Clinical Outcome of Sorafenib Treatment in Patients With Advanced Hepatocellular Carcinoma Refractory to Hepatic Arterial Infusion Chemotherapy

Daisuke Miyaki; Hiroshi Aikata; Hiromi Kan; Hatsue Fujino; Ayako Urabe; Keiichi Masaki; Takayuki Fukuhara; Tomoki Kobayashi; Noriaki Naeshiro; Takashi Nakahara; Tomokazu Kawaoka; Akira Hiramatsu; Shoichi Takahashi; Masaki Ishikawa; Hideaki Kakizawa; Kazuo Awai; Kazuaki Chayama


J Gastroenterol Hepatol. 2013;28(12):1834-1841. 

In This Article

Abstract and Introduction


Background and Aim It has been reported about poor prognosis in patients with advanced hepatocellular carcinoma (HCC) refractory to hepatic arterial infusion chemotherapy (HAIC). We assessed the survival benefits of sorafenib therapy for advanced HCC in HAIC refractory patients.

Methods The study subjects were 191 patients with advanced HCC who had been treated with HAIC. Sorafenib was used in 27 patients who finally failed to respond to HAIC (HAIC/sorafenib group). Clinical outcome was compared between HAIC/sorafenib and HAIC alone groups.

Results There were no significant differences in clinical characteristics and response rate of HAIC between the two groups (response rate: 25.9%, HAIC/sorafenib group; 30.4%, HAIC alone group). The median survival time (MST) for all patients was 11.0 months. The survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group (MST 22.2 vs 8.7 months, P = 0.017). From administration sorafenib, the disease control rate was 51.8% with MST of 10.4 months. Among HAIC non-responders, the survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group. Multivariate analysis identified additional therapy with sorafenib as significant and independent determinant of overall survival in all patients and HAIC non-responders.

Conclusion Additional therapy with sorafenib could probably improve the prognosis of HAIC refractory patients.


Hepatocellular carcinoma (HCC) remains one of the most common cancers and the third leading cause of cancer-related mortality worldwide.[1,2] The application of various treatment modalities, such as surgical resection, radiofrequency ablation, percutaneous ethanol injection, transcatheter arterial chemoembolization (TACE), radiotherapy, and hepatic arterial infusion chemotherapy (HAIC), has gradually improved the prognosis of HCC patients.[3–7] However, the survival rates of patients with advanced HCC and complications, such as portal vein tumor thrombosis (PVTT), venous tumor thrombosis (VTT), and refractory to TACE, remain extremely poor. Phase III trials of sorafenib for advanced HCC demonstrated significant efficacy in terms of overall survival (OS) compared with placebo.[8,9] Thus, sorafenib is a potentially effective systemic agent for the treatment of these patients. However, the survival advantage is modest, and long-term prognosis of sorafenib remains unknown.

HAIC is widely used in Asia, especially Japan. Several studies have reported the survival benefits of HAIC for advanced HCC, with a response rate ranging from 12.2% to 52%.[10–17] The survival rate was significantly better in patients who achieved complete and partial response (PR; responders) than non-responders. The median survival time (MST) in the responders was 18.4–31.6 months. Based on these data, the Japanese evidence-based guidelines for the diagnosis and treatment of HCC and the consensus-based treatment algorithm for HCC proposed by the Japan Society of Hepatology recommend HAIC for HCC with tumor thrombus in the first branch of the portal vein or in the trunk of the portal vein, without extrahepatic metastasis.[18] However, HAIC offers no survival benefits for non-responders; the reported MST in non-responders ranges from 5.4 to 6.7 months.[11,12,17] Responders to HAIC may have better prognosis than patients treated with sorafenib alone, whereas non-responders to HAIC may have poor prognosis. Currently, there are no criteria used for selection of patients with advanced HCC for sorafenib or HAIC. Many Japanese patients with advanced HCC have already been treated with HAIC. However, the study population of a phase III trial of sorafenib consisted of patients with advanced HCC who had not been treated previously with HAIC. Sorafenib might potentially improve the prognosis of HAIC refractory patients. However, little information is available on the survival benefits of sorafenib in patients who had previously received HAIC. The present study was designed to assess the survival benefits of sorafenib in HAIC refractory patients. For this purpose, we divided the patients into two groups; the HAIC/sorafenib group and HAIC alone group.