Repetitive High-Dose Topotecan, Carboplatin, and Paclitaxel with Peripheral Blood Progenitor Cell Support in Previously Untreated Ovarian Cancer: Results of a Phase I Study

Abstract Objective. In view of the significant activity of topotecan in ovarian cancer with dose-limiting toxicity (DLT) of myelosuppression, we evaluated the addition of topotecan to carboplatin and paclitaxel with peripheral blood progenitor cell (PBPC) support. Methods. Patients with previously untreated stage IIIC or IV ovarian cancer with macroscopic residual disease following primary debulking surgery were eligible. Patients received two cycles of carboplatin AUC=5 and 175 mg/m 2 of paclitaxel with collection of PBPCs after the second cycle. Patients subsequently received three cycles of high-dose therapy (HDT) with topotecan on a daily ×5 schedule, paclitaxel (250 mg/m 2 over 24 h), and carboplatin (AUC = 12–16). Results. Nineteen patients with a median age of 49 years (range 21–63) were enrolled and topotecan was escalated in 6 patient cohorts up to a dose of 4.5 mg/m 2 /day. Fifty-two of the planned 57 treatment cycles were delivered with no treatment-related deaths. Neutrophil and platelet recovery was rapid and the interval between HDT was 28 days. Febrile neutropenia occurred following 57% of all HDT cycles. DLTs of mucositis and diarrhea were observed at topotecan (4.5 mg/m 2 /day), paclitaxel (250 mg/m 2 ) and carboplatin (AUC = 12). The protocol was subsequently modified to administer topotecan (2.5 mg/m 2 /day) with carboplatin (AUC = 16); however, 2 patients developed grade 4 diarrhea (1 with grade 3 mucositis and 1 with grade 4 mucositis). The clinical CR rate was 73% (14/19) with an overall clinical response rate of 95% (18/19). Of the 14 patients with a CCR, 13 of these underwent a second-look laparotomy with 8 (61%) achieving a pthological CR. With a median follow-up of 28 months (range 11–40 months), the median PFS is 36 months and OS has not been reached. Conclusion. When combined with carboplatin (AUC = 12) and paclitaxel (250 mg/m 2 ), the recommended topotecan dose is 3.5 mg/m 2 /day for 5 days. This outpatient HDT regimen combines three of the most active drugs in ovarian cancer with acceptable toxicity and promising activity.