Phase III randomized clinical trial of cisplatin plus paclitaxel vs the non-platinum chemotherapy doublet of topotecan plus paclitaxel in women with recurrent, persistent, or advanced cervical carcinoma: A Gynecologic Oncology Group study

Abstract

Objective: With increasing use of radiosensitizing cisplatin-based chemoradiation for locally advanced cervical cancer, many patients with recurrent disease may be platinum-resistant. This is suggested by decreasing response rates (RR) to platinum-based therapy in the recurrent setting noted in the preceding randomized Gynecologic Oncology Group (GOG) trials in this population (GOG 169, 179, 204). We sought to determine whether the non-platinum chemotherapy doublet, topotecan plus paclitaxel (TP), improves overall survival (OS) when compared to cisplatin plus paclitaxel (CP) in recurrent, persistent, or advanced cervical carcinoma. (A 2x2 factorial design was used to also assess the independent question concerning the impact of anti- angiogenesis therapy, but these data are not yet mature.) Methods: Patients were randomly assigned to C 50 mg/m2 plus P 135-175 mg/m2 or T 0.75 mg/m2 d1-3 plus P 175 mg/m2 d1. Cycles were repeated every 3 weeks until progression, unacceptable toxicity, and/or complete response. OS was the primary endpoint, with a reduction in the hazard of death by 30% with substitution of T for C considered important (90% power, alpha=2.5%). Quality-of-life data were prospectively collected. Results: Four hundred fifty-two patients were accrued from 4/6/09 to 1/3/12. A planned interim analysis was conducted after 174 patients died. A total of 229 patients received the CP backbone and 223 received the TP backbone. Seventy-five percent of the entire study group had previously received platinum (75.5% CP arm, 74% TP arm). Patients were well-matched for age, histology, race/ethnicity, grade, and recurrent, persistent, or advanced disease. The experimental-to- CP HR of death was 1.20 (98.74% CI 0.82-1.76; 1-sided P=0.88). Median survival was 15 months (CP) and 12.5 months (TP). The HR for progression-free survival (PFS) was 1.39 (95% CI 1.09-1.77; 2- sided P=0.0083). The RR at the time of analysis were 38.4% CP and 28.7% TP (P=not significant). TP was associated with significantly less grade 3-5 nausea, neuropathy, and metabolic toxicities but performed unfavorably with leukopenia. Febrile neutropenia and infection with grade 3-4 neutropenia was not significantly increased with TP. Conclusions: This is the largest phase III randomized clinical trial in this population to complete accrual. The substitution of T for C does not result in improved OS. Consistent with previous experience, the RR for CP remains high. Treatment of recurrent/ persistent/advanced cervical cancerwith CP or TP should be predicated on toxicity screening.