• Cardiopulmonary bypass
• Case report
• Hepatectomy
• Hepatocellular carcinoma
• Inferior vena cava
• Sorafenib
• Thrombectomy
• Tumor thrombosis

The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.

• Hepatocellular carcinoma
• Lenvatinib
• Molecular targeted agent
• TACE-refractory
• TACE-unsuitable
• Barcelona Clinic Liver Cancer intermediate stage

Our previous study showed that hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin (FOLFOX) plus sorafenib provided a significant survival benefit over sorafenib for advanced hepatocellular carcinoma. However, it is unclear whether the survival benefit should be attributed to the synergism between HAIC and sorafenib or just HAIC alone. We aim to compare HAIC using FOLFOX plus sorafenib with HAIC alone in patients with advanced hepatocellular carcinoma.

This was a retrospective study including 225 eligible patients treated with HAIC using FOLFOX (HAIC alone group, n=126, oxaliplatin 85 mg/m², leucovorin 400 mg/m², fluorouracil bolus 400 mg/m² and 2400 mg/m² for 46 hours, every 3 weeks) alone or HAIC plus sorafenib (soraHAIC group, n=99, sorafenib 400 mg twice daily). Survival curves were calculated by the Kaplan-Meier method, and propensity-score matching was used to reduce bias.

The soraHAIC group showed a longer overall survival (12.9 [95% CI, 10.4-15.4] vs. 10.5 [95% CI, 9.5-11.5] months, HR=0.71 [95% CI, 0.53-0.96]; P=0.025), a better progression free survival (7.0 [95% CI, 5.3-8.8] vs. 5.3 [95% CI, 3.5-7.1] months, HR=0.76 [95% CI, 0.58-0.99]; P=0.046), and a higher disease control rate (RECIST 1.1: 74.8% vs. 61.1%, P=0.030) than the HAIC alone group. In multivariate analysis, soraHAIC was an independent favor factor for survival. In terms of the grade 3/4 adverse event, hand–foot skin reaction was more frequent in the soraHAIC group than the HAIC alone group. In the propensity-score matched cohorts (93 pairs), the overall survival, the progression free survival and disease control rates in the soraHAIC group were also better than those in the HAIC group (P<0.05).

HAIC plus sorafenib may improve overall survival and progression free survival compared with HAIC alone as initial treatment for advanced hepatocellular carcinoma.

• FOLFOX
• hepatic arterial infusion chemotherapy
• hepatocellular carcinoma
• sorafenib
• treatment

• Alpha-fetoprotein
• Hepatocellular carcinoma
• Japanese subanalysis
• Ramucirumab
• VEGFR2

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Double-Blind Method
• Female
• Humans
• Japan
• Liver Neoplasms/drug therapy
• Male
• Middle Aged
• Progression-Free Survival
• Sorafenib/administration & dosage
• Survival Rate
• Treatment Outcome
• alpha-Fetoproteins/metabolism
• Ramucirumab

• Eli Lilly Japan

• REFLECT
• early response
• lenvatinib
• real world

• Japan Agency for Medical Research and Development
• Japan Society for the Promotion of Science

The prognosis of hepatocellular carcinoma (HCC) patients exhibiting macroscopic vascular invasion (MVI) is poor, and the most appropriate treatment approach remains unclear. The current study aimed to investigate the efficacy and safety of sorafenib treatment following chemoradiotherapy for advanced HCC exhibiting MVI. A newly reported regimen, including 5-fluorouracil and cisplatin therapy (NewFP), plus three-dimensional conformal radiotherapy (3D-CRT) for MVI was used as the initial treatment. Additionally, sorafenib, as a secondary treatment, was administered after NewFP plus 3D-CRT for MVI. The present retrospective study enrolled patients with unresectable advanced HCC that was treated with NewFP plus 3D-CRT for MVI between January 2009 and December 2017. In total, 32 HCC patients with MVI were registered. Of these 32 patients, 18 were treated with NewFP plus 3D-CRT for MVI (NewFP + 3D-CRT group) and 14 were treated with sorafenib following NewFP plus 3D-CRT for MVI (sorafenib after NewFP + 3D-CRT group). The study endpoints were overall survival, overall response rate and disease control rate. Clinical factors influencing overall survival were identified using univariate and multivariate analyses. The median survival time in the NewFP + 3D-CRT group and sorafenib following NewFP + 3D-CRT group was 6.7 and 49.2 months, respectively (P=0.0003). For patients with advanced HCC exhibiting MVI, the initial treatment with NewFP plus 3D-CRT for MVI was well tolerated. The administration of sorafenib as the secondary treatment following NewFP plus 3D-CRT for MVI was associated with a significantly higher overall response rate, disease control rate and increased overall survival as compared with the NewFP plus 3D-CRT treatment.

