Phase III Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: A Gynecologic Oncology Group Study

Abstract

A B S T R A C T PurposeAssess toxicity and efficacy of cisplatin (Cis) doublet combinations in advanced and recurrent cervical carcinoma. Patients and MethodsPatients were randomly assigned to paclitaxel 135 mg/m 2 over 24 hours plus Cis 50 mg/m 2 day 2 every 3 weeks (PC, reference arm); vinorelbine 30 mg/m 2 days 1 and 8 plus Cis 50 mg/m 2 day 1 every 3 weeks (VC); gemcitabine 1,000 mg/m 2 day 1 and 8 plus Cis 50 mg/m 2 day 1 every 3 weeks (GC); or topotecan 0.75 mg/m 2 days 1, 2, and 3 plus Cis 50 mg/m 2 day 1 every 3 weeks (TC). Survival was the primary end point with a 33% improvement relative to PC considered important (85% power, alpha ϭ 5%). Quality-of-life data were prospectively collected. ResultsA total of 513 patients were enrolled when a planned interim analysis recommended early closure for futility. The experimental-to-PC hazard ratios of death were 1.15 (95% CI, 0.79 to 1.67) for VC, 1.32 (95% CI, 0.91 to 1.92) for GC, and 1.26 (95% CI, 0.86 to 1.82) for TC. The hazard ratios for progression-free survival (PFS) were 1.36 (95% CI, 0.97 to 1.90) for VC, 1.39 (95% CI, 0.99 to 1.96) for GC, and 1.27 (95% CI, 0.90 to 1.78) for TC. Response rates (RRs) for PC, VC, GC, and TC were 29.1%, 25.9%, 22.3%, and 23.4%, respectively. The arms were comparable with respect to toxicity except for leucopenia, neutropenia, infection, and alopecia. ConclusionVC, GC, and TC are not superior to PC in terms of overall survival (OS). However, the trend in RR, PFS, and OS favors PC. Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.

Immunotherapy: An Evolving Paradigm in the Treatment of Advanced Cervical Cancer

“…3,4 Since the publication of the initial studies examining cisplatin in the treatment of cervical cancer, a number of effective single-agent and combination drug regimens have been identified that exhibited improved response rates, without a significant effect on overall survival. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] The poor oncologic outcome in this patient population represents an unmet clinical need and has driven the exploration of new treatment paradigms. 3 Most recently, the results of Gynecologic Oncology Group (GOG) protocol 240 were presented and Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842.…”

PRO: Patients With Metastatic/Recurrent Cervical Cancer Should Be Treated With Cisplatin Plus Paclitaxel

“…Monk et al recently reported results from the largest and most complex randomized, multicenter phase III clinical trial performed in this population. 24 In this 4-arm trial, none of the experimental regimens was found to be superior to the control arm of cisplatin plus paclitaxel. The RRs for the control, cisplatin plus vinorelbine, cisplatin plus gemcitabine, and cisplatin plus topotecan were 29.1%, 25.9%, 22.3%, and 23.4%, respectively.…”

“…20, 24 Moore et al reported that, with the exception of select hematologic toxicities (eg, grade 3/4 neutropenia and anemia), the doublet was well tolerated, with all nonhematologic grade 3/4 toxicities and grade 3/4 thrombocytopenia occurring in Ͻ 10% of the subjects. 20 Similarly, Monk et al observed that grade 3/4 hematologic toxicities occurred more frequently in patients receiving the cisplatin/topotecan doublet than among patients treated with cisplatin plus paclitaxel (anemia, 34.9% vs. 16.8%; neutropenia, 82.6% vs. 78.2%; and thrombocytopenia, 34.9% vs. 6.9%, respectively).…”

“…Further testament to this hypothesis is the observation that in this study, the RR and PFS for the single-agent cisplatin arm were lower than that observed in previous trials. 17,18,20 Although the 4-arm study reported by Monk et al (described above) was designed while the cisplatin/topotecan study was ongoing, the combination of cisplatin plus paclitaxel was selected as the reference arm primarily because of its relatively high RR as reported by Moore et al 20,24 It was also deemed important to determine whether the activity of cisplatin plus paclitaxel would be sustained in the era of chemoradiation for locally advanced disease.…”

“…23 In the GOG's eighth randomized trial in this population (protocol 204), Monk et al tested 4 cisplatin-based doublets. 24 Because of the high RR reported by Moore et al, cisplatin plus paclitaxel was selected as the reference arm and was studied alongside doublets containing topotecan, gemcitabine (1000 mg/m 2 days 1 and 8), and vinorelbine (30 mg/m 2 days 1 and 8) on 21-days schedules. On April 24, 2007, results of a scheduled interim analysis of 513 evaluable patients were presented to the Data Monitoring Committee (DMC) indicating that all of the experimental arms in the clinical trial were unlikely to demonstrate improved survival over cisplatin plus paclitaxel by the end of the study.…”