Paclitaxel-ifosfamide-cisplatin as salvage chemotherapy in ovarian cancer patients pretreated with platinum compounds and paclitaxel

Background: The role of combination chemotherapy regimens in the management of ovarian cancer patients with tumors previously exposed to platinum compounds and paclitaxel has not yet been defined. The present phase II study evaluated the activity and toxicity of a paclitaxel-ifosfamide-cisplatin combination in the aforementioned group of patients. Given the in vitro and in vivo synergism between these three agents, it was believed that using a three drug combination would overcome tumor resistance to cisplatin. Patients and Methods: Thirty-five patients were enrolled in the study. The median age was 55 and the median performance status 1. Thirteen (37%) had potentially platinum sensitive, 12 (35%) had primary platinum-resistant and 10 (28%) patients had secondary platinum-resistant tumors. Treatment consisted of paclitaxel 175 mg/m(2) as a 3 h i.v. infusion on day 1, cisplatin 75 mg/m(2) i.v. over 2 h fractionated over days 1 and 2, and ifos/amide 5 mg/m(2) i.v. over 1 h fractionated on days 1-2 with mesna uroprotection. Courses were administered every 3 weeks on an outpatient basis. Gran ulocyte-colony stimulation factor (G-CSF) was given at a dose of 5 mu g/kg/day on days 4-10. A median of 4 cycles were administered with the delivered dose intensity at 85% of the planned dose for the three agents. Results: Among 35 patients evaluable for response and toxicity, there were 10 partial responses with a response rate of 28.6% (95% confidence interval 12%-45%). Stable disease was recorded in 9 (25.7%) and progressive disease in 16 (45.7%) patients. Subgroup analysis revealed a response rate of 38.5% in potentially platinum-sensitive, 16.5% in primary platinum-resistant and 30% in secondary platinum-resistant tumors. The median response duration was 5 months (range 3-14 months), the median time to progression 6 months (range 3-18 months) and the median survival 12 months (range 3-44 months). Myelotoxicity was significant with neutropenia grade 3 and 4 occurring in 35% and 45% of patients, respectively. Eight episodes (5% of all cycles) of febrile neutropenia were documented and well managed with oral or i.v. antibiotics and G-CSF continuation until complete recovery. Grade 1, 2 and 3 peripheral neuropathy developed in 30%, 30% and 10% of patients, respectively. In conclusion, the three drug combination demonstrated a significant effectiveness in potentially platinum-sensitive tumors and a moderate efficacy in platinum-resistant tumors. The regimen, although myelotoxic, is tolerable with G-CSF support. Further investigation via comparative studies is required to define any superiority of the present regimen over doublets of the three agents in this group of patients.