Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial

Abstract

Purpose: This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS).

Patients and methods: Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test.

Results: The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P < .01 for noninferiority, P > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = < 0.01 for noninferiority, P < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant.

Conclusion: PC was not inferior to the active regimen PI and should be standard treatment for UCS.

FIG 1.

CONSORT diagram. PC, paclitaxel and carboplatin; PI, paclitaxel and ifosfamide.

FIG 2.

(A) Survival by assigned treatment arms and for all eligible patients with UCS (HR = 0.87 PC relative to PI; 99% CI, 0.70 to 1.075). (B) Survival by assigned treatment arms for all eligible patients with OCS (HR = 1.15; 95% CI, 0.67 to 1.95). (C) PFS by assigned treatment arms for all eligible patients with UCS (16 v 12 months; HR = 0.735; 95% CI, 0.58 to 0.93; P < .001) considered both noninferior and statistically superior (P < .01). (D) PFS by assigned treatment arms for all eligible patients with OCS (HR = 1.01; 95% CI, 0.61 to 1.67). (E) OS for eligible patients with stage III UCS (HR = 0.82; 95% CI, 0.0.59 to 1.14). (F) PFS for eligible patients with stage III UCS (HR = 0.70; 95% CI, 0.0.51 to 0.96). HR, hazard ratio; OCS, ovarian carcinosarcoma; OS, overall survival; PC, paclitaxel and carboplatin; PFS, progression-free survival; PI, paclitaxel and ifosfamide; UCS, uterine carcinosarcoma. Paclitaxel and carboplatin is not inferior to paclitaxel and ifosfamide for gynecologic carcinosarcoma.

FIG 3.

(A) PFS for prior pelvic RT and stage I-III patients and (B) OS for prior pelvic RT and stage I-III uterine patients (SAS system). OS, overall survival; PFS, progression-free survival; RT, radiation therapy.

FIG A1.

Forest plot of treatment effect on OS by subgroup of (A) all eligible patients with UCS and (B) all eligible patients with OCS. Forest plot of treatment effect on PFS by subgroup of (C) all eligible patients with UCS and (D) all eligible patients with OCS. BMI, body mass index; OCS, ovarian carcinosarcoma; OS, overall survival; PC, paclitaxel and carboplatin; PFS, progression-free survival; PI, paclitaxel and ifosfamide; RT, radiation therapy; UCS, uterine carcinosarcoma.

FIG A2.

CONSORT diagram of PROs. PC, paclitaxel and carboplatin; PI, paclitaxel and ifosfamide; PRO, patient-reported outcome.

FIG A3.

(A) Patient-reported FACT-En TOI scores by treatment arms. (B) Patient-reported FACT with GOG-Ntx subscale scores by treatment arms. FACT with GOG-Ntx, Functional Assessment of Cancer Therapy with GOG-neurotoxicity subscale; FACT-En TOI, Trial Outcome Index of the Functional Assessment of Cancer Therapy—Endometrial; PC, paclitaxel and carboplatin; PI, paclitaxel and ifosfamide.