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Objective: In SILIUS (NCT01214343), combination of sorafenib and hepatic arterial infusion chemotherapy did not significantly improve overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) compared with sorafenib alone. In this study, we explored the relationship between objective response by mRECIST and OS in the sorafenib group, in the combination group, and in all patients in the SILIUS trial., Methods: Association between objective response and OS in patients treated with sorafenib ( n = 103) or combination ( n = 102) and all patients ( n = 205) were analyzed. The median OS of responders was compared with that of non-responders. Landmark analyses were performed according to objective response at several fixed time points, as sensitivity analyses, and the effect on OS was evaluated by Cox regression analysis with objective response as a time-dependent covariate, with other prognostic factors., Results: In the sorafenib group, OS of responders ( n = 18) was significantly better than that of non-responders ( n = 78) ( p < 0.0001), where median OS was 27.2 (95% CI, 16.0-not reached) months for responders and 8.9 (95% CI, 6.5-12.6) months for non-responders. HRs from landmark analyses at 4, 6, and 8 months were 0.45 ( p = 0.0330), 0.37 ( p = 0.0053), and 0.36 ( p = 0.0083), respectively. Objective response was an independent predictor of OS based on unstratified Cox regression analyses. In the all patients and the combination group, similar results were obtained., Conclusions: In the SILIUS trial, objective response by sorafenib assessed by mRECIST is an independent prognostic factor for OS in patients with HCC., Competing Interests: M.K. has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma, and Bristol-Myers Squibb; grants and personal fees from MSD, Eisai, and Bayer, and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly, and ONO Pharmaceutical. K.U., S. Og., and E.H. have received personal fees and honoraria from Bayer and Eisai. T.O. has received grants from Kowa K.K. and Kyowa Hakko Kirin, grants and personal fees from Novartis, Nippon Boehringer Ingelheim, Dainippon-Sumitomo, Pfizer Jana Inc., Bayer Yakuhin, Chugai Pharmaceuticals, Eli Lilly, Yakuruto Honsha, Ono Pharmceuticals, Eisai, AstraZeneca, Merck Serono, Baxter, Nano Carrier, Zeria Pharmaceuticals, NobelPharma, and TaihoPharmaceuticals, and personal fees from Bristol-Myers Squibb, Nipponchemofa, EA Pharma, Fujifilm RI Pharma, Nippon Kayaku, Daiichi Sankyo, Celgene, and Teiijin Pharma. T.K. has received personal fees from Gilead, Bristol-Myers Squibb, MSD, and AbbVie. All other authors declare no competing interests., (Copyright © 2019 by S. Karger AG, Basel.)

Tenofovir alafenamide (TAF) is a newly developed prodrug of tenofovir (TFV). We divided 48 chronic hepatitis B patients who had taken entecavir (ETV) for ≥2 years into two groups: the ETV continuation (n = 24) and the TAF switching (n = 24) groups, and compared the antiviral effects and safety until 48 weeks after the start of the study. There were no significant differences in the alterations in the serum levels of HBs antigen (HBsAg) level between the ETV continuation and the TAF switching groups at 24 or 48 weeks. We also examined the effect of baseline HBsAg level on the decrease of HBsAg during the treatment; in the TAF switching group, the decrease of HBsAg level at 48 weeks was more significant in patients with low baseline HBsAg (<800 IU/mL) than those with high baseline HBsAg ( >800 IU/mL) (change of HBsAg; - 0.029 vs - 0.132 for high and low baseline HBsAg, respectively, P = .007). Also, the effect on renal function was found to be comparable between the TAF switch group and the ETV continuation group. In this study, switching from ETV to TAF may represent higher efficacy for a decrease of HBsAg than a continuation of ETV among the patients with low baseline HBsAg level., (© 2019 Wiley Periodicals, Inc.)

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/m 2 on days 1 and 8 and fluorouracil 330 mg/m 2 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim/background: The ultimate aim of any treatment for hepatocellular carcinoma (HCC) is to improve overall survival (OS); however, the clinical significance of time to progression (TTP) after transarterial chemoembolization (TACE) is unclear. This retrospective study examined the association between OS and the newly defined time to TACE progression (TTTP) to assess whether TTTP can be an alternative to OS in HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B., Methods: Between January 2006 and December 2013, 592 patients with HCC (BCLC B1, n = 118; BCLC B2, n = 170) underwent TACE. TTTP was then redefined as time to progression from the first image taken after TACE. The relationship between TTTP and OS was then examined based on survival time., Results: Survival analysis revealed significant differences in the OS of patients with BCLC B1 and those with BCLC B2 (median OS: 42.3 months, 95% confidence interval [CI] 34.4-50.7; and 29.3 months, 95% CI 26.1-37.6, respectively, p = 0.0348). The median TTTP values were 9.5 months (95% CI 7.0-10.9) and 5.3 months (95% CI 4.6-6.7), respectively ( p = 0.0078). There was a moderate positive correlation between OS and TTTP for both B1 ( R 2 = 0.6563, p = 0.0045) and B2 ( R 2 = 0.6433, p = 0.0052) substages. There was also a positive correlation between OS and TTTP for the combined B1 and B2 substages ( R 2 = 0.6590, p = 0.0024)., Conclusions: There was a moderate correlation between the TTTP and OS of patients with HCC after TACE therapy, where the patients with short TTTP represented short OS, indicating that TTTP is an alternative parameter for survival analysis of HCC patients with BCLC stage B tumors who undergo TACE.

