Research article

Thymostimulin in advanced hepatocellular carcinoma: A phase II trial

Matthias M Dollinger¹ , Christa M Behrens¹ , Joachim Lesske^1,2 , Susanne Behl¹ , Curd Behrmann³ and Wolfgang E Fleig^1,4

¹First Department of Medicine, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120 Halle, Germany

²Department of Medicine, Bad Reichenhall Hospital, Riedelstr. 5, 83435 Bad Reichenhall, Germany

³Department of Radiology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120 Halle, Germany

⁴University of Leipzig Hospitals and Clinics, Philipp-Rosenthal-Straße 27, 04103 Leipzig, Germany

author email corresponding author email

BMC Cancer 2008, 8:72doi:10.1186/1471-2407-8-72

Published:	13 March 2008

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.

Conclusion

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.

Trial registration

Current Controlled Trials ISRCTN29319366.