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    Original Investigation
    January 10, 2020

    Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Groupe d’investigateurs national des Etudes des Cancers Ovariens (GINECO), Paris, France
    • 2Gustave Roussy Cancer Center and Institut National de la Santé et de la Recherche Medicale Oncostat, Villejuif, France
    • 3Department of Biostatistics, University of Versailles St Quentin, Institut Curie, Saint-Cloud, France
    • 4Scottish Gynaecological Cancer Trials Group (SGCTG), Cancer Research United Kingdom Clinical Trial Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
    • 5Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Clinical Trials Unit, Istituto Nazionale Tumori– Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli, Italia
    • 6Medical Research Counsel Clinical Trials Unit, University College London, London, United Kingdom
    • 7Japanese Gynecologic Oncology Group (JGOG), Jikei University School of Medicine, Tokyo, Japan
    • 8Canadian Cancer Trials Group (CCTG), University of British Columbia, Vancouver, British Columbia, Canada
    • 9Nordic Society of Gynaecological Oncology, Norwegian Radium Hospital, Oslo, Norway
    • 10European Organisation for Research and Treatment of Cancer, Radboud University Medical Center, Nijmegen, the Netherlands
    • 11Hellenic Cooperative Oncology Group, General Oncology Hospital of Kifissia, Nea Kifissia, Greece
    • 12Gynecologic Oncology Group (GOG), Roswell Park Comprehensive Cancer Center, Buffalo, New York
    • 13Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
    • 14University of Milan Bicocca, San Gerardo Hospital, Monza, Italy
    • 15University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
    • 16Association de Recherche sur les Cancers dont Gynécologiques–GINECO, Université Paris Descartes, Assistance Publique–Hôpitaux de Paris, Paris, France
    • 17MITO, Istituto Nazionale Tumori di Napoli IRCCS Fondazione G Pascale, Napoli, Italy
    • 18JGOG, Foundation for Biomedical Research and Innovation at Kobe, Translational Research Center for Medical Innovation, Kobe, Japan
    • 19CCTG, London Health Sciences Centre, London, Ontario, Canada
    • 20Gustave Roussy Cancer Center, Villejuif, France
    • 21SGCTG, Beatson West of Scotland Cancer Centre, NHS (National Health Service) Greater Glasgow and Clyde, Glasgow, United Kingdom
    JAMA Netw Open. 2020;3(1):e1918939. doi:10.1001/jamanetworkopen.2019.18939
    Key Points español 中文 (chinese)

    Question  Is progression-free survival a validated surrogate end point for overall survival in first-line systemic treatment of ovarian cancer?

    Findings  In this systematic review and meta-analysis of 17 unique trials with individual data from 11 029 unique patients, a high correlation between progression-free and overall survival was found at the individual level, but a low correlation was found at the trial level.

    Meaning  These findings suggest that overall survival is the preferred end point in trials of first-line treatment or maintenance treatment, and progressive-free survival must be supported by additional end points if used as the primary end point.


    Importance  The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types.

    Objective  To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer.

    Data Sources  In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials.

    Study Selection  Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm.

    Data Extraction and Synthesis  Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019.

    Main Outcomes and Measures  Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria.

    Results  In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS.

    Conclusions and Relevance  This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.