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BACKGROUND: The median survival time for patients with unresectable hepatocellular carcinoma (HCC) is <6 months, and no effective standard systemic chemotherapy is available. Both epirubicin (Ellence); Pfizer Pharmaceuticals, New York, NY, http://www.pfizer.com) and thalidomide (Thalomid); Celgene Corporation, Warren, NJ, http://www.celgene.com) have reported activity for HCC as single agents, and they have different mechanisms of action and nonoverlapping toxicities. Therefore, we performed a phase II study using the combination of epirubicin and thalidomide in patients with unresectable and metastatic HCC. METHODS: Nineteen patients with measurable, unresectable, or metastatic HCC were enrolled. All patients were required to have adequate major organ function and performance status. The treatment consisted of weekly epirubicin at a dose of 20 mg/m(2) administered i.v. and daily thalidomide at a dose of 200 mg orally given as a 3-weeks-on/1-week-off schedule. Intrapatient dose escalation of thalidomide was allowed every 2 weeks up to 800 mg daily as long as tolerated. Physical examinations, toxicity assessments, and serum chemistry analyses were performed weekly, and tumor measurements were conducted every 8 weeks. RESULTS: All 19 patients enrolled into the study were evaluable for toxicity assessment and 17 patients were evaluable for response assessment. A total of 71 cycles of chemotherapy was administered, with a median of two cycles administered to each patient (range 1-14). No complete or partial responses were observed. Seven patients (41%) had stable disease, with a median duration of 6 months (range 5-14). The median survival time for all 19 patients was 196 days (95% confidence interval 93-302). The treatment was generally well tolerated. Treatment-related toxicities included constipation (grade 3, 5%; grade 2, 37%; grade 1, 21%), fatigue (grade 3, 5%; grade 2, 42%), and sensory neuropathy (grade 2, 5%; grade 1, 32%). Four patients required dose reductions of thalidomide due to treatment-related toxicities, and the median tolerated dose of thalidomide was 200 mg daily. CONCLUSIONS: The combination of epirubicin and thalidomide was well tolerated when administered in the schedule used in this study. This regimen has limited activity in HCC, with some patients achieving stable disease and clinical benefit. There is a need for defining more effective systemic therapies for HCC.