Pilot study of gemcitabine (10 mg/m(2) per min) and cisplatin

Gemcitabine and cisplatin are routinely used in combination. In this combination, gemcitabine at conventional doses of 1000-1500 mg/m(2) is delivered weekly as a 30-minute bolus. Laboratory data suggest that the synthesis of gemcitabine triphosphate is saturable, and that gemcitabine infused at a rate of 10 mg/m(2) per min optimizes accumulation of the triphosphate. Early clinical experience suggests that gemcitabine delivered by a more prolonged infusion is more myelosuppressive. In this pilot study, we wished to assess if full-dose gemcitabine when given with cisplatin could be delivered by this more prolonged infusion.

In this study, all patients received cisplatin 75 mg/m(2). All gemcitabine doses were delivered at 10 mg/m(2) per min. For the initial cohort (level 1) the gemcitabine dose was 800 mg/m(2) per min. Subsequent escalations were 1000 mg/m(2) per min (level 2), and 1250 mg/m(2) per min (levels 3 and 4). For the first three cohorts, patients received gemcitabine on days 1, 8, and 15 and cisplatin on day 15 on a 28-day cycle. Patients on level 4 received gemcitabine on days 1 and 8 and cisplatin on day 8 on a 21-day cycle. Dose omissions or delays (holds) were mandated for NCI CTC grade 3 or 4 granulocytopenia or grade 2-4 thrombocytopenia.

Entered onto this dose-finding study were 23 patients (12 male, 11 female) with advanced solid tumors. Seven patients were treatment-naive. Six patients were treated on level 1, five each on levels 2 and 3 and seven on level 4. Patients received one to seven cycles of treatment. Myelosuppression-related dose holds occurred at all levels. First-cycle dose holds occurred in three of six, four of five, three of five and two of seven patients on successive levels. First-cycle grade 3 or 4 granulocytopenia/thrombocytopenia occurred in three patients on level 1, one patient on level 2, two patients on level 3 and three patients on level 4. There were no partial or complete responses. Four patients were removed for toxicity (three myelosuppression, one nephrotoxicity), one at physician discretion, and 15 with disease progression. Three patients stopped therapy with stable disease after 5-6 months. On level 3, three of five patients remained on therapy for 4 months or more, compared to only one patient on each of the other three levels. CONCLUSIONS Weekly gemcitabine 1250 mg/m(2), utilizing a 10 mg/m(2) per min infusion rate, can be delivered with cisplatin 75 mg/m(2) with tolerable toxicity. When used in combination with cisplatin, however, the benefit of this fixed dose rate infusion gemcitabine compared to standard bolus gemcitabine remains to be determined.