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Aim: The aim of this study is to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) between 5‐fluorouracil (5‐FU)‐based continuous infusion chemotherapy and low‐dose cisplatin (CDDP) monotherapy in patients with advanced hepatocellular carcinoma (HCC). Methods: Patients were grouped according to HAIC regimen (5‐FU group, n = 317/CDDP group, n = 66). A two‐to‐one match was created using propensity score analysis (5‐FU group, n = 102/CDDP group, n = 51). After matching, response rate (RR) and adverse events as primary end‐points, and survival and progression‐free survival as secondary end‐points, were analyzed. Results: In the analysis of primary end‐points, the RR in the 5‐FU group was significantly higher than in the CDDP group (32.4% vs. 15.7%, P = 0.033). In patients with a Child–Pugh (CP) score of 5–7, the RR in the 5‐FU group was significantly higher than that in the CDDP group (36.1% vs. 15.4%, P = 0.020). In those with a CP score of 8–9, there was no significant difference in RR between the two groups (15.8% vs. 16.6%, P = 1.000). The reservoir system‐related complications were 9.8% in the 5‐FU group, and there was no significant difference in the incidence of grade 3/4 adverse events between the two matched groups (P > 0.05). In terms of secondary end‐points, the median survival time was 9.1 and 8.7 months for the 5‐FU and CDDP groups, respectively (P = 0.4917). Progression‐free survival was 3.9 months for the 5‐FU group and 4.9 months for the CDDP group (P = 0.4). Conclusions: 5‐Fluorouracil‐based continuous infusion chemotherapy could be suitable for advanced HCC patients with a CP score of 5–7 considering the treatment response. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Regorafenib became second‐line treatment for the patients with sorafenib refractory. In our study, two patients could not continue regorafenib for its adverse effects. It was suggested that appropriate use criteria of regorafenib should be observed and manage adverse effects earlier. Regorafenib became second‐line treatment for the patients with sorafenib refractory. In our study, two patients could not continue regorafenib for its adverse effects. It was suggested that appropriate use criteria of regorafenib should be observed and manage adverse effects earlier. [ABSTRACT FROM AUTHOR]

Aim: As second‐line therapy, regorafenib has been shown to provide a survival benefit for patients with hepatocellular carcinoma (HCC) who progress on sorafenib. In this retrospective study, we assessed the clinical outcomes of sorafenib treatment failure with regard to second‐line chemotherapy. Methods: Patients (n = 160) with advanced HCC, Child–Pugh A liver function and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 treated with sorafenib between June 2009 and September 2016 were enrolled. Among 147 patients with progressive disease (PD), we defined those with Child–Pugh A liver function and ECOG PS 0–1 at progression as candidates for second‐line chemotherapy and those who had tolerated sorafenib (≥400 mg/day for ≥20 of the last 28 days of treatment) as candidates eligible for regorafenib treatment. Results: Among all 160 patients, median overall survival was 10 months, and median progression‐free survival was 3.5 months. Among the 147 patients with PD, 74 (50.3%) were candidates for second‐line chemotherapy, and 45 (30.6%) were eligible for regorafenib treatment. The median post progression survival of the candidates for second‐line chemotherapy (8.8 months) was statistically longer (P = 0.0002) than that of the non‐candidates (3.6 months). Predictive factors for candidates were absence of macroscopic vascular invasion (MVI) (odds ratio [OR], 0.39; P = 0.009) and serum albumin >3.5 g/dL (OR, 3.3; P = 0.005) at sorafenib initiation. Conclusion: Among patients with PD on sorafenib, approximately 30% were eligible for regorafenib treatment, whereas few patients with MVI or hypoalbuminemia at sorafenib initiation were eligible for regorafenib treatment. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of hepatocellular carcinoma (HCC) in elderly patients. Methods: From 2008 to 2015, 117 patients with HCC (≤3 nodules, ≤30 mm in diameter, Child–Pugh score ≤7, and no vascular or extracellular metastasis) were treated with SBRT at our hospital. We evaluated overall survival (OS), disease‐free survival (DFS), local control, and adverse events. Patients were stratified according to age 75 years and older (elderly group, n = 54) and age younger than 75 years (young group, n = 63). Results: The median OS in the elderly group was not significantly different from that in the young group (52 months vs. not reached, P = 0.27). The 1‐, 2‐, and 3‐year OS rates were 96.2%, 77.6%, and 63.9%, respectively, in the elderly group, and 96.8%, 84.8%, and 67.7%, respectively, in the young group. The median DFS in the elderly group was significantly shorter than that in the young group (13 vs. 25 months, respectively; P = 0.03). The 1‐, 2‐, and 3‐year DFS rates were 50.6%, 30.4%, and 26.6%, respectively, in the elderly group and 66.5%, 50.7%, and 45.3%, respectively, in the young group. The 3‐year local tumor control rate in the elderly group was 98.1%, and that in the young group was 98.4% (P = 0.83). There was no difference between groups in the incidence of any adverse events. Conclusions: Stereotactic body radiotherapy can be effective and safe for the treatment of HCC in elderly patients. [ABSTRACT FROM AUTHOR]

