Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study

Abstract

Background and aim: It is unknown whether sorafenib can be combined with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma. This study assesses the safety and tolerability of a continuous regimen of sorafenib combined with TACE.

Methods: This was an open-label phase I study testing a continuous administration of sorafenib (dose escalation from 200 mg twice daily [bid] to 400 mg bid) starting 7 days prior to TACE with doxorubicin (50 mg).

Results: Twenty-one patients were screened and 14 received sorafenib combined with TACE. Because there were no dose-limiting toxicities in the first three patients who received sorafenib at a dose of 200 mg bid, subsequent patients received 400 mg bid. Twenty-seven procedures were performed (median, two per patient) and two local therapy-related severe adverse events occurred. The median duration of sorafenib therapy was 246 days (range, 14-547 days). Sorafenib-related adverse events of grade ≥3 were hand-foot skin reaction (n = 3), weight loss (n = 2), diarrhea (n = 1), abdominal pain (n = 1), and thrombocytopenia (n = 3). After treatment with sorafenib and TACE, there was a significant decrease in the concentration of plasma vascular endothelial growth factor (VEGF) from 93 ng/l to 67 ng/l.

Conclusions: Continuous administration of sorafenib at a dose of 400 mg bid combined with TACE was tolerable. The adverse event profile of this regimen was comparable with that of sorafenib monotherapy with the exception of thrombocytopenia, which may be more frequent. There were no increases in the circulating VEGF levels after TACE with this combined regimen. (Swiss Association for the Study of the Liver study number 25; ClinicalTrials.gov trial identifier, NCT00478374).

Figure 1.

Design of the phase I study. ^aGrade 4 neutropenia and thrombocytopenia lasting >7 days; grade >3 febrile neutropenia; grade >3 nonhematological toxicities (excluding alanine aminotransferase and aspartate aminotransferase levels, alopecia, and nonpremedicated nausea or vomiting). ^bOne month after their last session of TACE, these patients experienced an increase in the dose of sorafenib they received from 200 mg to 400 mg bid. ^cTACE is repeated as often as necessary (determined by computed tomography review). Abbreviations: bid, twice daily; DLT, dose-limiting toxicity; TACE, transarterial chemoembolization.

Figure 2.

Patient enrollment and outcomes. Abbreviations: bid, twice daily; DLT, dose-limiting toxicity; TACE, transarterial chemoembolization.