title: Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial.
abstract: BACKGROUND
  Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT.
  
  
  METHODS
  Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT).
  
  
  RESULTS
  The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs.
  
  
  CONCLUSIONS
  The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group.
  
  
  BACKGROUND
  ISRCTN24081794.
authors.affiliation: Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. katrin.hoffmann@med.uni-heidelberg.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: Department of Internal Medicine, Ruprecht-Karls-University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. tom.ganten@med.uni-heidelberg.de.
authors.forename: Tom
authors.initials: T
authors.lastname: Ganten
authors.affiliation: Department of Internal Medicine, Ruprecht-Karls-University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. daniel.gotthardt@med.uni-heidelberg.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gotthardtp
authors.affiliation: Department of Radiology, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. boris.radeleff@med.uni-heidelberg.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Radeleff
authors.affiliation: Department of General-, Visceral- and Vascular-Surgery, University Hospital, Erlanger Allee 101, 07747, Jena, Germany. avg@med.uni-jena.de.
authors.forename: Utz
authors.initials: U
authors.lastname: Settmacher
authors.affiliation: Department of General and Visceral Surgery, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany. otto.kollmar@med.uni-goettingen.de.
authors.forename: Otto
authors.initials: O
authors.lastname: Kollmar
authors.affiliation: Department of Surgery, University Hospital, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany. silvio.nadalin@med.uni-tuebingen.de.
authors.forename: Silvio
authors.initials: S
authors.lastname: Nadalin
authors.affiliation: National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. irini.schenkel@nct-heidelberg.de.
authors.forename: Irini
authors.initials: I
authors.lastname: Karapanagiotou-Schenkel
authors.affiliation: National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. christof.kalle@nct-heidelberg.de.
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.affiliation: National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. dirk.jaeger@nct-heidelberg.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.affiliation: Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. markus.buechler@med.uni-heidelberg.de.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.affiliation: Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. peter.schemmer@med.uni-heidelberg.de.|Department of General- Visceral- and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120, Heidelberg, Germany. peter.schemmer@med.uni-heidelberg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D005260:Female; D005858:Germany; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib