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Original Investigation
April 22, 2021

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

Author Affiliations
  • 1Groupe d’Investigateurs Nationaux pour l’Étude des Cancers de l’Ovaire et du sein (GINECO), Laboratoire CarMEN, INSERM U1060/INRA U1397, Université Lyon 1, INSA de Lyon, and Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France
  • 2GINECO and Institut Paoli Calmettes, Marseille, France
  • 3GINECO and Centre Jean Perrin, Clermont-Ferrand, France
  • 4GINECO and Institut de Cancérologie de la Loire, St Priest en Jarez, France
  • 5Multicentre Italian Trials in Ovarian cancer (MITO) and Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, and Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy
  • 6Nordic Society of Gynecologic Oncology (NSGO), Odense University Hospital, Odense, and Zealand University Hospital, Roskilde, Denmark
  • 7GINECO and Institut Jean Godinot, Reims, France
  • 8GINECO and Centre Hospitalier Annecy Genevois, Pringy, France
  • 9GINECO and Institut de Cancérologie de l’Ouest René Gauducheau, Saint Herblain, France
  • 10GINECO and Groupe Hospitalier Paris Saint Joseph, Paris, France
  • 11GINECO and Institut du Cancer de Montpellier, Montpellier, France
  • 12GINECO and Hôpital Privé du Confluent, Nantes, France
  • 13GINECO and Centre François Baclesse, Caen, France
  • 14GINECO and Centre Hospitalier de Cholet, Cholet, France
  • 15GINECO and Centre Hospitalier Intercommunal de Créteil, Créteil, France
  • 16GINECO and Centre Hospitalier Universitaire Dupuytren, Limoges, France
  • 17GINECO and Centre Léon Bérard, Lyon, France
  • 18GINECO and Institut Claudius Regaud, Toulouse, France
  • 19GINECO, Paris, France
  • 20GINECO and Centre Hospitalier Lyon-Sud, Lyon, France
JAMA Oncol. 2021;7(6):853-861. doi:10.1001/jamaoncol.2021.0696
Key Points

Question  What is the optimal chemotherapy regimen for vulnerable older patients with ovarian cancer?

Findings  In this randomized clinical trial of 120 vulnerable older patients with ovarian cancer, single-agent carboplatin was less feasible and active than a conventional every-3-weeks carboplatin–paclitaxel regimen (6 cycles completed in 48% vs 60% of patients, respectively), with significantly worse progression-free and overall survival outcomes, leading to premature termination of the trial.

Meaning  Despite relatively high toxic effects, a conventional doublet regimen should be offered to all older adult patients with ovarian cancer, irrespective of vulnerability.

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

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    2 Comments for this article
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    Useful clinical information regarding chemotherapy for vulnerable older adult women with ovarian cancer
    takuma hayashi, MBBS, DMSci, GMRC, PhD | National Hospital Organization Kyoto Medical Center
    This randomized clinical trial, which was performed by Falandry C et al., demonstrates 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.

    Depending on the tumor biological status of ovarian cancer, our medical staff prescribe chemotherapy for patients according to the following treatment schemes.

    I: The use of the anti-VEGF antibody, bevacizumab is strictly prohibited in patients with ovarian cancer who are at high risk of adverse events such as intestinal perforation. Therefore, a combination therapy of platinum and taxanes is prescribed
    for such patients. Then, if no tumor progression is not observed, maintenance therapy is performed by taking a PRAP inhibitor, Niraparibu.

    II: On the other hand, for patients with ovarian cancer who can receive bevacizumab, a combination therapy of platinum, taxane, and bevacizumab is prescribed. Then, if no tumor progression is not observed, HRD is determined by a companion diagnostic for HRD, myChoice.

    1. Patients with HRD-positive ovarian cancer are prescribed maintenance therapy with a combination of the PRAP inhibitor, olaparib and bevacizumab.

    2. Patients with HRD-negative ovarian cancer are prescribed maintenance therapy with bevacizumab.

    In the treatment of chemotherapy for vulnerable older adult women with ovarian cancer, our medical staff have obtained more useful information from the results of clinical trials performed by Falandry C et al.

    Dr. Hayashi T. and Dr. Konishi I. National Hospital Organization Kyoto Medical Center
    CONFLICT OF INTEREST: None Reported
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    Importance of developing clinical treatments for platinum-resistant ovarian cancer
    takuma hayashi, MBBS, DMSci, GMRC, PhD | National Hospital Organization Kyoto Medical Center
    Recent advances in medicine have been remarkable. Various insured molecular-targeted drugs have been prescribed for ovarian cancer. Significant changes have been seeing in chemotherapy for ovarian cancer.

    This randomized clinical trial conducted by Dr. Claire Falandry et al. reveals 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.

    Carboplatin plus paclitaxel combination therapy is the first-line clinical treatment for patients with various histological types of ovarian cancer. However, the incidence of adverse events (AEs) with carboplatin plus paclitaxel is high in vulnerable
    elderly patients with ovarian cancer. Therefore, carboplatin monotherapy for vulnerable elderly patients with ovarian cancer should be considered as the recommended clinical treatment.

    Olaparib, an oral medication, is prescribed as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer or patients with homologous recombination deficiency (HRD)-positive ovarian cancer. Therefore, the antitumor effect of olaparib is not observed for ovarian cancer resistant to carboplatin monotherapy, which is a platinum preparation.

    In the current clinical treatment for ovarian cancer, the treatment method for platinum-resistant ovarian cancer has become a major problem. Our medical team is trying to identify pathogenic variants in platinum-resistant ovarian cancer. In our clinical studies so far, MUTYH mutation, PMS2 mutation, S100A4 amplification, etc. have been detected as pathogenic variants of platinum-resistant ovarian cancer. The development of drugs for these specific pathogenic variants in platinum-resistant ovarian cancer is important as future advances in clinical treatments for ovarian cancer.

    Dr. Hayashi T, and Dr. Konishi I.
    National Hospital Organization Kyoto Medical Center
    CONFLICT OF INTEREST: None Reported
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