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.
| Louie, S G; Ely, B; Lenz, H-J et al. (2013) Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030). Br J Cancer 109:1744-9 |
