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.

Conflict of interest statement

Matthew A. Powell Consulting or Advisory Role: Roche/Genentech, AstraZeneca, Tesaro, Clovis Oncology, Eisai, GOG partners, Seattle Genetics, GlaxoSmithKline/Tesaro Research Funding: GlaxoSmithKline/Tesaro (Inst) Virginia L. Filiaci Other Relationship: GOG Foundation Martee L. Hensley Employment: Sanofi (I) Stock and Other Ownership Interests: Sanofi (I) Consulting or Advisory Role: Lilly, Tesaro, GlaxoSmithKline, Thrive, An Exact Sciences Company Patents, Royalties, Other Intellectual Property: author, UpToDate Kathleen N. Moore Honoraria: Research To Practice, Prime Oncology, Physicans' Education Resource, Great Debates and Updates Consulting or Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, TESARO (Inst), VBL Therapeutics, Merck, Aravive, Eisai, Vavotar Life Sciences, Mersana (Inst), Myriad Genetics, Alkermes (Inst), Blueprint Pharmaceuticals (Inst), GlaxoSmithKline/Tesaro (Inst), I-Mab (Inst), InxMed (Inst), Mereo BioPharma (Inst) Research Funding: PTC Therapeutics (Inst), Lilly (Inst), Merck (Inst), Tesaro (Inst), Genentech (Inst), Clovis Oncology (Inst), Lilly Foundation (Inst), Regeneron (Inst), Advaxis (Inst), Bristol Myers Squibb (Inst), Verastem (Inst), Novartis Pharmaceuticals UK Ltd (Inst), AstraZeneca (Inst), Agenus (Inst), Takeda (Inst), Forty Seven (Inst), Stemcentrx (Inst), Immunogen (Inst), Bayer (Inst), Novogen (Inst), AbbVie/Stemcentrx (Inst) Other Relationship: GOG Partners (Inst) Krishnansu S. Tewari Honoraria: Tesaro, Clovis Oncology, Merck, Eisai, AstraZeneca, Genmab Consulting or Advisory Role: Roche/Genentech, Tesaro, Clovis Oncology, AstraZeneca Speakers' Bureau: Roche/Genentech, AstraZeneca, Merck, Tesaro, Clovis Oncology, Eisai, Genmab Research Funding: AbbVie (Inst), Genentech/Roche (Inst), Morphotek (Inst), Merck (Inst), Regeneron (Inst) Travel, Accommodations, Expenses: Roche/Genentech Larry J. Copeland Consulting or Advisory Role: Tarveda Therapeutics, Tarveda Therapeutics, Myriad Genetics, GlaxoSmithKline, Elevar Therapeutics, Toray Industries, Rubius Therapeutics, Sorrento Therapeutics, Celsion, Corcept Therapeutics Angeles Secord Honoraria: Myriad Genetics Research Funding: Tesaro (Inst), AstraZeneca (Inst), Genentech (Inst), Boehringer Ingelheim (Inst), AbbVie (Inst), Merck (Inst), PharmaMar (Inst), Clovis Oncology (Inst), Eisai (Inst), Seattle Genetics (Inst), Immutep (Inst), GlaxoSmithKline (Inst), VBL Therapeutics (Inst), OncoQuest Pharmaceuticals (Inst) Travel, Accommodations, Expenses: GlaxoSmithKline Uncompensated Relationships: Roche/Genentech, VBL Therapeutics, GOG Foundation, OncoQuest Pharmaceuticals, Regeneron, Aravive David G. Mutch Consulting or Advisory Role: Lilly Alessandro Santin Consulting or Advisory Role: Merck, Tesaro Research Funding: Tesaro (Inst), Merck (Inst), Boehringer Ingelheim (Inst), Gilead Sciences (Inst), Puma Biotechnology (Inst), Genentech/Roche (Inst), Genentech/Roche (Inst), R-Pharm (Inst), Immunomedics (Inst) Nick M. Spirtos Research Funding: AbbVie (Inst), AstraZeneca (Inst), Genentech/Roche (Inst), Clovis Oncology (Inst), Seattle Genetics (Inst) Patents, Royalties, Other Intellectual Property: Application No. PCT/US 2019/19465, Cannabis Based Therapeutic and Method of Use; Application No.: US Patent 0024098766, Compounds Cannabidiol and Flavanones, 63/047550 (July 1, 2020) 63/055458 (July 23, 2020), Title Country Status Filed Date Application No. Patent Ref. No. 199236-701611/EP, Title: Cannabis Based Therapeutic and Method of Use Country, European Patent Status: Published February 25, 2019, 19710540.6; Patent Ref. No. 199236-701691/PCT-BR, Title: Cannabis Based Therapeutic and Method of Use Country Brazil Status: Application February 25, 2019, 1120200170232; Patent Ref. No. 199236-701831/PCT-US, Title: Cannabis Based Therapeutic and Method of Use Country United States of America Status: Published February 25, 2019, 16/971,781; Patent Ref. No. 199236-701891/HK, Title: Cannabis Based Therapeutic and Method of Use Country Hong Kong Status: Published June 25, 2021, 62021033676.9; Patent Ref. No. Title Country Status Filed Date; Application No. Patent Ref. No. 199237-701601/PCT, Title: Compositions Comprising Cannabidiol and Flavanones Country: Patent Cooperation Treaty Status: Application July 1, 2021, PCT/US21/40115; Patent Ref. No. 199237-701691/BR, Title: Compositions Comprising Cannabidiol and Flavanones Country: Brazil Status: Application November 19, 2020, 1020200236644; Patent Ref. No. 199237-7019761/UY, Title: Compositions Comprising and Flavanones Country: Uruguay Status: Application November 20, 2020, 38965, John Wiley and Sons Editor 12th Edition Bonney's Gynaecological Surgery Open Payments Link: https://openpaymentsdata.cms.gov/physician/8054, https://openpaymentsdata.cms.gov/physician/8054 Paul A. DiSilvestro Consulting or Advisory Role: AstraZeneca, Agenus Research Funding: Janssen Oncology (Inst), Tesaro (Inst), AstraZeneca (Inst), Genentech (Inst), AbbVie (Inst) David S. Miller Consulting or Advisory Role: Genentech, Tesaro, Eisai, AstraZeneca, Guardant Health, Janssen Oncology, Alexion Pharmaceuticals, Karyopharm Therapeutics, Incyte, Guardant Health, Janssen, Alexion Pharmaceuticals, Clovis Oncology, Merck Sharp & Dohme (Inst), Asymmetric Therapeutics, Boston Biomedical Research Institute, Tarveda Therapeutics, Myriad Genetic Laboratories, GlaxoSmithKline, AbbVie, Incyte, EMD Serono, Seattle Genetics, Clinical Education Alliance, LLC, Eisai, GlaxoSmithKline, iTeos Belgium SA, Novocure, Novartis, Immunogen, Agenus Speakers' Bureau: Clovis Oncology, Genentech Research Funding: US Biotest (Inst), Advenchen Laboratories (Inst), Tesaro (Inst), Xenetic Biosciences (Inst), Advaxis (Inst), Janssen (Inst), Aeterna Zentaris (Inst), TRACON Pharma (Inst), Pfizer (Inst), Immunogen (Inst), Mateon Therapeutics (Inst), Merck Sharp & Dohme (Inst), AstraZeneca (Inst), Millennium Pharmaceuticals (Inst), Aprea AB (Inst), Regeneron (Inst), NVision (Inst), Leap Therapeutics (Inst), Novartis (Inst), Syros Pharmaceuticals (Inst), Karyopharm Therapeutics (Inst), Agenus (Inst), Akesobio (Inst), EMD Serono Research & Development Institute, Incyte (Inst)No other potential conflicts of interest were reported.

Figures

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.