Prolonged infusion of gemcitabine in stage IV breast cancer: a phase I study

Gemcitabine is an effective agent in the treatment of metastatic breast can cer. The phosphorylation of gemcitabine into the active gemcitabine triphos phate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturat ed at plasma concentrations achieved after an infusion over 30 min. Therefo re accumulation of higher intracellular dFdCTP concentrations, which may re sult in an enhanced antineoplastic activity, cannot be achieved by higher d osage, but only by prolonged infusion time. The objectives of this phase I trial were to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of gemcitabine given as a 6 h i.v. infusion. Patients with metastatic breast cancer were treated with gemcitabine as a 6 h infusi on on days 1, 8 and 15 every 4 weeks. The starting dose was 200 mg/m(2) wit h an interindividual escalation in 50 mg/m(2) increments. Sixteen patients received 196 doses through three dose levels. All patients were assessable for toxicity, 13 assessable for response. The MTD was 250 mg/m(2). DLT was observed at 300 mg/m(2) consisting of a reversible elevation of transaminas es WHO grade 3 in two patients and cutaneous toxicity grade 3 in one patien t. Most common non-hematologic toxicities were mild to moderate and rapidly reversible elevation of liver enzymes in all patients, nausea and vomiting (four patients grade 2, five patients grade 3), and mild alopecia. Hematol ogic toxicity was mild with neutropenia WHO grade 3 and 4 in only one patie nt each, and no grade 3 thrombocytopenia. One patient achieved a complete r emission and another patient a partial response, for an overall response ra te of 15% (two of 13). In addition, seven patients (54%) had stable disease and four (31%) failed to respond to the treatment. We conclude gemcitabine 250 mg/m2 days 1, 8 and 15 every 4 weeks can be safely administered as 6 h infusion. Toxicity, especially myelosuppression, is surprisingly mild. Bas ed on this result a phase II study with 250 mg/m(2) administered over 6 h w as initiated to determine the efficacy. [(C) 1999 Lippincott Williams & Wil kins.].