title: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma.
  
  
  METHODS
  Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752.
  
  
  RESULTS
  271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation.
  
  
  CONCLUSIONS
  Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Chen
authors.forename: Chao-Jung
authors.initials: CJ
authors.lastname: Tsao
authors.forename: Shukui
authors.initials: S
authors.lastname: Qin
authors.forename: Jun Suk
authors.initials: JS
authors.lastname: Kim
authors.forename: Rongcheng
authors.initials: R
authors.lastname: Luo
authors.forename: Jifeng
authors.initials: J
authors.lastname: Feng
authors.forename: Shenglong
authors.initials: S
authors.lastname: Ye
authors.forename: Tsai-Sheng
authors.initials: TS
authors.lastname: Yang
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Houjie
authors.initials: H
authors.lastname: Liang
authors.forename: Jiwei
authors.initials: J
authors.lastname: Liu
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wang
authors.forename: Won Young
authors.initials: WY
authors.lastname: Tak
authors.forename: Hongming
authors.initials: H
authors.lastname: Pan
authors.forename: Karin
authors.initials: K
authors.lastname: Burock
authors.forename: Jessie
authors.initials: J
authors.lastname: Zou
authors.forename: Dimitris
authors.initials: D
authors.lastname: Voliotis
authors.forename: Zhongzhen
authors.initials: Z
authors.lastname: Guan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D003362:Cost-Benefit Analysis; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib