A multicenter, randomized, phase III study comparing paclitaxel/carboplatin (PC) versus topotecan/paclitaxe/carboplatin (TPC) in patients with stage III (residual tumor > 1 cm after primary surgery) and IV ovarian cancer (OC)

Background: Despite treatment with standard first-line PC, survival rates of patients with OC is disappointing, especially in patients suboptimally debulked. In this phase III, open-label, randomised, parallel-arm study topotecan, a non cross-resistant topoisomerase I inhibitor was added to the standard platinum-taxane doublet in order to improve survival and progression-free interval compared to PC alone. Methods: 326 ITT patients with FIGO stage III (residual tumor > 1 cm) and IV OC were randomly allocated to receive either carboplatin AUC 5 and paclitaxel 175 mg/sqm d1q21 (arm A; 170 pts) or topotecan 1 mg/sqm dd1-3q21 + carboplatin AUC 5 and paclitaxel 175 mg/sqm d3q21 (arm B, 156 pts) for 6 cycles. Primary endpoint was the 3-year survival rate with 350 patients originally planned to show an increase in 3-year survival from 20 in arm A to 35% in arm B with 80% power and alfa = 0.05. Results: 81.8% and 77.6% of patients in arm A and B respectively completed the 6 cycles planned. The 2 arms were well balanced for demography, tumor staging and histology except for an excess of serous histotype in the arm B (68.2% vs 75%). Best overall response was CR/PR in 51.5%/33.7% (ORR 85.2%) in arm A and 57.8%/36.3% (ORR 92.5%) in arm B (p = 0.586 with ψ2 test, NS). Median time to progression (TTP) was 70.4 and 71.8 weeks in arm A and B respectively (p = 0.5058 with Wilcoxon test, NS). Most common G3/4 hematological toxicity was neutropenia (7.1% and 13.2% of courses and 23.5% and 39.7% of pts in arm A and B) and most common non-hematological toxicities were alopecia (78.2% and 72.4% in arm A and B) and nausea/vomiting (43.5% and 50.5% in arm A and B). 13.9% and 15.5% of courses were delayed and 2.1%/2.4% and 7.2%/6.2% of carboplatin/paclitaxel doses reduced for toxicity in arm A and B respectively. 9.4% and 23.3% of courses required transfusions in arm A and B respectively. Conclusions: The addition of topotecan to standard PC primary chemotherapy does not increase RR and TTP in stage III (residual tumor > 1 cm) or IV OC compared to PC alone. The TPC regimen was well tolerated with a minority of patients experiencing G3/4 hematological toxicity. Study funded by GlaxoSmithKline.