Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients.

INTRODUCTION: The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab. MATERIALS AND METHODS: A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line. RESULTS: 49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio [HR]= 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46). CONCLUSION: Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.

Utility of the Virtual Liver Parenchymal Perfusion Area Using a Commercially Available Workstation in Transarterial Chemoembolization for Hepatocellular Carcinoma.

PURPOSE: To evaluate the accuracy of the virtual liver parenchymal perfusion area using a commercially available workstation and liver analysis software in conventional transarterial chemoembolization (cTACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This method was retrospectively applied to 29 treated HCCs in 23 patients. The virtual embolic area (VEA) was estimated based on cone beam computed tomography during hepatic arteriography using a commercially available workstation and liver analysis software by two observer groups (group A: experts; group B: semi-experts). The real embolic area (REA) was defined as the area where iodized oil accumulated on computed tomography at 1 week after cTACE. The REA was estimated by each of the two groups, and the mean REA between the groups (mREA) was used as a standard reference. Agreement of volume and cross-sectional area in three orthogonal planes between the VEA and mREA were analyzed using intraclass correlation coefficients (ICCs) and Bland-Altman plots. RESULTS: The ICCs for volume between VEA and mREA were 0.97 and 0.88 for groups A and B, respectively, and those for cross-sectional area were 0.94 and 0.88 for the axial plane, 0.95 and 0.83 for the coronal plane, and 0.87 and 0.74 for the sagittal plane, respectively. Thus, the overall agreement was excellent, except for the sagittal imaging plane in group B. CONCLUSION: This method using a commercially available workstation and liver analysis software can be useful for estimating the embolic area in cTACE.

Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial.

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.

Hand-Foot Syndrome and Post-Progression Treatment Are the Good Predictors of Better Survival in Advanced Hepatocellular Carcinoma Treated with Sorafenib: A Multicenter Study.

OBJECTIVE: To determine the relationship between treatment outcomes and hand-foot syndrome (HFS), and the relationship between survival rate and post-progression treatment after sorafenib therapy. METHODS: The study assessed 314 patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib at 5 general hospitals in Kagawa Prefecture, Japan. RESULTS: At the start of sorafenib therapy, 23.6% of the patients had HCC of a Child-Pugh class other than A. The initial sorafenib dose was 800 mg in 9.2% of the patients and 400 mg in 64.3%. Time to progression was 129 days (95% CI: 87.3-170.7) and the median overall survival (OS) was 392 days (95% CI: 316.0-468.0). The OS of the patients with Child-Pugh class A HCC was significantly better than that of the patients with Child-Pugh class B HCC (p < 0.0001). The survival curves for Child-Pugh class A-5 points and class A-6 points were significantly different, with that for class A-5 points being better (p < 0.0001). A significant difference was observed between the patients who exhibited HFS and those who did not, with the former exhibiting a better survival rate (p < 0.001). In addition, the survival rate of the patients who received post-progression treatment after sorafenib therapy was significantly better than that of the patients who did not (p < 0.001). CONCLUSION: In sorafenib therapy, patients with HFS and those who received post-progression treatment exhibited good OS.

Clinical features associated with radiological response to sorafenib in unresectable hepatocellular carcinoma: a large multicenter study in Japan.

BACKGROUND & AIMS: There have been no established predictive factors of responders to sorafenib in patients with unresectable hepatocellular carcinoma (HCC). This study aimed to investigate the factors predicting a good response to sorafenib in Japanese patients with HCC. METHODS: A total of 465 patients with unresectable HCC in the Japanese Red Cross Liver Study Group were treated with sorafenib between January 2008 and August 2013, and 316 patients with sufficient clinical data were analysed. To determine the factors predicting a good response, the relationships between radiological response and the following clinicopathological factors were analysed: age, gender, performance status, liver function, tumour status and decrease in serum alpha-foetoprotein (AFP) level after 1 month. RESULTS: This study included 259 males and 57 females with a median age of 70 years (range, 37-90 years), of which 191 (60.4%) were classified as Barcelona Clinic Liver Cancer stage C, and 271 (85.8%) had Child-Pugh class A liver function. The median overall survival time was 307 days and progression-free survival time was 109 days. According to the modified Response Evaluation Criteria In Solid Tumours, four patients achieved a complete response, 51 achieved a partial response, 136 had stable disease and 125 had progressive disease. Multivariate analysis identified female gender (P = 0.003) and decreased serum AFP level after 1 month (P = 0.042) as independent predictors of a complete or partial response. CONCLUSION: Our results suggest female gender and a decrease in serum AFP level are independent predictors of good response to sorafenib.

Comparison of standard-dose and half­dose sorafenib therapy on clinical outcome in patients with unresectable hepatocellular carcinoma in field practice: A propensity score matching analysis.

The aims of the present study were to examine whether unresectable hepatocellular carcinoma (HCC) patients treated with initial dose of sorafenib of 400 mg/day (half-dose group) had comparable treatment efficacy, safety and survival merit as compared with those treated with initial dose of sorafenib of 800 mg/day (standard-dose group) in a multicenter large study. For reducing the bias in patient selection, we compared clinical outcomes of these two groups using propensity score matching analysis. A total of 465 patients were treated with sorafenib at fourteen hospitals in Japanese Red Cross Liver Study Group from 2008 to 2013. After propensity score matching, 139 matched HCC patients were selected for analysis in both groups. We retrospectively compared overall survival (OS), progression-free survival (PFS), best treatment response and sorafenib related serious adverse events (SAEs) in the two groups. There were no relevant differences in terms of OS (median OS intervals: 9.2 months in the standard-dose group and 9.7 months in the half­dose group, P=0.350), PFS (median PFS intervals: 3.4 months in the standard-dose group and 3.2 months in the half-dose group, P=0.729) and best treatment efficacy (objective response rate: P=0.416; disease control rate: P=0.719). Grade 3 or more SAEs were observed in 37 patients (26.6%) in the standard-dose group and 33 patients (23.7%) in the half-dose group (P=0.580). Furthermore, in all subgroup analyses according to Child-Pugh classification and Barcelona Clinic Liver Cancer stage, there were no significant differences in the two groups. In conclusion, unresectable HCC patients treated with initial half­dose sorafenib had comparable prognosis compared with those treated with initial standard-dose sorafenib.