Phase II Trial of Thalidomide for Treatment of Nonresectable Hepatocellular Carcinoma*

Therapy of hepatocellular carcinoma in cirrhotic patients is challenging. Liver dysfunction, portal hypertension, third spacing, thrombocytopenia, and neutropenia limit the choice of chemotherapeutic agents. However, the abundant vascularity of hepatocellular carcinoma presents an attractive target for antiangiogenic therapy, potentially tolerable even in cirrhotics.

Thalidomide (Thalomid), a sedative with putative antiangiogenic properties, was tested in a phase II trial in hepatocellular carcinoma patients using 400 mg at bedtime daily for the first week, and escalating to 1,000 mg by the fifth week. One-third of the dose was given in the afternoon and two-thirds at bedtime. The trial was prompted by the observation of a radiologic partial response and a decrease in alpha-fetoprotein from 109,000 to 99 ng/mL in a patient who failed all prior therapies but responded to thalidomide.

Twenty-seven patients were accrued between March 18, 1999, and October 14, 1999, and 10 more are anticipated. The pretreatment median platelet count was 122.5 ´ 10⁹/L (range: 43–390 ´ 10⁹/L), and the median alpha-fetoprotein level was 1,435.2 ng/mL. Twenty-one patients. were evaluable for response; four were too early and two were not restaged following treatment. One partial response and one minor response were observed, and 10 patients had stable disease for at least 2 months. Responses were associated with a slight decrease in serum alpha-fetoprotein ( £ 25%).

Toxicities included somnolence in all patients, with grade 3/4 (³ 3 hours of sleep during the normal waking hours) in nine patients (35%) and grade 2 in 30%.

Grade 3/4 skin reactions were observed in 20%, and an exfoliative dermatitis prompted treatment discontinuation in one responding patient. Thus, thalidomide may be administered to patients with significant liver cirrhosis even if they are not candidates for other therapies.

CONCLUSION: With a 5% partial response, 5% minor response, and 48% stable disease rate, it would seem that thalidomide may offer hepatocellular carcinoma patients disease stabilization, but not significant antitumor activity. However, thalidomide should be considered for combination with other agents that could be safely administered to patients with severe cirrhosis, such as capecitabine (Xeloda).

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