Docetaxel and gemcitabine is a well described regimen in soft tissue sarcoma. Hensley examined gemcitabine and docetaxel in a phase II study of patients with metastatic leiomyosarcoma. That study also examined the pharmacokinetics of gemcitabine in a 30- and 90-minute infusion schedule on separate cycles of therapy, described above. The study enrolled 34 patients, all but five with uterine leiomyosarcoma, and demonstrated a surprising response rate of 53% (three complete responses, 15 PRs). Importantly, 50% of patients previously treated with doxorubicin responded. The median time to progression was 5.6 months, and the median survival duration was 17.9 months. This study was impressive in its demonstration of uterine leiomyosarcoma as a subtype relatively sensitive to this chemotherapy combination, and also indicated that part of the reason for this high response rate was the synergy of gemcitabine and docetaxel, given the 21% response rate for gemcitabine alone in second-line therapy in a Gynecologic Oncology Group (GOG) study and low response rate of docetaxel against sarcomas in first- and second-line therapy in phase II and randomized phase II studies.
These data were supported by two other clinical studies of patients consecutively treated with gemcitabine and docetaxel at the University of Michigan and in a retrospective analysis of patients treated with gemcitabine plus docetaxel in France. In the clinical analysis from Michigan, the response rate for patients treated mostly with first- and second-line therapy was 43%; the response rate in the French cohort of patients receiving any number of lines of prior therapy was 18%. These data confirmed the activity of gemcitabine and docetaxel in leiomyosarcoma, with patients with a few other histologies responding as well.
The question remained whether the activity of gemcitabine and docetaxel lay in the fixed-dose-rate infusion schedule (10 mg/m2 per minute) or in the synergy between gemcitabine and docetaxel. The Sarcoma Alliance for Research through Collaboration (SARC) performed a randomized phase II study to examine this question, comparing between patients given a higher dose fixed-dose-rate infusion of gemcitabine and those given a lower dose of fixed-dose-rate gemcitabine and docetaxel. A novel Bayesian clinical trial design was employed that randomized patients to the better therapy as the study proceeded. The details of the model and the interpretation of the study design are described elsewhere. In all, 73 patients were randomized to the two-drug combination, and 49 were randomized to gemcitabine as a single agent, indicating in and of itself the superiority of the combination. The response rate for gemcitabine was 9%, versus 16% for gemcitabine and docetaxel, and more patients on the combination took longer to progress than on the single agent, accounting for the model’s imbalance of randomization in favor of the combination.
NCCN lists this regimen as recommended for soft tissue sarcoma. However, a number of questions about schedule, sequence and kinetics remain and there are still trials ongoing to answer them.
R. G. Maki, M. L. Hensley, J. K. Wathen, S. R. Patel, D. A. Priebat, S. Okuno, D. Reinke, P. F. Thall, R. S. Benjamin, L. H. Baker,A SARC multicenter phase III study of gemcitabine (G) vs. gemcitabine and docetaxel (G+D) in patients (pts) with metastatic soft tissue sarcomas (STS). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 9514
Bay JO, Ray-Coquard I, Fayette J, Leyvraz S, Cherix S, Piperno-Neumann S, Chevreau C, Isambert N, Brain E, Emile G, Le Cesne A, Cioffi A, Kwiatkowski F, Coindre JM, Bui NB, Peyrade F, Penel N, Blay JY;Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis.Int J Cancer. 2007 Jan 15;120(2):450.
Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future
Robert G. Maki The Oncologist, Vol. 12, No. 8, 999-1006, August 2007; doi:10.1634/theoncologist.12-8-999