Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study

[摘要] Background. Few data are available on the pharmacokinetics (PK) of sorafenib in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis. This study aimed to explore the sorafenib PK and its relationship with efficacy and toxicity in these patients. Methods. Patients with advanced HCC and Child-Pugh B7-8 liver function were prospectively recruited at a tertiary center. Adverse events (AEs), progression-free survival (PFS), and overall survival (OS) were recorded. Patients received a starting dose of 200 b.i.d. with toxicity-adjusted dose escalation to a target dose of 400 mg b.i.d. with PK sampling at fixed time points. Results. Between May 2014 and March 2017, 12 patients were screened, of whom 7 progressed to a terminal stage during the screening (n = 6) or shortly after recruitment (n = 1). The five included patients had median PFS of 3.8 months (range, 1.7–10.8) and OS of 7.4 months (range, 1.7–25.8). Three patients had severe AEs and one patient had a partial response with an OS of 25.8 months. In 2017, the trial was aborted for lack of accrual. Conclusion. Because of low accrual, no conclusion can be drawn on the sorafenib PK in patients with advanced HCC and Child-Pugh B liver cirrhosis. The poor survival and frequent cirrhosis-related AEs suggest limited benefit for most of these patients. The Oncologist 2020;25:e1274–e1279 DISCUSSION Sorafenib, a tyrosine kinase inhibitor, is recommended for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh class A liver function [1–3]. Nonetheless, real-life studies showed that sorafenib is still commonly (12%–44%) prescribed to patients with Child-Pugh B liver function [4–14]. Sorafenib undergoes hepatic metabolism and biliary excretion, which could potentially be influenced by concomitant liver cirrhosis [15]. Prior studies analyzing the association between hepatic impairment and sorafenib’s pharmacokinetics (PK) had small Child-Pugh B subgroups (n < 20) [16–19]. The present study aimed to prospectively recruit 45 patients to study sorafenib PK parameters and identify potential predictors for sorafenib exposure (i.e., bilirubin, CYP3A4 activity) and its relationship with toxicity, progression-free survival (PFS), and overall survival (OS). Patients with advanced HCC, an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2, and a Child-Pugh score of B7 or 8 were recruited at a large referral center. Patients received a starting dose of 200 b.i.d. with ramp-dosing to a target dose of 400 mg b.i.d. with PK sampling at fixed time points [20].

[学科分类] 地质学