Efficacy and Safety of First-line Single-Agent Carboplatin vs Carboplatin Plus Paclitaxel for Vulnerable Older Adult Women With Ovarian Cancer: A GINECO/GCIG Randomized Clinical Trial

Abstract

Importance: Single-agent carboplatin is often proposed instead of a conventional carboplatin-paclitaxel doublet in vulnerable older patients with ovarian cancer. Such an approach could have a detrimental effect on outcomes for these patients.

Objective: To compare the feasibility, efficacy, and safety of single-agent carboplatin every 3 weeks, weekly carboplatin-paclitaxel, or conventional every-3-weeks carboplatin-paclitaxel in vulnerable older patients with ovarian cancer.

Design, setting, and participants: This international, open-label, 3-arm randomized clinical trial screened 447 women 70 years and older with newly diagnosed stage III/IV ovarian cancer by determining their Geriatric Vulnerability Score; 120 patients with a Geriatric Vulnerability Score of 3 or higher were stratified by country and surgical outcome. Enrollment took place at 48 academic centers in France, Italy, Finland, Denmark, Sweden, and Canada from December 11, 2013, to April 26, 2017. Final analysis database lock April 2019. Data analysis was performed from February 1 to December 31, 2019.

Interventions: Patients were randomized to receive 6 cycles of (1) carboplatin, area under the curve (AUC) 5 mg/mL·min, plus paclitaxel, 175 mg/m2, every 3 weeks; (2) single-agent carboplatin, AUC 5 mg/mL·min or AUC 6 mg/mL·min, every 3 weeks; or (3) weekly carboplatin, AUC 2 mg/mL·min, plus paclitaxel, 60 mg/m2, on days 1, 8, and 15 every 4 weeks.

Main outcomes and measures: The primary outcome was treatment feasibility, defined as the ability to complete 6 chemotherapy cycles without disease progression, premature toxic effects-related treatment discontinuation, or death.

Results: A total of 120 women were randomized. The mean and median age was 80 (interquartile range, 76-83; range, 70-94) years; 43 (36%) had a Geriatric Vulnerability Score of 4 and 13 (11%) had a Geriatric Vulnerability Score of 5; 40 (33%) had stage IV disease. During its third meeting, the independent data monitoring committee's recommendation led to the termination of the trial because single-agent carboplatin was associated with significantly worse survival. Six cycles were completed in 26 of 40 (65%), 19 of 40 (48%), and 24 of 40 (60%) patients in the every-3-weeks combination, single-agent carboplatin, and weekly combination groups, respectively. Treatment-related adverse events were less common with the standard every-3-weeks combination (17 of 40 [43%]) than single-agent carboplatin or weekly combination therapy (both 23 of 40 [58%]). Treatment-related deaths occurred in 4 patients (2 of 40 [5%] in each combination group).

Conclusions and relevance: This randomized clinical trial shows that compared with every-3-weeks or weekly carboplatin-paclitaxel regimens, single-agent carboplatin was less active with significantly worse survival outcomes in vulnerable older patients with ovarian cancer.

Trial registration: ClinicalTrials.gov Identifier: NCT02001272.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Falandry reported receiving grants from the French National Cancer Institute (INCa) and nonfinancial support from ARCAGY for medical writer fees during the conduct of the study; and personal fees from Leo Pharma, Pfizer, MSD Oncology, Teva, AstraZeneca, Baxter, Eisai, Janssen Oncology, Novartis, Chugai Pharma, and Astellas Pharma; grants from Chugai Pharma, Pfizer, Pierre Fabre, and Astellas Pharma; and nonfinancial support from Janssen Oncology, Pierre Fabre, AstraZeneca, and Léo Pharma outside the submitted work. Dr Rousseau reported participating in a specialist advisory board for Bristol Myers Squibb. Dr Lorusso reported receiving personal advisory board fees from AstraZeneca, GlaxoSmithKline, Clovis Oncology, Immunogen, and Genmab; personal consulting fees from Pharma Mar and Merck Serono; institutional grants for research from Clovis Oncology, GlaxoSmithKline, Merck Sharp & Dohme, Pharma Mar, and Roche; and nonfinancial support (travel support for meetings) from AstraZeneca and GlaxoSmithKline outside the submitted work. Dr Herrstedt reported receiving personal fees from SOBI Education outside the submitted work. Dr Savoye reported serving in leadership roles for AstraZeneca, Novartis, and Roche. Dr Stefani reported receiving travel, accommodation, and expense fees from Ipsen and Pfizer. Dr Trédan reported receiving grants from Bristol Myers Squibb and personal fees from Roche, Novartis-Sandoz, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Merck Sharp & Dohme, Pierre Fabre, and Eisai outside the submitted work. Dr Mourey reported receiving personal fees and nonfinancial support from Sanofi, Astellas, Ipsen, Pfizer, and Janssen; nonfinancial support from AstraZeneca; and personal fees from Bristol Myers Squibb outside the submitted work. Dr Pujade-Lauraine reported receiving personal fees from AstraZeneca, Tesaro/GlaxoSmithKline, Clovis Oncology, Roche, Incyte, and Pfizer; serving as Research Chair for ARCAGY; and receiving nonfinancial support from AstraZeneca, Tesaro/GlaxoSmithKline, and Roche outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Trial Profile

EWOC-1 indicates Elderly Women With Ovarian Cancer trial; GVS, Geriatric Vulnerability Score. aHematologic events (n = 2); neuropathy (n = 2); other adverse events (AEs) (n = 2); toxic effect–related death (n = 2). bRecorded as unacceptable toxic effect (hematologic toxic effect [n = 1]; allergy [n = 1]; other reason [n = 1]); investigator’s decision due to excess toxic effects (n = 2); patient’s decision because of toxic effects (n = 1). cProgressive disease (n = 8); death due to progression (n = 4). dNon–chemotherapy-related AEs (n = 2). eHematologic toxic effect (n = 3); neuropathy (n = 3); other reasons (n = 3). fNon–chemotherapy-related AEs (n = 1); loss to follow-up (n = 1).

Figure 2.. Progression-Free Survival (PFS) and Overall Survival (OS) in All Patients and Those With Geriatric Vulnerability Score (GVS) 4-5