Masatoshi Kudo1, Kazuomi Ueshima2, Osamu Yokosuka3, Sadahisa Ogasawara3, Shuntaro Obi4, Namiki Izumi5, Hiroshi Aikata6, Hiroaki Nagano7, Etsuro Hatano8, Yutaka Sasaki9, Keisuke Hino10, Takashi Kumada11, Kazuhide Yamamoto12, Yasuharu Imai13, Shouta Iwadou14, Chikara Ogawa15, Takuji Okusaka16, Fumihiko Kanai3, Kohei Akazawa17, Ken-Ichi Yoshimura18, Philip Johnson19, Yasuaki Arai16. 1. Kindai University Faculty of Medicine, Osaka-Sayama, Japan. Electronic address: m-kudo@med.kindai.ac.jp. 2. Kindai University Faculty of Medicine, Osaka-Sayama, Japan. 3. Chiba University Graduate School of Medicine, Chiba, Japan. 4. Kyoundo Hospital, Tokyo, Japan. 5. Japanese Red Cross Musashino Hospital, Musashino, Japan. 6. Hiroshima University Hospital, Hiroshima, Japan. 7. Osaka University Graduate School of Medicine, Osaka, Japan. 8. Kyoto University, Graduate School of Medicine, Kyoto, Japan. 9. Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan. 10. Kawasaki Medical School, Kurashiki, Japan. 11. Ogaki Municipal Hospital, Ogaki, Japan. 12. Okayama University Medical School, Okayama, Japan. 13. Ikeda Municipal Hospital, Ikeda, Japan. 14. Hiroshima City Hospital, Hiroshima, Japan. 15. Takamatsu Red Cross Hospital, Takamatsu, Japan. 16. National Cancer Center Hospital, Tokyo, Japan. 17. Niigata University, Niigata, Japan. 18. Kanazawa University, Kanazawa, Japan. 19. University of Liverpool, Liverpool, UK.
Abstract
BACKGROUND:Hepatic arterial infusion chemotherapy plus sorafenib in phase 2 trials has shown favourable tumour control and a manageable safety profile in patients with advanced, unresectable hepatocellular carcinoma. However, no randomised phase 3 trial has tested the combination of sorafenib with continuous arterial infusion chemotherapy. We aimed to compare continuous hepatic arterial infusion chemotherapy plus sorafenib with sorafenib alone in patients with advanced, unresectable hepatocellular carcinoma. METHODS: We did an open-label, randomised, phase 3 trial (SILIUS) at 31 sites in Japan. Eligible patients were aged 20 years or older, with advanced hepatocellular carcinoma not suitable for resection, local ablation, or transarterial chemoembolisation; Eastern Cooperative Oncology Group (ECOG) performance status 0-1; Child-Pugh score 7 or lower; and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) via an interactive web response system with a computer-generated sequence to receive 400 mg sorafenib orally twice daily or 400 mg sorafenib orally twice daily plus hepatic arterial infusion chemotherapy (cisplatin 20 mg/m2 on days 1 and 8 and fluorouracil 330 mg/m2 continuously on days 1-5 and 8-12 of every 28-day cycle via an implanted catheter system). The primary endpoint was overall survival. The primary efficacy analysis comprised all randomised patients (the intention-to-treat population), and the safety analysis comprised all randomised patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01214343. FINDINGS:Between Nov 4, 2010, and June 10, 2014, 206 patients were randomly assigned (103 to the sorafenib group, 103 to the sorafenib plus hepatic arterial infusion chemotherapy group). One patient in the sorafenib plus hepatic arterial infusion chemotherapy group withdrew after randomisation. Median overall survival was similar in the sorafenib plus hepatic arterial infusion chemotherapy (n=102) and sorafenib monotherapy (n=103) groups (11·8 months [95% CI 9·1-14·5] vs 11·5 months [8·2-14·8]; hazard ratio 1·009 [95% CI 0·743-1·371]; p=0·955). Grade 3-4 adverse events that were more frequent in the sorafenib plus hepatic arterial infusion chemotherapy group than in the sorafenib monotherapy group included anaemia (15 [17%] of 88 vs six [6%] of 102), neutropenia (15 [17%] vs one [1%]), thrombocytopenia (30 [34%] vs 12 [12%]), and anorexia (12 [14%] vs six [6%]). INTERPRETATION: Addition of hepatic arterial infusion chemotherapy to sorafenib did not significantly improve overall survival in patients with advanced hepatocellular carcinoma. FUNDING: Japanese Ministry of Health, Labour and Welfare.
RCT Entities:
BACKGROUND: Hepatic arterial infusion chemotherapy plus sorafenib in phase 2 trials has shown favourable tumour control and a manageable safety profile in patients with advanced, unresectable hepatocellular carcinoma. However, no randomised phase 3 trial has tested the combination of sorafenib with continuous arterial infusion chemotherapy. We aimed to compare continuous hepatic arterial infusion chemotherapy plus sorafenib with sorafenib alone in patients with advanced, unresectable hepatocellular carcinoma. METHODS: We did an open-label, randomised, phase 3 trial (SILIUS) at 31 sites in Japan. Eligible patients were aged 20 years or older, with advanced hepatocellular carcinoma not suitable for resection, local ablation, or transarterial chemoembolisation; Eastern Cooperative Oncology Group (ECOG) performance status 0-1; Child-Pugh score 7 or lower; and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) via an interactive web response system with a computer-generated sequence to receive 400 mg sorafenib orally twice daily or 400 mg sorafenib orally twice daily plus hepatic arterial infusion chemotherapy (cisplatin 20 mg/m2 on days 1 and 8 and fluorouracil 330 mg/m2 continuously on days 1-5 and 8-12 of every 28-day cycle via an implanted catheter system). The primary endpoint was overall survival. The primary efficacy analysis comprised all randomised patients (the intention-to-treat population), and the safety analysis comprised all randomised patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01214343. FINDINGS: Between Nov 4, 2010, and June 10, 2014, 206 patients were randomly assigned (103 to the sorafenib group, 103 to the sorafenib plus hepatic arterial infusion chemotherapy group). One patient in the sorafenib plus hepatic arterial infusion chemotherapy group withdrew after randomisation. Median overall survival was similar in the sorafenib plus hepatic arterial infusion chemotherapy (n=102) and sorafenib monotherapy (n=103) groups (11·8 months [95% CI 9·1-14·5] vs 11·5 months [8·2-14·8]; hazard ratio 1·009 [95% CI 0·743-1·371]; p=0·955). Grade 3-4 adverse events that were more frequent in the sorafenib plus hepatic arterial infusion chemotherapy group than in the sorafenib monotherapy group included anaemia (15 [17%] of 88 vs six [6%] of 102), neutropenia (15 [17%] vs one [1%]), thrombocytopenia (30 [34%] vs 12 [12%]), and anorexia (12 [14%] vs six [6%]). INTERPRETATION: Addition of hepatic arterial infusion chemotherapy to sorafenib did not significantly improve overall survival in patients with advanced hepatocellular carcinoma. FUNDING: Japanese Ministry of Health, Labour and Welfare.