Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma: a phase III clinical trial.
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 the efficacy of thymostimulin in a phase III trial.


METHODS
The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky >or=60%/Child-Pugh <or= 12) were randomised to receive thymostimulin 75 mg s.c. 5x/week or placebo stratified according to liver function. Primary endpoint was twelve-month survival, secondary endpoints overall survival (OS), time to progression (TTP), tumor response, safety and quality of life. A subgroup analysis according to liver function, KPS and tumor stage (Okuda, CLIP and BCLC) formed part of the protocol.


RESULTS
Twelve-month survival was 28% [95%CI 17-41; treatment] and 32% [95%CI 19-44; control] with no significant differences in median OS (5.0 [95% CI 3.7-6.3] vs. 5.2 [95% CI 3.5-6.9] months; p = 0.87, HR = 1.04 [95% CI 0.7-1.6]) or TTP (5.3 [95%CI 2.0-8.6] vs. 2.9 [95%CI 2.6-3.1] months; p = 0.60, HR = 1.13 [95% CI 0.7-1.8]). Adjustment for liver function, Karnofsky status or tumor stage did not affect results. While quality of life was similar in both groups, fewer patients on thymostimulin suffered from accumulating ascites and renal failure.


CONCLUSIONS
In our phase III trial, we found no evidence of any benefit to thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of thymostimulin on hepato-renal function requires further confirmation.


BACKGROUND
Current Controlled Trials ISRCTN64487365.
Dollinger
Matthias M
MM
Department of Medicine I, Martin-Luther-University Halle-Wittenberg, Germany. matthias.dollinger@medizin.uni-halle.de
Lautenschlaeger
Christine
C
Lesske
Joachim
J
Tannapfel
Andrea
A
Wagner
Anna-Dorothea
AD
Schoppmeyer
Konrad
K
Nehls
Oliver
O
Welker
Martin-Walter
MW
Wiest
Reiner
R
Fleig
Wolfgang E
WE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000556:secondary; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007369:Interferon Inducers / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010166:Palliative Care; D010919:Placebos; D011446:Prospective Studies; D015996:Survival Rate; D013949:Thymus Extracts / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D007369:Interferon Inducers; D010919:Placebos; D013949:Thymus Extracts; C031407:thymostimulin