Background: Biomarkers predicting the response to the anticancer treatment and prognosis in patients with advanced hepatocellular carcinoma (HCC) are required. Recently, high mobility group box 1 (HMGB1) was reported to promote HCC progression and be associated with poor prognosis for patients with HCC. The purpose of this study was to assess serum HMGB1 concentrations before and during sorafenib treatment or hepatic arterial infusion chemotherapy (HAIC) and to explore the ability of serum HMGB1 concentrations to predict prognosis.Methods: Serum HMGB1 concentrations were measured in 71 and 72 patients with advanced HCC treated with sorafenib and HAIC, respectively, to assess their usefulness for prediction of the response to the treatment and prognosis.Results: Multivariate analysis identified high HMGB1 at 4 weeks (P = 0.001), high α-fetoprotein (AFP) at baseline (P = 0.025), tumor liver occupying rate (P = 0.009) and modified RECIST (mRECIST, P < 0.0001) as independent predictors of poor overall survival in sorafenib treatment. High HMGB1 at 4 weeks (P = 0.025), vascular invasion to the hepatic vein (Vv) (P = 0.009), mRECIST (P < 0.0001) and Child-Pugh B (P = 0.004) were identified as independent predictors of poor overall survival in HAIC treatment. The concentrations of HMGB1 at baseline and 4 weeks were not correlated with conventional tumor markers and progressive disease assessed by mRECIST at 8 weeks.Conclusions: These results suggest that serum HMGB1 at 4 weeks after the start of treatment might be a useful biomarker with added value to the conventional tumor marker and radiologic responses to predict poor overall survival in patients with advanced HCC treated with sorafenib or HAIC. [ABSTRACT FROM AUTHOR]

The risk of hepatocellular carcinoma (HCC) development is reduced following viral elimination by interferon therapy in chronic hepatitis C patients. However, the risk in patients treated with interferon-free direct-acting antivirals (DAAs) is unknown. We evaluated chronic hepatitis C patients who achieved viral eradication by pegylated-interferon plus ribavirin (PEG-IFN/RBV, n = 244) or daclatasvir plus asunaprevir (DCV/ASV, n = 154) therapy. None of the patients had prior history of HCC or antiviral therapy. The median observation period after the end of treatment for the PEG-IFN/RBV and DCV/ASV groups were 96 (range 10–196) and 23 (range 4–78) months, respectively. During the observation period, HCC developed in 13 (5.3%) and 7 (4.5%) patients in the PEG-IFN/RBV and DCV/ASV groups, respectively. The cumulative HCC development rate after 1-, 3- and 5-years (0.4%, 3% and 5% for the PEG-IFN/RBV group and 0.6%, 9% and 9% for the DAA group, respectively) were similar between the two groups. Propensity score matching analysis also showed no significant difference in HCC development rates between the two groups. Serum AFP levels decreased to similar levels between PEG-IFN/RBV and DCV/ASV groups following the achievement of viral eradication. The risk for HCC development following viral eradication by IFN-free DAA therapy may be similar to that in IFN-based therapy. [ABSTRACT FROM AUTHOR]

Background: Post-transplant hepatitis B virus (HBV) reinfection is one of the major problems facing patients who undergo HBV-related liver transplantation (LT). We analyzed the clinical impact of serum hepatitis B core-related antigen (HBcrAg) on HBV reinfection in post-LT patients with HBV-related liver diseases.Methods: Serum hepatitis B surface antigen (HBsAg), HBV DNA, and HBcrAg were measured over time in 32 post-LT patients. Twenty-one out of 32 patients had HCC at LT. The effects of HBcrAg, hepatocellular carcinoma (HCC) recurrence, and HBs gene mutation on HBV reinfection and withdrawal from hepatitis B immune globulin (HBIG) were analyzed.Results: Sixteen out of 32 patients (50 %) were positive for HBcrAg even though only six patients were thought to have experienced HBV reinfection based on reappearance of either HBV DNA or HBsAg during a median follow-up time of 75 months. Three of these six patients who became re-infected with HBV experienced HCC recurrence after LT. The HBV DNA reappearance rate was significantly higher in patients with HCC recurrence after LT (p < 0.001). Two HBV re-infected patients without HCC recurrence had HBs gene mutations G145R and G145A, respectively. Anti-HBs antibody development rate by HB vaccination was similar between HBcrAg-positive and negative patients (p = 0.325).Conclusions: HBV reinfection is more common than is usually considered based on conventional measurement of HBsAg and HBV DNA. HCC recurrence and mutations in the HBV S gene were associated with HBV reinfection after LT. [ABSTRACT FROM AUTHOR]

