Surrogate endpoints in advanced sarcoma trials: a meta-analysis
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Marion Savina1,2,3,4, Saskia Litière5, Antoine Italiano6, Tomasz Burzykowski7, Franck Bonnetain8, Sophie Gourgou9, Virginie Rondeau3,10, Jean-Yves Blay11,12, Sophie Cousin6, Florence Duffaud13, Hans Gelderblom14, Alessandro Gronchi15, Ian Judson16, Axel Le Cesne17, Paul Lorigan18, Joan Maurel19, Winette van der Graaf20,21,23, Jaap Verweij22, Simone Mathoulin-Pélissier1,2,3,4 and Carine Bellera1,2,3,4
1Clinical and Epidemiological Research Unit, Institut Bergonié, Comprehensive Cancer Center, Bordeaux cedex 33076, France
2INSERM CIC-EC 14.01 (Clinical Epidemiology), Bordeaux 33000, France
3INSERM, ISPED, Centre INSERM U1219 Bordeaux Population Health Center, Epicene Team, Bordeaux 33000, France
4University of Bordeaux, ISPED, Centre INSER M U1219 Bordeaux Population Health, Epicene Team, Bordeaux 33000, France
5European Organisation for Research and Treatment of Cancer (EORTC), Brussels 1200, Belgium
6Medical Oncology Unit, Institut Bergonié, Comprehensive Cancer Center, Bordeaux cedex 33076, France
7Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), Hasselt University, Hasselt 3500, Belgium
8Methodology and Quality of life in Oncology Unit, Besançon EA3181, France
9Biometrics Unit, Institut du Cancer de Montpellier, Univ. Montpellier, Montpellier 34298, France
10INSERM, ISPED, Centre INSERM U1219 Bordeaux Population Health Center, Biostatistic Team, Bordeaux 33000, France
11Centre Léon Bérard, Comprehensive Cancer Center, Lyon 69008, France
12University Claude Bernard Lyon I, Lyon 69000, France
13Medical Oncology Unit, University Hospital La Timone and University of Aix-Marseille, Marseille 13005, France
14Department of Medical Oncology, Leiden University Medical Center, Leiden 2300RC, The Netherlands
15Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
16Institute of Cancer Research, Sutton, Surrey, United Kingdom
17Medicine Department, Institut Gustave Roussy, Comprehensive Cancer Center, Villejuif 94800, France
18University of Manchester and Christie NHS Foundation Trust, Manchester M20 4BX, UK
19Department of Medical Oncology, Hospital Clinic, CIBERehd, Translational Genomics and Targeted Therapeutics in Solid Tumors (IDIBAPS), Barcelona 08036, Spain
20The Institute of Cancer Research, Sutton, London SM2 5NG, United Kingdom
21Radboud University Medical Centre, Department of Medical Oncology, GA Nijmegen 6525, The Netherlands
22Department of Medical Oncology, Erasmus University Medical Center, CE Rotterdam 3015, The Netherlands
23Royal Marsden NHS Foundation Trust, Chelsea, London, United Kingdom
Carine Bellera, email: C.Bellera@bordeaux.unicancer.fr
Keywords: sarcoma; surrogate endpoints; meta-analysis; randomized trial; survival
Received: August 20, 2018 Accepted: September 13, 2018 Published: October 02, 2018
Background: Alternative endpoints to overall survival (OS) are frequently used to assess treatment efficacy in randomized controlled trials (RCT). Their properties in terms of surrogate outcomes for OS need to be assessed. We evaluated the surrogate properties of progression-free survival (PFS), time-to-progression (TTP) and time-to-treatment failure (TTF) in advanced soft tissue sarcomas (STS).
Results: A total of 21 trials originally met the selection criteria and 14 RCTs (N = 2846) were included in the analysis. Individual-level associations were moderate (highest for 12-month PFS: Spearman’s rho = 0.66; 95% CI [0.63; 0.68]). Trial-level associations were ranked as low for the three endpoints as per the IQWiG criterion.
Materials and Methods: We performed a meta-analysis using individual-patient data (IPD). Phase II/III RCTs evaluating therapies for adults with advanced STS were eligible. We estimated the individual- and the trial-level associations between then candidate surrogates and OS. Statistical methods included weighted linear regression and the two-stage model introduced by Buyse and Burzykowski. The strength of the trial-level association was ranked according to the German Institute for Quality and Efficiency in Health Care (IQWiG) guidelines.
Conclusions: Our results do not support strong surrogate properties of PFS, TTP and TTF for OS in advanced STS.
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