A phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma

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Abstract
Chemotherapy of advanced hepatocellular carcinoma (HCC) is frequently limited by unacceptable toxicity. Long-circulating polyethylene glycol-coated (PEGylated) liposomal doxorubicin (PLD) has low systemic toxicity. Its safety and efficacy in patients with advanced HCC and the relationship between hepatic function and pharmacokinetics were investigated in this phase II study.Patients were given 30 mg/m(2) PLD every 3 weeks and the dose was escalated to 45 mg/m(2) from the third course if the toxicity was deemed tolerable. The plasma level of doxorubicin was determined with fluorometry.A total of 40 patients were recruited into this phase II study. The toxicities were usually mild but unexpectedly, three cirrhotic patients died of infection without neutropenia. Four had a partial response (response rate 10%, confidence interval 0-20%). The median duration of response was 5.6 months. The median time to tumor progression and the median survival of all patients was only 2 and 3 months, respectively. Patients with advanced HCC had lower initial serum concentration, larger volume of distribution and more rapid clearance than patients with other malignancies and normal liver function. However, the pharmacokinetic parameters correlated with neither toxicity nor response.The disposition of PLD in patients with liver dysfunction was not hampered, but it did not exhibit higher activity compared with free drug, and the risk of infection must be watched closely especially in patients with liver cirrhosis.