title: Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib.
abstract: OBJECTIVE
  Response to sorafenib is highly variable in hepatocellular carcinoma (HCC). Baseline inflammatory parameters and treatment toxicities may improve survival prediction in patients on sorafenib therapy.
  
  
  RESULTS
  442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385-0.872, p=0.009), Cancer of Liver Italian Program (CLIP) score (HR 1.723, 95% CI 1.462-2.047, p<0.0001), baseline red cell distribution width (RDW; HR 1.234, 95% CI 1.115-1.290, p<0.0001) and neutrophil to lymphocyte ratio (NLR; HR 1.218, 95% CI 1.108-1.322, p<0.0001) were significant independent risks for shorter survival, whilst sorafenib-related diarrhoea was associated with prolonged survival (HR 0.533, 95% CI 0.373-0.763, p=0.001). The combination of RD-CLIP score (CLIP score multiplied by RDW) ≥ 70 and no treatment-related diarrhoea had good utility for predicting 3-month survival (AUC of 0.808 (95% CI 0.734-0.882), positive predictive value of 86.4% and negative predictive value of 83.3%), compared with CLIP (AUC=0.642) or BCLC score alone (AUC=0.579). RD-CLIP score ≥ 35 and no treatment-related diarrhoea had an AUC of 0.787 for predicting 12-month survival.
  
  
  METHODS
  Patients with HCC were consecutively recruited from three tertiary centres (Japan, Italy and UK) and clinical data were prospectively collected. The primary study endpoint was overall survival (OS) after commencing sorafenib.
  
  
  CONCLUSIONS
  The novel prognostic index of CLIP score combined with inflammatory marker RDW and treatment-related diarrhoea has good accuracy for predicting overall, 3 month and 12 month survival in patients on sorafenib.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.|Centre for Population Health, Burnet Institute, Melbourne, Australia.|Department of Medicine, University of Melbourne, Melbourne, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Howell
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinato
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Ramya
authors.initials: R
authors.lastname: Ramaswami
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Arizumi
authors.affiliation: Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Ferrari
authors.affiliation: Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Gibbin
authors.affiliation: Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Michela 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: Giulia
authors.initials: G
authors.lastname: Guaschino
authors.affiliation: Department of Experimental and Clinical Medicine, University of Udine, Udine, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Toniutto
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Black
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Sellers
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Pirisi
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Rohini
authors.initials: R
authors.lastname: Sharma
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009504:Neutrophils / Q000276:immunology*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D012306:Risk; D000077157:Sorafenib; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: BCLC; CLIP score; VEGF inhibitor; inflammation; liver cancer