title: Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma.
abstract: BACKGROUND
  Rapalogs are emerging as promising targeted anticancer drugs. Activation of the PI3K/Akt/mTOR pathway has been observed in 15-50% of hepatocellular carcinomas.
  
  
  METHODS
  In this phase II study, patients with advanced hepatocellular carcinoma and underlying cirrhosis received sirolimus (20 mg/week for 1 month then 30 mg/week). Tumour response was assessed every 8 weeks. The primary endpoint was the objective tumour response rate according to the Response Evaluation Criteria in Solid Tumours criteria. Secondary endpoints included the objective response according to the modified Response Evaluation Criteria in Solid Tumours criteria, safety, and pharmacokinetic parameters.
  
  
  RESULTS
  Twenty-five patients received sirolimus for a median of 20.6 weeks. Two patients had an objective response (8%, 95CI: 0.98-26.03), including one complete response, and 8 patients had stable disease. There were 2 cases of grade 5 toxicity (infections) and 5 cases of grade 3 toxicity. The main grade 1/2 toxicity was mild transient fatigue (76%). Median time to radiological progression and overall survival were 15.3 weeks (range: 8.2-173.9) and 26.4 weeks (range: 8.2-173.9) respectively. Use of the modified Response Evaluation Criteria in Solid Tumours criteria did not identify any further responders.
  
  
  CONCLUSIONS
  These data suggest that first-line sirolimus shows antitumoural efficacy in advanced hepatocellular carcinoma. Larger trials with Child A patients are needed.
authors.affiliation: AP-HP, Groupe hospitalier Henri Mondor, Department of Hepatology, Creteil, France. thomas.decaens@hmn.aphp.fr
authors.forename: Thomas
authors.initials: T
authors.lastname: Decaens
authors.forename: Alain
authors.initials: A
authors.lastname: Luciani
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Itti
authors.forename: Anne
authors.initials: A
authors.lastname: Hulin
authors.forename: Françoise
authors.initials: F
authors.lastname: Roudot-Thoraval
authors.forename: Alexis
authors.initials: A
authors.lastname: Laurent
authors.forename: Elie Serge
authors.initials: ES
authors.lastname: Zafrani
authors.forename: Ariane
authors.initials: A
authors.lastname: Mallat
authors.forename: Christophe
authors.initials: C
authors.lastname: Duvoux
mesh_terms: D000152:Acne Vulgaris / Q000139:chemically induced; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D018450:Disease Progression; D004844:Epistaxis / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007239:Infections / Q000139:chemically induced; D053208:Kaplan-Meier Estimate; D008103:Liver Cirrhosis / Q000150:complications; D008113:Liver Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D020123:Sirolimus / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus