title: Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC.
abstract: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this end-point as a potential surrogate of OS.
  
  
  
  Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n=334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point.
  
  
  
  Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4months, p<0.001). In addition, objective response had an independent prognostic value (HR=0.48; 95% confidence interval [CI], 0.26-0.91, p=0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R=-0.92; 95% CI, -1 to -0.73, p<0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4months).
  
  
  
  Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding.
  
  
  
  There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population.
  
  
  
  NCT00825955.
authors.affiliation: Department of Interventional Radiology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Lencioni
authors.affiliation: Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Robert
authors.initials: R
authors.lastname: Montal
authors.affiliation: Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain; Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Torres
authors.affiliation: Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Joong-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Service d'Hépato-gastro-entérologie, Hôpital Henri Mondor, Faculty of Medicine, University of Paris-Est, and INSERM, Creteil, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Decaens
authors.affiliation: Service d'Oncologie Médicale, Institut Paoli Calmette, Marseille, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Raoul
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Ichan School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Charissa
authors.initials: C
authors.lastname: Chang
authors.affiliation: Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain; Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Ríos
authors.affiliation: Service de Gastro-enterologie, Institut Gustave Roussy, Villejuif, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Boige
authors.affiliation: Service d'Hépato-gastro-entérologie, Hôpital Saint Eloi, Montpellier Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Assenat
authors.affiliation: Department of Oncology, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Division of Hematology-Oncology, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Ho-Yeong
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Walters
authors.affiliation: Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain; Liver Cancer Program, Division of Liver Diseases, Ichan School of Medicine at Mount Sinai, New York, NY, USA; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain. Electronic address: jmllovet@clinic.cat.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D014227:Triazines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D014227:Triazines; C509922:brivanib; D000409:Alanine
keywords: Advanced BCLC; Brivanib, mRECIST; Carcinoma, hepatocellular; Liver cancer; Objective response; Response evaluation criteria in solid tumours; Surrogate end-point