Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup

Abstract

Purpose: To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel.

Patients and methods: Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons.

Results: Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup.

Conclusion: Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.

Fig 1.

Patient demographic characteristics, prognostic factors (including stage, histology, and measurable disease), and stratification parameters (including maximal residual disease and intent to perform interval cytoreductive surgery). FIGO, International Federation of Gynecology and Obstetrics; CP, carboplatin and paclitaxel; CPG, carboplatin, paclitaxel, and gemcitabine; CPD, carboplatin, paclitaxel, and doxorubicin; CT→CP, carboplatin plus topotecan, then carboplatin plus paclitaxel; CG→CP, carboplatin plus gemcitabine, then carboplatin plus paclitaxel.

Fig 2.

Clinically important (A) hematologic and (B) nonhematologic toxicities. A Pearson χ² test to assess the null hypothesis (ie, the probability of adverse events is independent of treatment) was statistically significant at P < .005 for grade 4 and worse neutropenia (absolute neutrophils count [ANC]) and thrombocytopenia (platelets [PLT]); grade 3 or worse hemoglobin (Hgb), infection/fever (fever), and GI toxicity; and grade 2 or worse peripheral neuropathy, pulmonary, and hepatic toxicity. CP, carboplatin and paclitaxel; CPG, carboplatin, paclitaxel, and gemcitabine; CPD, carboplatin, paclitaxel, and doxorubicin; CT-CP, carboplatin plus topotecan, then carboplatin plus paclitaxel; CG-CP, carboplatin plus gemcitabine, then carboplatin plus paclitaxel.

Fig 3.

Estimates of (A) progression-free survival and (B) overall survival for each treatment arm, including the cumulative number of events, the number of patients at risk, and a summary of hazard ratios; P values were adjusted for extent of residual disease and participating cooperative group. Median progression-free survival rates varied from 15.4 to 16.4 months, and median overall survival rates varied from 39.6 to 44.2 months. CP, carboplatin and paclitaxel; CPG, carboplatin, paclitaxel, and gemcitabine; CPD, carboplatin, paclitaxel, and doxorubicin; CT-CP, carboplatin plus topotecan, then carboplatin plus paclitaxel; CG-CP, carboplatin plus gemcitabine, then carboplatin plus paclitaxel.

Fig 4.

(A) Estimate of overall survival and (B) progression-free survival according to the extent of residual disease, which remains a highly significant prognostic factor across all treatment regimens. (C) The potential benefit of experimental treatment regimens evaluated in subpopulations according to the extent of residual disease, illustrated by hazard ratios for survival. Prog, progression; CPG, carboplatin, paclitaxel, and gemcitabine; CPD, carboplatin, paclitaxel, and doxorubicin; CT-CP, carboplatin plus topotecan, then carboplatin plus paclitaxel; CG-CP, carboplatin plus gemcitabine, then carboplatin plus paclitaxel.