title: Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation.
  
  
  METHODS
  We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770.
  
  
  RESULTS
  We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6-35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1-38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9-19·5) in the sorafenib group and 8·4 months (2·9-19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780-1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group.
  
  
  CONCLUSIONS
  Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation.
authors.affiliation: BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, Liver Unit, IDIBAPS, CIBERehd, Barcelona, Spain. Electronic address: jbruix@clinic.ub.es.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.affiliation: Department of Digestive Surgery, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Liver Unit, Hepato-Oncology Group, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.affiliation: Taipei Veterans General Hospital, Department of Surgery, Beitou District, Taipei City, Taiwan.
authors.forename: Gar-Yang
authors.initials: GY
authors.lastname: Chau
authors.affiliation: Eastern Hepatobiliary Hospital, Shanghai District, Shanghai, China.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Chaoyang District, Beijing, China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Cai
authors.affiliation: Queen Mary Hospital, Pok Fu Lam, Hong Kong, China.
authors.forename: Ronnie T
authors.initials: RT
authors.lastname: Poon
authors.affiliation: Severance Hospital, Seodaemun-gu, Seoul, South Korea.
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Liver Research Institute, Graduate School of Medicine, Kyungpook National University, Jung-gu, Daegu, Korea.
authors.forename: Won Young
authors.initials: WY
authors.lastname: Tak
authors.affiliation: Asan Medical Center, Songpa-gu, Seoul, South Korea.
authors.forename: Han Chu
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Tianjin Medical University Cancer Hospital Huanhuxilu, Hexi District, Tianjin, China.
authors.forename: Tianqiang
authors.initials: T
authors.lastname: Song
authors.affiliation: Liver Cancer Program, Hofstra-North Shore-LIJ School of Medicine, Lenox Hill Hospital, New York, NY, USA.
authors.forename: Sasan
authors.initials: S
authors.lastname: Roayaie
authors.affiliation: University of Bologna, Bologna, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bolondi
authors.affiliation: Gangnam Severance Hospital, Gangnam-gu, Seoul, South Korea.
authors.forename: Kwan Sik
authors.initials: KS
authors.lastname: Lee
authors.affiliation: University of Tokyo, Bunkyo, Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Makuuchi
authors.affiliation: Bayer HealthCare Pharmaceuticals, Socorro, São Paulo, Brazil.
authors.forename: Fabricio
authors.initials: F
authors.lastname: Souza
authors.affiliation: Bayer HealthCare Pharmaceuticals, Loos, France.
authors.forename: Marie-Aude Le
authors.initials: MA
authors.lastname: Berre
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
authors.forename: Gerold
authors.initials: G
authors.lastname: Meinhardt
authors.affiliation: BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, Liver Unit, IDIBAPS, CIBERehd, Barcelona, Spain; Liver Cancer Program, Mount Sinai Medical Center, New York, NY, USA.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D001315:Australia; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D017115:Catheter Ablation / Q000009:adverse effects / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006498:Hepatectomy / Q000009:adverse effects / Q000401:mortality; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009520:New Zealand; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009656:North America; 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*; D012307:Risk Factors; D000077157:Sorafenib; D013020:South America; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib