Sequential cycles of high-dose chemotherapy with dose escalation of carboplatin with or without paclitaxel supported by G-CSF mobilized peripheral blood progenitor cells: a phase I/II study in advanced ovarian cancer

Abstract

To assess high-dose carboplatin chemotherapy with or without paclitaxel with filgrastim mobilized peripheral blood progenitor cell (PBPC) support in a phase I/II study, a total of 21 patients with mostly chemonaive disease received four cycles of high-dose chemotherapy. Cycle 1 (cyclophosphamide, 6 g/m²) was followed by two cycles of carboplatin (1600 mg/m² or 1800 mg/m²). Cycle 4 consisted of carboplatin (1600 mg/m²), etoposide (1600 mg/m²), and melphalan (140 mg/m²). Further chemotherapy intensification was achieved by adding paclitaxel (175 mg/m²) to all cycles with a fixed carboplatin dose (1600 mg/m²). Ototoxicity was dose-limiting for escalation of sequential cycles of carboplatin. Grade 2 and grade 3 ototoxicity, hearing loss not requiring a hearing aid, or hearing loss correctable with a hearing aid, was observed with carboplatin at 1800 mg/m². The maximum tolerated dose (MTD) of sequential carboplatin, therefore, was identified in this study as 1600 mg/m². After cycles 1, 2, 3 and 4 the median duration of leukopenia (<1.0 × 10⁹/l) was 7, 4, 4 and 6 days. Severe grade 3 and 4 infections were seen in only 7% of cycles. Of the 21 patients evaluable for disease response, 57% had complete remissions and 43% experienced partial remissions resulting in an overall response rate of 100%. The median progression-free survival is 25 (15–36) months, the median overall survial 36.5 (15–38) months. Most patients were suboptimally debulked or had bulky residual disease at the start of chemotherapy. Sequential high-dose chemotherapy to a maximum dose of 1600 mg/m² carboplatin is effective and feasible. A randomized, prospective trial comparing sequential high-dose chemotherapy with optimal standard chemotherapy is now warranted.