• hepatic arterial injection chemotherapy
• hepatocellular carcinoma
• major vascular invasion
• sorafenib
• three-dimensional conformal radiotherapy

• Anticoagulants/pharmacology
• Carcinogenesis/drug effects
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Genetic Pleiotropy/drug effects
• Heparin/pharmacology
• Humans
• Liver Neoplasms/complications
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Venous Thromboembolism/drug therapy
• Venous Thromboembolism/etiology

Brain metastases from hepatocellular carcinoma (HCC) are rare, but their incidence is increasing because of developments in recent therapeutic advances. The purpose of this study was to investigate the characteristics of brain metastases from HCC, to evaluate the predictive factors, and to assess the efficacy of gamma knife surgery (GKS).

A retrospective study was performed on patients with brain metastases from HCC who were treated at Tokyo Gamma Unit Center from 2005 to 2014.

Nineteen patients were identified. The median age at diagnosis of brain metastases was 67.0 years. Fifteen patients were male and four patients were female. Six patients were infected with hepatitis B virus (HBV). Two patients were infected with hepatitis C virus (HCV). Eleven patients were not infected with HBV or HCV. The median interval from the diagnosis of HCC to brain metastases was 32.0 months. The median number of brain metastases was two. The median Karnofsky performance score at first GKS was 70. The median survival time following brain metastases was 21.0 weeks. Six-month and 1-year survival rates were 41.2 and 0%, respectively. One month after GKS, no tumor showed progressive disease. The HBV infection (positive vs. negative) was significantly associated with survival according to univariate analysis (p = 0.002).

The patients having brain metastases from HCC had poor prognosis and low performance state. Therefore, GKS is an acceptable option for controlling brain metastases from HCC because GKS is noninvasive remedy and local control is reasonable.

• Brain metastases
• Gamma knife surgery
• Hepatitis B virus
• Hepatocellular carcinoma

• Clinical trial
• Japan
• Liver neoplasms
• Vascular endothelial growth factor receptor 2
• α-Fetoprotein

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/adverse effects
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/drug therapy
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms/blood
• Liver Neoplasms/drug therapy
• Male
• Middle Aged
• Niacinamide/administration & dosage
• Niacinamide/adverse effects
• Niacinamide/analogs & derivatives
• Phenylurea Compounds/administration & dosage
• Phenylurea Compounds/adverse effects
• Sorafenib
• Treatment Outcome
• alpha-Fetoproteins/analysis
• Ramucirumab

In a randomized phase II study of sorafenib plus hepatic arterial infusion chemotherapy with cisplatin in comparison with sorafenib alone in patients with advanced hepatocellular carcinoma, it yielded favorable overall survival when compared with sorafenib alone. This is the first report of its effectiveness in relation to the overall survival in comparison with that of sorafenib alone in patients with advanced hepatocellular carcinoma.

Sorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC.

We conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5–7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m², day 1, every 4–6 weeks) or Sor (400 mg bid). The primary end point was overall survival.

A total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38–0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated.

SorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC.

UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.

• cisplatin
• hepatic arterial infusion chemotherapy
• hepatocellular carcinoma
• randomized phase II trial
• sorafenib

• chemotherapy
• hepatocellular carcinoma
• immune-oncologic agents
• individualized treatment
• sorafenib