并验证我们的 根据已发表的文献进行药代动力学测定。这将使我们的 来自老年人的药代动力学数据将被纳入背景。比较 老年人口和有限的年轻人口之间的差距不会 由于适合该阶段的病例数量有限，因此可能 II每次试验的设计，但数据采集的可行性将 测试并探索药代动力学之间任何明显的相关性 将尝试比较特性与功效/毒性，但只会 意图中的假设生成。