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Phase I clinical trial of fixed–dose rate infusional gemcitabine and dacarbazine in the treatment of advanced soft tissue sarcoma, with assessment of gemcitabine triphosphate accumulation†
Article first published online: 13 OCT 2004
Copyright © 2004 American Cancer Society
Volume 101, Issue 10, pages 2261–2269, 15 November 2004
How to Cite
Buesa, J. M., Losa, R., Fernández, A., Sierra, M., Esteban, E., Díaz, Á., López-Pousa, A. and Fra, J. (2004), Phase I clinical trial of fixed–dose rate infusional gemcitabine and dacarbazine in the treatment of advanced soft tissue sarcoma, with assessment of gemcitabine triphosphate accumulation. Cancer, 101: 2261–2269. doi: 10.1002/cncr.20612
Presented in part at the 22nd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31–June 3, 2003.
- Issue published online: 29 OCT 2004
- Article first published online: 13 OCT 2004
- Manuscript Accepted: 20 JUL 2004
- Manuscript Revised: 25 JUN 2004
- Manuscript Received: 5 MAY 2004
- European Community's Funds for Regional Development (FEDER.FSE)
- Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (Madrid, Spain). Grant Number: 01/0319
- Obra Social Cajastur (Asturias, Spain)
- Program 9 of the Redes Temáticas de Investigación Cooperativa de Centros de Cáncer (C03/10), Instituto de Salud Carlos III
- soft tissue sarcoma;
- Phase I trial
In the current study, the authors set out to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) associated with a combination of gemcitabine and dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (ASTS), to obtain preliminary information on the activity of this combination, and to explore possible pharmacodynamic interactions between gemcitabine and DTIC.
Every 2 weeks, 22 patients with refractory ASTS received fixed–dose rate gemcitabine (10 mg/m2/min) at escalating doses, which ranged from 800 mg/m2 to 2160 mg/m2, plus 500 mg/m2 DTIC. Plasma concentrations of gemcitabine and 2′,2′-difluorodeoxyuridine, along with gemcitabine triphosphate (dFdCTP) levels in peripheral blood mononuclear cells (PBMCs), were evaluated during the course of treatment.
Grade 3 elevation of transaminase and γ-glutamyltransferase levels represented the DLT associated with the administration of 2160 mg/m2 gemcitabine plus 500 mg/m2 DTIC. This side effect was reversible, rather than cumulative, and did not exceed Grade 3 in its severity. The doses recommended for use in subsequent Phase II studies are 1800 mg/m2 gemcitabine (administered over the course of 3 hours) and 500 mg/m2 DTIC. Hematologic toxicity was moderate, and nonhematologic side effects that did not exceed Grade 2 in severity included the following: asthenia (75% of patients), fever (59%), nausea (52%), stomatitis (48%), anorexia (44%), emesis (40%), flulike syndrome (37%), and erythematous rash (26%). Alopecia was common. Intracellular dFdCTP levels, which were evaluated in 6 patients, reached a mean maximum value of 209 pmol per 106 cells (standard deviation, 59 pmol per 106 cells) at the conclusion of gemcitabine administration. DTIC had a limited effect on the elimination of dFdCTP from PBMCs. Objective responses were observed in 5 of the 19 patients who were evaluable for treatment efficacy.
The combination of gemcitabine and DTIC possesses an acceptable toxicity profile and may warrant further investigation in patients with ASTS. Cancer 2004. © 2004 American Cancer Society.