title: VESPRO: An Individual Patient Data Prospective Meta-Analysis of Selective Internal Radiation Therapy Versus Sorafenib for Advanced, Locally Advanced, or Recurrent Hepatocellular Carcinoma of the SARAH and SIRveNIB Trials.
abstract: BACKGROUND
  Untreated advanced hepatocellular carcinoma (HCC) has an overall poor prognosis. Currently there are 2 ongoing prospective randomized controlled trials that are evaluating the efficacy and safety of sorafenib and selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres in patients with advanced HCC. The SorAfenib versus Radioembolisation in Advanced Hepatocellular carcinoma (SARAH; 459 patients) trial is being performed in Europe and the SIRt VErsus SorafeNIB (SIRveNIB; 360 patients) trial in the Asia Pacific region. Prospectively combining the results, these trials will not only allow for increased precision to estimate efficacy (in terms of survival), but will also provide increased statistical power for subgroup analyses.
  
  
  OBJECTIVE
  To ensure the prospectivity and transparency of the meta-analysis.
  
  
  METHODS
  The sirVEnib and SARAH merge PROject (VESPRO) is an individual, patient-data prospective meta-analysis of the SIRveNIB and SARAH randomized trials. The VESPRO protocol includes prespecified hypotheses, inclusion criteria, and outcome measures. The primary outcome measure is overall survival and secondary outcomes include tumor response rate, progression-free survival, progression in the liver as first event, and disease control in the liver. Pooling of toxicity results will allow for robust safety profiles to be established for both therapies, and provides increased statistical power to investigate treatment effects in key subgroups. Analyses will be performed in the intent-to-treat population stratified by trial.
  
  
  RESULTS
  Both studies are expected to demonstrate a survival benefit for SIRT together with a better toxicity profile compared with sorafenib. It is also anticipated that liver progression as the first event would be longer in the intervention compared with the control.
  
  
  CONCLUSIONS
  As the results of the 2 trials are not yet known, the methodological strength is enhanced, as biases inherent in conventional meta-analyses are avoided. This has the effect of providing this meta-analysis with the advantages of a single, large,randomized study of 819 patients. It is anticipated that the SARAH and SIRveNIB trial results will be published separately and together with the combined meta-analysis results from VESPRO. The combined dataset will allow the effect of the interventions to be explored with improved reliability/precision with respect to prespecified patient and intervention-level characteristics.
  
  
  BACKGROUND
  Australian New Zealand Trials Registry: ACTRN12617000030370.
authors.affiliation: NHMRC Clinical Trials Centre, University Sydney, Camperdown, Australia.
authors.forename: Val
authors.identifier: http://orcid.org/0000-0001-8748-1844
authors.initials: V
authors.lastname: Gebski
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia.
authors.forename: Emma
authors.identifier: http://orcid.org/0000-0002-7199-9486
authors.initials: E
authors.lastname: Gibbs
authors.affiliation: Biostatistics, Singapore Clinical Research Institute, Singapore, Singapore.
authors.forename: Mihir
authors.identifier: http://orcid.org/0000-0002-8902-2710
authors.initials: M
authors.lastname: Gandhi
authors.affiliation: Clinical Research Unit, Assistance Publique, Hôpitaux de Paris, Paris, France.
authors.forename: Gilles
authors.identifier: http://orcid.org/0000-0002-6373-8956
authors.initials: G
authors.lastname: Chatellier
authors.affiliation: Clinical Research Unit, Assistance Publique, Hôpitaux de Paris, Paris, France.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Dinut
authors.affiliation: Clinical Research Unit, Assistance Publique, Hôpitaux de Paris, Paris, France.
authors.forename: Helena
authors.initials: H
authors.lastname: Pereira
authors.affiliation: Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Pierce Kh
authors.identifier: http://orcid.org/0000-0003-0584-2584
authors.initials: PK
authors.lastname: Chow
authors.affiliation: Department of Radiology, Assistance Publique, Hôpitaux de Paris, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vilgrain
keywords: advanced hepatocellular carcinoma; individual patient data prospective meta-analysis; noninferiority; percentage of active control retained; selective internal radiation therapy; sorafenib