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

• Published in: Cancer 2004-11, Vol.101 (10), p.2261-2269
• Main Authors: Buesa, José M., Losa, Raquel, Fernández, Aida, Sierra, Marta, Esteban, Emilio, Díaz, Ángela, López‐Pousa, Antonio, Fra, Joaquín
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - blood; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; dacarbazine; Dacarbazine - administration & dosage; Dacarbazine - adverse effects; Deoxycytidine - administration & dosage; Deoxycytidine - adverse effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - blood; Dermatology; Dose-Response Relationship, Drug; Female; Floxuridine - analogs & derivatives; Floxuridine - blood; gemcitabine; Humans; Infusions, Intravenous; Leukocytes, Mononuclear - chemistry; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Phase I trial; Sarcoma - drug therapy; soft tissue sarcoma; Treatment Outcome; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.20612

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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. In the current Phase I trial, the authors investigated the efficacy and safety of a regimen containing gemcitabine and dacarbazine in the treatment of advanced soft tissue sarcoma. Based on the results of this trial, the authors recommend the use of 1800 mg/m2 gemcitabine administered via 3‐hour infusion followed by 500 mg/m2 dacarbazine administered intravenously o