Objective: It is a generally accepted fact that eradication of hepatitis virus C inhibits the subsequent development of hepatocellular carcinoma (HCC). On the contrary, a significant population of patients developed HCC despite sustained virological responses (SVRs) to interferon (IFN) therapy., Methods: A total of 415 patients with chronic hepatitis C, who were treated at our hospital between 2004 and 2014, were enrolled for this study. We examined the risk factors for HCC development after IFN therapy., Results: After analyzing various clinical parameters, it was concluded that a serum albumin (ALB) level <4.0 g/dL and the presence or absence of SVR achievement were risk factors for the development of HCC. When analyzing pre- and posttreatment factors, only a serum ALB level <4.0 g/dL was considered a significant risk factor. The presence or absence of liver fibrosis progression was not identified as a risk factor., Conclusions: In patients with a serum ALB level <4.0 g/dL before IFN therapy, hepatic carcinogenesis after SVR achievement need to be considered. Furthermore, the serum ALB level may be more useful than the degree of fibrosis for the prediction of HCC after SVR in chronic hepatitis C., (© 2017 S. Karger AG, Basel.)

Background and Aims: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR., Methods: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on α-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP >5 ng/mL and ALT level ≥20 IU/L after SVR were clarified using multivariate analyses., Results: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP (p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 (p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level ≥ 30 IU/L after SVR (p = 0.0430)., Conclusions: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC., (© 2017 S. Karger AG, Basel.)

The Response Evaluation Criteria in Solid Tumors (RECIST) is inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE). Therefore, establishment of response evaluation criteria solely devoted to HCC is needed urgently in clinical practice as well as in clinical trials of HCC treatment, such as molecular-targeted therapies, which cause necrosis of the tumor. The Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2015 by the Liver Cancer Study Group of Japan based on the 2009 version of RECICL, which was commonly used in Japan. Major revised points of the RECICL 2015 is to define the target lesions of two lesions per organ or three lesions per liver, up to a maximum of five lesions. The second revised point is that setting the timing at which the overall treatment response has been changed. The third point is that the definition of treatment effect 1 has been changed to more than 50% tumor enlargement, excluding the area of necrosis after treatment. Overall evaluation of treatment response has been amended to make it possible to evaluate the overall response including extrahepatic lesions by systemic therapy, which is similar to RECIST or modified RECIST. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit HCC treatment response evaluation in the setting of daily clinical practice and clinical trials, not only in Japan, but also internationally., (© 2015 The Japan Society of Hepatology.)

Most hepatocellular carcinomas (HCCs) develop in the context of chronic liver inflammation. Oxidative stress is thought to play a major role in the pathogenesis of HCC development. In this study, we examined whether cold-inducible RNA-binding protein (Cirp) controls reactive oxygen species (ROS) accumulation and development of HCC by using murine models of hepatocarcinogenesis and human liver samples. Cirp expression, ROS accumulation, and CD133 expression were increased in the liver of tumor-harboring mice. Cirp deficiency reduced production of interleukin-1β and interleukin-6 in Kupffer cells, ROS accumulation, and CD133 expression, leading to attenuated hepatocarcinogenesis. Thioacetamide treatment enhanced hepatic expression of CD133 and phosphorylated signal transducer and activator of transcription 3 (STAT3), which was prevented by treatment with the antioxidant butylated hydroxyanisole. Intriguingly, the risk of human HCC recurrence is positively correlated with Cirp expression in liver. Cirp appears to play a critical carcinogenic function and its expression might be a useful biomarker for HCC risk prediction., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: To test the hypothesis that use of the response evaluation criteria in cancer of the liver (RECICL), an improved evaluation system designed to address the limitations of the response evaluation criteria in solid tumors 1.1 (RECIST1.1) and modified RECIST (mRECIST), provides for more accurate evaluation of response of patients with hepatocellular carcinoma (HCC) to treatment with sorafenib, a molecularly targeted agent, as assessed by overall survival (OS)., Methods: The therapeutic response of 156 patients with advanced HCC who had been treated with sorafenib therapy for more than 1 month was evaluated using the RECIST1.1, mRECIST, and RECICL. After categorization as showing progressive disease (PD), stable disease (SD), or objective response, the association between OS and categorization was examined using the Kaplan-Meier method to develop survival curves. The 141 cases categorized as PD or SD by the RECIST1.1, but objective response by the mRECIST and RECICL, were further analyzed for determination of the association between OS and categorization., Results: Only categorization using the RECICL was found to be significantly correlated with OS (p = 0.0033). Among the patients categorized as SD or PD by the RECIST1.1, reclassification by the RECICL but not the mRECIST was found to be significantly associated with OS and allowed for precise prediction of prognosis (p = 0.0066)., Conclusions: Only the use of the RECICL allowed for identification of a subgroup of HCC patients treated with sorafenib with improved prognosis. The RECICL should, therefore, be considered a superior system for assessment of therapeutic response.

The patients with chronic viral hepatitis or cirrhosis are a high-risk group for hepatocellular carcinoma. Thus, those who should be screened for detecting HCC can be specified easily. Early detection of HCC leads to performing the curative therapy. However, HCC is easy to recur because of the underlying viral hepatitis and intrahepatic metastasis. After radical therapy, strict surveillance should be performed and if HCC recurs, strategy of treatment should follow the treatment algorithm of Japanese Clinical Practice Guidelines for hepatocellular carcinoma.

The ideal approach to treat chronic hepatitis B remains controversial. This pilot study aimed to evaluate the effectiveness of peginterferon (PEG-IFN) α-2b and entecavir hydrate (ETV) as a combination therapy for patients with chronic hepatitis B, particularly in the context of virological response and the reduction of intrahepatic covalently closed circular DNA (cccDNA). A total of 17 patients with hepatitis B virus (HBV) genotype C were enrolled in this study. All subjects were treated with this combination therapy for 48 weeks and observed for an additional 24 weeks. All patients underwent liver biopsy before and after the therapy period. Changes in cccDNA levels and liver histology were monitored between biopsies. Among the 11 patients who exhibited pre-therapy hepatitis B e antigen (HBeAg), 8 (73%) showed evidence of HBeAg seroconversion by the end of the follow-up period. Serum HBV DNA levels decreased by 5.2 and 3.3 log copies/ml (mean) by the end of the therapy and follow-up periods, respectively. In addition, intrahepatic cccDNA decreased significantly to 1.4 log copies/µg (mean) by the end of the therapy period. Among the 11 patients who did not experience viral relapse, only 2 (18%) exhibited high levels of cccDNA (>4.5 log copies/µg) by the end of the treatment period. In contrast, all relapsed subjects exhibited significantly higher levels of cccDNA than subjects who did not relapse (P  = 0.027). The combination regimen is a promising approach to treat chronic hepatitis B and may achieve significant reduction in serum HBV DNA and intrahepatic cccDNA. Wiley Periodicals, Inc., (Copyright © 2013 Wiley Periodicals, Inc.)

Unlabelled: The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%-3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico-pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real-time polymerase chain reaction-based copy number assay revealed that FGF3/FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P = 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico-pathological features showed that multiple lung metastases (5/13, P = 0.006) and a poorly differentiated histological type (5/13, P = 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4-amplified and three FGFR2-amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3., Conclusion: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies., (Copyright © 2012 American Association for the Study of Liver Diseases.)

S-1, an oral fluoropyrimidine derivative, has been shown to be clinically effective against various solid tumors, and preclinical studies have demonstrated activity against hepatocellular carcinoma. We conducted a phase I/II study in patients with advanced hepatocellular carcinoma to examine the pharmacokinetics, recommended dose, safety and efficacy of S-1. In phase I, the administered dose of S-1 was approximately 64 mg/m(2) per day in three patients (level 1) and approximately 80 mg/m(2) per day in six patients (level 2). There was no dose-limiting toxicity at level 1, but two patients had dose-limiting toxicity at level 2 (grade 3 anorexia and grade 2 rash requiring eight or more consecutive days of rest). The recommended dose was finally estimated to be 80 mg/m(2) per day. There were no significant differences in the pharmacokinetics of S-1 between patients with Child-Pugh A and those with B. In phase II, five of 23 patients (21.7%) had partial responses. The median progression-free survival and overall survival were 3.7 and 16.6 months, respectively. The most common toxicities of grade 3 or 4 were elevated serum aspartate aminotransferase levels, hypochromia and thrombocytopenia. In conclusion, S-1 showed an acceptable toxicity profile and promising antitumor activity for hepatocellular carcinoma, warranting further evaluation in randomized clinical trials., (© 2010 Japanese Cancer Association.)

Several staging systems have been developed to classify patients with hepatocellular carcinoma (HCC), however, there is no consensus on which of these is the most useful and reliable. In this review article, currently available integrated staging systems taking into account both liver function and tumor progression are presented, and their characteristics and applicability for current HCC patients, many of whom are diagnosed in the early stage of the disease and treated by curative therapy, are discussed. Based on the original andsubsequent validation studies of these staging systems, we recommend that further validation studies of staging systems for HCC should focus on the revised Barcelona Clinic Liver Cancer (BCLC) staging classification, Japan Integrated Staging (JIS) score and Tokyo score.