title: Thymostimulin in advanced hepatocellular carcinoma: a phase II trial.
abstract: BACKGROUND
  Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma.
  
  
  METHODS
  44 patients (84 % male, median age 69 years) not suitable or refractory to conventional therapy received thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival.
  
  
  RESULTS
  Median survival was 11.5 months (95% CI 7.9-15.0) with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01), a low score in the Okuda- and CLIP-classification (p < 0.001) or a low AFP-level (p < 0.001) were associated with better survival, but not therapy modalities other than thymostimulin (p = 0.1) or signs of an invasive HCC phenotype such as vascular invasion (p = 0.3) and metastases (p = 0.1). The only variables independently related to survival in the Cox's regression model were Okuda stage and presence of liver cirrhosis (p < 0.01) as well as response to thymostimulin (p < 0.05). Of 39/44 patients evaluable for response, two obtained complete responses (one after concomitant radiofrequency ablation), five partial responses (objective response 18%), twenty-four stable disease (tumor control rate 79%) and eight progressed. Median progression-free survival was 6.4 months (95% CI 0.8-12). Grade 1 local reactions following injection were the only side effects.
  
  
  CONCLUSIONS
  Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage) in addition to response to thymostimulin, while an invasive HCC phenotype had no influence in the multivariate analysis. Thymostimulin could therefore be considered a safe and promising candidate for palliative treatment in a selected target population with advanced hepatocellular carcinoma, in particular as component of a multimodal therapy concept.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN29319366.
authors: First Department of Medicine, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120 Halle, Germany. matthias.dollinger@medizin.uni-halle.de
authors: Matthias M
authors: MM
authors: Dollinger
authors: Christa M
authors: CM
authors: Behrens
authors: Joachim
authors: J
authors: Lesske
authors: Susanne
authors: S
authors: Behl
authors: Curd
authors: C
authors: Behrmann
authors: Wolfgang E
authors: WE
authors: Fleig
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D012044:Regression Analysis; D013949:Thymus Extracts / Q000378:metabolism / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D013949:Thymus Extracts; C031407:thymostimulin