title: TTP as a surrogate endpoint in advanced hepatocellular carcinoma treated with molecular targeted therapy: meta-analysis of randomised controlled trials.
abstract: BACKGROUND
  Time to progression (TTP) is suggested as a reliable endpoint compared with the progression-free survival in the clinical trials of hepatocellular carcinoma (HCC). However, the correlation between TTP and overall survival (OS) has never been studied.
  
  
  METHODS
  We searched PubMed and Embase data to obtain data source. Eligible studies were randomised controlled phase III trials, which evaluated the efficacy of systemic chemotherapy or molecular targeted therapy in advanced HCC. The association of treatment effects as shown by the hazard ratio (HR) of TTP and OS in each trial was assessed by the Spearman rank correlation coefficient (rs) and linear regression analysis. The association between median TTP and OS was also investigated.
  
  
  RESULTS
  Nine studies with a total of 18 treatment arms and 6318 patients were included. Incremental benefit from the study treatment in TTP from each trial was correlated with incremental benefit in OS. The rsvalue and R2value between log (HRTTP) and log (HROS) was 0.73 (95% confidence interval (CI) 0.12-0.94, P=0.024) and 0.57. The minimum TTP effect to predict a treatment effect on OS was 0.63. Median TTP was associated with median OS. The rsvalue between TTP and OS was 0.73 (95% CI 0.40-0.89, P<0.001) and the corresponding R2was 0.42.
  
  
  CONCLUSIONS
  Our study results suggest that TTP could be used as a surrogate marker for OS in the clinical trials of advanced HCC. However, the results suggest modest correlation between treatment effects on TTP and OS.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Dae-Won
authors.initials: DW
authors.lastname: Lee
authors.affiliation: Medical Research Collaborating Center, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Myoung-Jin
authors.initials: MJ
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Su Jong
authors.initials: SJ
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D017326:Clinical Trials, Phase III as Topic; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D058990:Molecular Targeted Therapy / Q000379:methods; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers