Topotecan in combination with carboplatin: phase I trial evaluation of two treatment schedules

Topotecan and cisplatin combinations have shown schedule-dependent toxicity, which may in part be due to cisplatin nephrotoxicity. As carboplatin is less nephrotoxic and increasingly replacing cisplatin in clinical practice, the aim of this study was to define the optimal sequence and dose for topotecan in combination with carboplatin.

Two parallel phase I trials, with pharmacokinetic studies, were conducted administering carboplatin on day 1 with topotecan on days 1-5 (schedule A) or days 8-12 (schedule B). repeated every 3 weeks.

Twenty-one patients were treated over two dose levels, carboplatin AUC 4 [glomerular filtration rate (GFR) calculated from 51Cr-EDTA clearance] with topotecan 0.5 or 0.75 mg/m2. At the first dose level, six patients were evaluable for each schedule. With schedule A, from 34 cycles, there were two dose reductions and 10 treatment delays due to myelosuppression. With schedule B from 25 cycles, there was one reduction and 10 delays. At dose level 2, both patients in schedule A had dose-limiting neutropenia. In contrast, there was no dose-limiting toxicity with schedule B in six patients, although the majority of cycles were delayed.

The combination of topotecan and carboplatin using these 3-weekly schedules lead to significant myelotoxicity with attendant dose reductions and delays; the optimal scheduling of these agents remains to be defined.