Thymostimulin versus placebo for treatment of advanced hepatocellular carcinoma: A randomised, controlled, double-blind, multicenter study

Abstract

4519 Background: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess its efficacy in a phase III trial. Methods: Patients (age 18 to 75 years) with biopsy-proven HCC not amenable to or failing local and surgical therapy were randomized to receive thymostimulin 75 mg s.c. five times per week or placebo for one year or until progression. Exclusion criteria were Karnofsky score < 60%, severe concomitant disease or decompensated liver function (bilirubin > 5 mg/dl, INR > 2.2). Primary endpoint was overall survival, secondary endpoints progression-free survival, side effects and quality of life (FACT-Hep questionnaire). The Kaplan-Meier-method was used for survival probabilities, the Cox’s proportional hazards model for assessing the effect of treatment or prognostic variables on survival. 55 patients per arm were projected to detect a 20% difference in survival (power 90%, type I error 5%) with a higher number finally included due to drop-out. Results: Between 10/2002 and 03/2005 133 patients (83 % male, median age 63 years) were randomly assigned thymostimulin (n=65) or placebo (n=68). Groups were comparable regarding age, gender, Karnofsky score and tumor stage (UICC, Okuda, CLIP and BCLC). There was no difference in survival with a median cumulative survival of 5.0 months (95% CI 3.7–6.3) in the treatment group vs. 5.2 months (95% CI 3.5–6.9) in the control group or median progression-free survival of 5.3 months (95% CI 2.0–8.6) vs. 2.9 months (95% CI 2.6–3.1), respectively. 6-month survival rates were 40% (treatment group) and 38% (control group), adjustment for liver function (Child-Pugh) or tumor stage did not affect results. Neither quality and quantity of side-effects nor quality of life as assessed in the questionnaire’s subdomains differed between groups. Conclusions: This is the first phase III trial analysing the efficacy of thymostimulin for advanced HCC. There was no survival benefit or improved progression-free survival and thymostimulin cannot be recommended as single-agent treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cytochemia AG, Germany