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.].