title: On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study.
abstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable.
  
  
  
  To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC.
  
  
  
  In this prospective multicentre cohort study, patients with advanced-stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively.
  
  
  
  A total of 634 patients with advanced-stage HCC receiving sorafenib were recruited to the study, with a median follow-up of 6692.3 person-months at risk. The majority of patients were male (81%) with Child-Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8-18.6 months). 94% experienced at least one sorafenib-related toxicity: 34% diarrhoea, 16% hypertension and 37% hand-foot syndrome (HFS). Twenty-one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib-related diarrhoea (HR 0.76, 95% CI 0.61-0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37-0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51-0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose.
  
  
  
  Development of sorafenib-related toxicity including diarrhoea, hypertension and hand-foot syndrome is associated with prolonged overall survival in patients with advanced-stage HCC on sorafenib.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.|Department of Medicine, University of Melbourne, St Vincent's Hospital, Melbourne, Vic., Australia.|Centre for Population Health, Macfarlane-Burnet Institute, Melbourne, Vic., Australia.
authors.forename: J
authors.identifier: 0000-0002-9269-6249
authors.initials: J
authors.lastname: Howell
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Pinato
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Ramaswami
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Bettinger
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Arizumi
authors.affiliation: Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ferrari
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Yen
authors.affiliation: Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gibbin
authors.affiliation: Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: M E
authors.initials: ME
authors.lastname: Burlone
authors.affiliation: Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Guaschino
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Sellers
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Black
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Pirisi
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Center for Liver Cancer, National Cancer Center, Goyang, Gyeonggi, South Korea.
authors.forename: J-W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Sharma
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality*; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D012189:Retrospective Studies; D000077157:Sorafenib; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib