Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study.

BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. GOV NUMBER: NCT01761266. IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2021 version (5th JSH-HCC Guidelines).

The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine and partly to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance-diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described.

Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection.

AIM: The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. METHODS: This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. RESULTS: Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty-eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. CONCLUSION: In rare cases, HBsAg-positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.

Progression from early to advanced stage of immune-related cholangitis.

AIM: We report a rare case of immune-related cholangitis in which the natural course could be demonstrated. CASE PRESENTATION: Eight courses of pembrolizumab maintenance therapy were given as first-line treatment for squamous cell lung cancer; however, the patient was subsequently hospitalized due to a rapid increase in hepatobiliary enzymes. On endoscopic ultrasound, the common bile duct was dilated to 11 mm, and the wall, throughout its length from the papilla, was thickened. Endoscopic retrograde cholangiopancreatography showed no obvious stenosis in the lower bile duct; however, a parapapillary diverticulum was found, and papillary incision and bile duct plastic stent insertion were carried out. However, the liver disorder did not improve and overt jaundice appeared subsequently; therefore, an immune-related cholangitis was suspected, and prednisolone (PSL) 35 mg/day was introduced from day 59 of admission. Following PSL initiation, a decrease in serum bilirubin level was observed; however, significant decrease was not observed in alkaline phosphatase. Given the history of recurrent infectious cholangitis, magnetic resonance cholangiopancreatography was carried out on day 70 of admission. The intrahepatic bile duct showed stenosis and dilated findings, which was considered to be a factor for repeated infectious cholangitis. CONCLUSION: No previous case reports have described the changes and progression in bile duct images in immune-related adverse events. Therefore, this case is noteworthy for considering the progression of immune-related cholangitis.

Response Evaluation Criteria in Cancer of the liver version 6 (Response Evaluation Criteria in Cancer of the Liver 2021 revised version).

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 or transarterial chemoembolization. Therefore, establishment of response evaluation criteria solely devoted to HCC is needed in clinical practice, as well as in clinical trials of HCC treatment, such as systemic therapies, which cause necrosis of the tumor. Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2021 by the Liver Cancer Study Group of Japan based on the 2019 version of RECICL, which was commonly used in Japan. The major revised points of the RECICL 2021 is inclusion of RECIST version 1.1 and modified RECIST as response evaluation criteria in systemic therapy for HCC. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit the HCC treatment response evaluation in the setting of daily clinical practice and clinical trials as well, not only in Japan, but also internationally.

Comparison of efficacy and safety of entecavir and switching from entecavir to tenofovir alafenamide fumarate in chronic hepatitis B: Long-term effects from a prospective study.

AIM: Both entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are widely used to treat chronic hepatitis B (CHB) in Japan. However, it remains unclear whether the efficacy of TAF in decreasing the hepatitis B surface antigen (HBsAg) level, and its safety, are superior to those of ETV. This study aimed to report the long-term effects and safety of 96-week ETV and TAF treatment in patients with CHB. METHODS: A prospective comparative observational study was undertaken on the following two groups: patients with CHB who received continuous ETV (n = 32) and patients with CHB who were switched from ETV to TAF upon request (n = 48). The HBsAg, urinary ß2-microglobulin (ß2MG)/creatinine (Cr), urinary N-acetyl-ß-D-glucosaminidase (NAG)/Cr, and serum alanine aminotransferase (ALT) levels, estimated glomerular filtration rate (eGFR), and bone mineral density (lumbar spine and femur) at 96 weeks were compared. RESULTS: The two groups did not significantly differ with respect to mean age, male / female patient ratio, or rate of hepatitis B e antigen-positive status. The mean changes in serum HBsAg level and eGFR at 96 weeks were not significantly different between the two groups. The ß2MG/Cr and NAG/Cr levels at 96 weeks were similar between the two groups. Additionally, the bone mineral density of the lumbar spine and femur as well as the serum ALT did not significantly differ. CONCLUSIONS: When compared with patients who received continuous ETV, those who were introduced to TAF after ETV showed similar effects in terms of the decrease in HBsAg level and safety.

Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.

OBJECTIVE: This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE. DESIGN: Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing. RESULTS: Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities. CONCLUSION: TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials. TRIAL REGISTRATION NUMBER: NCT01217034.

A randomized, double-blind, placebo-controlled, phase 3 study of tivantinib in Japanese patients with MET-high hepatocellular carcinoma.

A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c-Met inhibitor tivantinib as second-line treatment significantly prolonged progression-free survival in a subpopulation whose tumor samples highly expressed c-Met (MET-high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. This randomized, double-blind, placebo-controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET-high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice-a-day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression-free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression-free survival was 2.8 (95% confidence interval: 2.7-2.9) and 2.3 (1.5-2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52-1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1-11.6) and 8.5 (6.2-11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58-1.15). The most common tivantinib-related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. (NCT02029157).

Radiofrequency ablation for hepatocellular carcinoma: Clinical value of ultrasound-ultrasound overlay fusion for optimal ablation and local controllability.

AIM: To retrospectively investigate the potential benefit of ultrasound-ultrasound (US-US) overlay fusion guidance for local controllability of radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC). METHODS: Patients (n = 101) with 121 HCCs (mean ± SD, 1.8 ± 0.7 cm) who underwent RFA guided by US-US overlay fusion were included in the retrospective study. By overlaying pre/postoperative US, the tumor image could be projected onto the ablative hyperechoic zone. The ablative margin could thereby be evaluated three-dimensionally during the RFA procedure. As a control group, all 325 patients with 453 HCCs who underwent conventional RFA during the same study period were selected. RESULTS: The total number of RF needle insertions per tumor for ablation was significantly more in the US overlay fusion group (mean 1.9 vs. 1.2; P < 0.01). The technical success rates of ablation after a single session were 100% (101/101) and 96.6% (314/325) for the US overlay fusion group and the control group, respectively. For early assessment of RFA response, 5-mm safety margins were achieved in 89.3% (108/121) and 47.0% (213/453) of nodules in the US overlay fusion group and the control group, respectively (P < 0.01). During the follow-up period (median 19 months), the 2-year local tumor progression rates were 0.8% (1/121) and 6.0% (27/453) in the US overlay fusion group and the control group, respectively (P = 0.022, log-rank test). CONCLUSIONS: US-US overlay fusion guidance can be highly effective for safety margin achievement in RFA for HCC, providing a lower risk of local tumor progression.

Switching from entecavir to tenofovir alafenamide versus maintaining entecavir for chronic hepatitis B.

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.

Response Evaluation Criteria in Cancer of the Liver version 5 (RECICL 2019 revised version).

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 and transarterial chemoembolization. Therefore, establishment of response evaluation criteria solely devoted to HCC is needed in clinical practice, as well as in clinical trials of HCC treatment, such as systemic therapies, which cause necrosis of the tumor. Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2019 by the Liver Cancer Study Group of Japan based on the 2015 version of RECICL, which was commonly used in Japan. The major revised points of the RECICL 2019 are as follows: (i) CEA and CA19-9 have been newly added as tumor markers that should be recorded for use as criteria in the response evaluation for intrahepatic cholangiocarcinoma; (ii) the criteria now state that the details of molecular targeted therapy should be specified; and (iii) specific methods for overall evaluation are now described. Also, as an assessment of overall TE4 requires that TE4 is achieved in all nodules (even non-target lesions), the same calculation methods described above are used. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit the HCC treatment response evaluation in the setting of daily clinical practice and clinical trials as well, not only in Japan, but also internationally.

Ultrasound-ultrasound image overlay fusion improves real-time control of radiofrequency ablation margin in the treatment of hepatocellular carcinoma.

OBJECTIVES: To assess the clinical feasibility of US-US image overlay fusion with evaluation of the ablative margin in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: Fifty-three patients with 68 HCCs measuring 0.9-4.0 cm who underwent RFA guided by US-US overlay image fusion were included in this retrospective study. By an overlay of pre-/postoperative US, the tumor image could be projected onto the ablative hyperechoic zone. Therefore, the ablative margin three-dimensionally could be shown during the RFA procedure. US-US image overlay was compared to dynamic CT a few days after RFA for assessment of early treatment response. Accuracy of graded response was calculated, and the performance of US-US image overlay fusion was compared with that of CT using a Kappa agreement test. RESULTS: Technically effective ablation was achieved in a single session, and 59 HCCs (86.8 %) succeeded in obtaining a 5-mm margin on CT. The response with US-US image overlay correctly predicted early CT evaluation with an accuracy of 92.6 % (63/68) (k = 0.67; 95 % CI: 0.39-0.95). CONCLUSION: US-US image overlay fusion can be proposed as a feasible guidance in RFA with a safety margin and predicts early response of treatment assessment with high accuracy. KEY POINTS: • US-US image overlay fusion visualizes the ablative margin during RFA procedure. • Visualizing the margin during the procedure can prompt immediate complementary treatment. • US image fusion correlates with the results of early evaluation CT.

Outcome of Combination Therapy with Sofosbuvir and Ledipasvir for Chronic Type C Liver Disease.

INTRODUCTION: Recently, the treatment of chronic hepatitis C has markedly advanced. A phase III clinical study of combination therapy with sofosbuvir (SOF) and ledipasvir (LDV) was conducted in Japan, and the additive therapeutic effects were reported. In this study, we report the results of treatment in our hospital. METHODS: Of 147 patients with chronic type C liver disease who had consulted our hospital since September 2015 and received SOF/LDV therapy, in 91 subjects a sustained virological response of 12 weeks (SVR12) could be evaluated. RESULTS: In all 91 patients, end treatment response was achieved. Subsequently, recrudescence was noted in 1 before the completion of treatment (week 12); an SVR12 was achieved in 90 patients (99%). The following adverse reactions were observed in 3 patients (3.3%): bradycardia, paroxysmal atrial fibrillation, and heart failure with QT prolongation, which were associated with heart disease. CONCLUSION: A favorable SVR was achieved by SOF/LDV therapy even in elderly patients, those with liver cirrhosis, or those having undergone radical treatment of liver cancer. Furthermore, a high tolerance was demonstrated, but adverse reactions associated with the heart may appear in patients with heart disease as an underlying disease; strict management during treatment is necessary.

Influence of Liver Inflammation on Liver Stiffness Measurement in Patients with Autoimmune Hepatitis Evaluation by Combinational Elastography.

OBJECTIVE: In order to evaluate the influence of liver inflammation on liver stiffness measurement (LSM) by the simultaneous use of shear wave and strain imaging (combinational elastography), shear wave and strain imaging were compared before and after initial therapy for autoimmune hepatitis (AIH). METHODS: Nine AIH patients initially treated with steroid were enrolled. Transient elastography and real-time tissue elastography were performed just before and 1 month after the start of initial steroid treatment. Blood samples, LSM, and the liver fibrosis index (LFI) were compared. RESULTS: Aspartate aminotransferase (p = 0.002) and alanine aminotransferase (ALT) (p = 0.015) were significantly decreased after initial treatment. The LSM was 15.5 ± 9.6 kPa at baseline, decreasing to 7.2 ± 2.3 kPa after initial treatment p = 0.034). The LFI was 1.67 ± 0.67 at baseline and 1.61 ± 0.66 after initial treatment; no significant change in LFI was recognized (p = 0.842). Between ΔALT and ΔLSM, a significant regression equation could be calculated as follows: ΔALT = -0.55 + 0.654 × ΔLSM. CONCLUSIONS: Combinational elastography was useful in evaluating not only the degree of liver fibrosis, but also the degree of liver inflammation in AIH.

Contrast-Enhanced Tissue Harmonic Imaging versus Phase Inversion Harmonic Sonographic Imaging for the Delineation of Hepatocellular Carcinomas.

OBJECTIVE: To compare contrast tissue harmonic imaging (THI) with low mechanical index (MI) and conventional contrast harmonic imaging (CHI) with respect to lesion visibility of hepatocellular carcinoma (HCC). METHODS: One hundred and twenty-five patients (84 men and 41 women, age range 39-94 years, mean age 74 years) with 100 naïve HCCs and 30 lesions after radiofrequency ablation (RFA) for HCC were evaluated. One hundred and four patients had liver cirrhosis of Child-Pugh class A, and the remaining 21 had Child-Pugh class B cirrhosis. The lesion conspicuity and intratumoral echogenicity during the postvascular phase were compared using conventional CHI and contrast THI with low MI. RESULTS: The MI values ranged from 0.20 to 0.30 on conventional CHI and from 0.30 to 0.35 on contrast THI. Regarding HCC lesion conspicuity, contrast THI with low MI was clearer in 79 lesions (60.8%), equal in 34 lesions (26.2%), and less clear in 17 lesions (13.1%) when compared with conventional CHI. The lesion conspicuity with contrast THI was significantly better than that with conventional CHI (p < 0.01). All of the postablative lesions were well delineated in patients who received RFA. CONCLUSION: Low-MI contrast THI was superior to conventional CHI with respect to lesion visibility of HCCs and might offer good imaging for the guiding of RFA.

Malignant Transformation of Hepatocellular Adenoma.

The patient was a 20-year-old male in whom a hepatic hypervascular mass accompanied by intratumoral hemorrhage was detected on examination for epigastric pain. Based on the enlargement of the mass and diagnostic imaging, hepatocellular adenoma (HCA) was suspected and hepatectomy was performed. The lesion was diagnosed as malignant transformation of ß-catenin-activated HCA. There are only few reports of cases with malignant transformation of HCA in Japan; it is necessary to accumulate cases to investigate it.

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.

Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience.

OBJECTIVES: Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. METHODS: Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. RESULTS: The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. CONCLUSION: Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC.

Hepatocarcinogenesis Is Associated with Serum Albumin Levels after Sustained Virological Responses with Interferon-Based Therapy in Patients with Hepatitis C.

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.

Hepatocellular Carcinoma after Achievement of Sustained Viral Response with Daclatasvir and Asunaprevir in Patients with Chronic Hepatitis C Virus Infection.

BACKGROUND: Interferon-based antiviral therapies against hepatitis C virus (HCV) infection have been shown to reduce the incidence of hepatocellular carcinoma (HCC) in patients with sustained viral response (SVR). Recently, direct-acting antivirals (DAAs) have been proven to be much more effective in achieving SVR than interferon-based therapies. However, whether DAAs can efficiently prevent the occurrence of HCC after SVR remains controversial. To clarify this issue, we analyzed the clinical features of patients in whom HCC developed after achievement of SVR with DAAs for chronic HCV infection. SUMMARY: Among patients who achieved SVR with daclatasvir and asunaprevir (n = 100), HCC developed in 17 patients (HCC group; n = 17) and did not develop in 83 patients (non-HCC group; n = 83) during a mean observation period of 15 months. A multivariate Cox proportional hazards analysis identified past history of HCC and male sex as significant risk factors for the emergence of HCC after DAAs. Sixteen cases with HCC after DAAs were in the very early or early stage (16/17, 94.1%), and one case was in the advanced stage (1/17, 5.9%) with portal venous tumor thrombus. Radiofrequency ablation and/or transarterial chemoembolization were performed in most cases as curative therapy (16/17, 94.1%). Key Messages: SVR by DAAs did not completely prevent the occurrence of HCC. However, even if HCC did develop after SVR, curative anticancer therapy was applicable in most cases.