Postprogression survival of patients with advanced hepatocellular carcinoma: Rationale for second-line trial design

Authors

  • Maria Reig,

    1. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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  • Jordi Rimola,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    2. Barcelona Clinic Liver Cancer (BCLC) Group, Radiology Department, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
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  • Ferran Torres,

    1. Biostatistics and Data Management Platform, IDIBAPS, Hospital Clínic, Biostatistics Unit, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Anna Darnell,

    1. Barcelona Clinic Liver Cancer (BCLC) Group, Radiology Department, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
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  • Carlos Rodriguez-Lope,

    1. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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  • Alejandro Forner,

    1. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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  • Neus LLarch,

    1. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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  • José Ríos,

    1. Biostatistics and Data Management Platform, IDIBAPS, Hospital Clínic, Biostatistics Unit, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Carmen Ayuso,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    2. Barcelona Clinic Liver Cancer (BCLC) Group, Radiology Department, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
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  • Jordi Bruix

    Corresponding author
    1. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    • Address reprint requests to: Jordi Bruix, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), C/Villarroel 170, 08036 Barcelona, Spain. E-mail: jbruix@clinic.ub.es

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  • Potential conflict of interest: Jordi Bruix: consulting for Bayer Schering Pharma, Sumitomo, Pharmexa, Eisai, Eli Lilly, Biocompatibles, ArQule, BioAlliance, Novartis, ImClone, Schering-Plough, MedImmune, Roche, Abbott, Bristol-Myers Squibb, Jennerex, OSI, Sanofi, GlaxoSmithKline, AngioDynamics, Chugai Pharma, Terumo, Wako and Kowa. Research funding by ArQule, Daiichi Sankyo, Bayer Schering Pharma. Maria Reig and Alejandro Forner: consulting and advising for and research grants from for Bayer. Carlos Rodriguez-Lope, Ferran Torres, Neus LLarch, Jordi Rimola, Anna Darnell, José Ríos and Carmen Ayuso: no conflict of interest.

  • Supported by a grant from the Instituto de Salud Carlos III (PI11/01830). CIBERehd is funded by Instituto de Salud Carlos III. Carlos Rodríguez de Lope is supported by a grant from the Instituto de Salud Carlos III (FI09/00510). Maria Reig was partially supported by a grant from the University of Barcelona (APIF RD63/2006).

Abstract

Sorafenib improves overall survival (OS) of patients with hepatocellular carcinoma (HCC) in the absence of objective response. Thus, time to tumor progression (TTP) is used to capture benefits of novel molecular agents, but proof of its surrogacy with survival is lacking. Furthermore, survival predictors upon progression are not established and there is a need to characterize postprogression survival (PPS) and assess with time-dependent covariates analysis if it is influenced by progression pattern, and not solely by simultaneous impairment of liver function and performance status. We prospectively followed HCC patients treated with sorafenib. Clinical and biochemical evaluation were done every 4 weeks. Radiologic assessment of progression was done at week 4 and then every 8 weeks using RECIST 1.1. The progression pattern was divided into: intrahepatic/extrahepatic increase in tumor size, new intrahepatic lesion, and new extrahepatic lesion (NEH). We included 147 patients (hepatitis C virus [HCV] 57.1%, performance status [PS] 0 83.6%, Child-Pugh A 82.3%, and BCLC-C 47.3%). The median OS was 12.7 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were: baseline BCLC 2.49 [1.66-3.73], PS 1.86 [1.12-3.10], registration during follow-up of Child-Pugh B or Child-Pugh C scores (2.36 [1.51-3.69] and 2.89 [1.62-5.15], respectively), definitive sorafenib interruption 2.48 [1.54-4.01], and TTP 3.39 [1.89-6.1]. The presence of NEH 2.42 [1.32-4.44] is also an independent predictor of OS and PPS in patients with radiologic progression. Conclusion: Tumor progression is a surrogate of survival but its impact varies according to progression pattern. Thus, PPS is influenced by progression pattern and this is key in prognostic prediction and second-line trial design and analysis. (Hepatology 2013; 58:2023–2031)

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