Background: We assessed the risk factors for the development of hepatocellular carcinoma (HCC) following successful eradication of hepatitis C virus (HCV) with interferon (IFN) therapy in a long-term, large-scale cohort study. Methods: We reviewed 1094 consecutive patients with HCV who achieved sustained virological response (SVR) following IFN therapy between January 1995 and September 2013. Results: During the observation period (median 50 months: range 13-224), 36 (3%) of 1094 patients developed HCC after SVR. The median period from SVR to diagnosis of HCC was 37 months (range 17-141), and the cumulative rates of HCC at 5, 10, and 15 years were 4%, 6%, and 12%, respectively. Multivariate analysis identified old age (≥60 years, HR, 3.1: 95%CI, 1.3-6.6: P = 0.009), male sex (HR, 12.0: 95%CI, 2.8-50.0: P < 0.0001), advanced fibrosis stage (F3/4, HR, 3.2: 95%CI, 1.6-7.2: P < 0.0001), and alpha-fetoprotein ≥10 ng/mL at 1 year after SVR (HR, 7.8: 95%CI, 2.9-16.8: P < 0.0001) as significant and independent risk factors for post-SVR HCC. Conclusions: Older age and male sex (host factors), advanced fibrosis stage (pre-IFN treatment factor), and higher alpha-fetoprotein values (post-treatment factor) were significantly associated with HCC development after HCV eradication. [ABSTRACT FROM AUTHOR]

Objective: Non-simple nodules in hepatocellular carcinoma (HCC) correlate with poor prognosis. Therefore, we examined the diagnostic ability of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) and contrast-enhanced ultrasound (CEUS) for diagnosing the macroscopic classification of small HCCs.Methods: A total of 85 surgically resected nodules (≤30 mm) were analyzed. HCCs were pathologically classified as simple nodular (SN) and non-SN. By evaluating hepatobiliary phase (HBP) of EOB-MRI and Kupffer phase of CEUS, the diagnostic abilities of both modalities to correctly distinguish between SN and non-SN were compared.Results: Forty-six nodules were diagnosed as SN and the remaining 39 nodules as non-SN. The area under the ROC curve (AUROCs, 95% confidence interval) for the diagnosis of non-SN were EOB-MRI, 0.786 (0.682-0.890): CEUS, 0.784 (0.679-0.889), in combination, 0.876 (0.792-0.959). The sensitivity, specificity, and accuracy were 64.1%, 95.7%, and 81.2% in EOB-MRI, 56.4%, 97.8%, and 78.8% in CEUS, and 84.6%, 95.7%, and 90.6% in combination, respectively. High diagnostic ability was obtained when diagnosed in both modalities combined. The sensitivity was especially statistically significant compared to CEUS.Conclusion: Combined diagnosis by EOB-MRI and CEUS can provide high-quality imaging assessment for determining non-SN in small HCCs.Key Points: • Non-SN has a higher frequency of MVI and intrahepatic metastasis than SN. • Macroscopic classification is useful to choose the treatment strategy for small HCCs. • Diagnostic ability for macroscopic findings of EOB-MRI and CEUS were statistically equal. • The diagnosis of macroscopic findings by individual modality has limitations. • Combined diagnosis of EOB-MRI and CEUS provides high diagnostic ability. [ABSTRACT FROM AUTHOR]

Background and Aim It has been reported about poor prognosis in patients with advanced hepatocellular carcinoma ( HCC) refractory to hepatic arterial infusion chemotherapy ( HAIC). We assessed the survival benefits of sorafenib therapy for advanced HCC in HAIC refractory patients. Methods The study subjects were 191 patients with advanced HCC who had been treated with HAIC. Sorafenib was used in 27 patients who finally failed to respond to HAIC ( HAIC/sorafenib group). Clinical outcome was compared between HAIC/sorafenib and HAIC alone groups. Results There were no significant differences in clinical characteristics and response rate of HAIC between the two groups (response rate: 25.9%, HAIC/sorafenib group; 30.4%, HAIC alone group). The median survival time ( MST) for all patients was 11.0 months. The survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group ( MST 22.2 vs 8.7 months, P = 0.017). From administration sorafenib, the disease control rate was 51.8% with MST of 10.4 months. Among HAIC non-responders, the survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group. Multivariate analysis identified additional therapy with sorafenib as significant and independent determinant of overall survival in all patients and HAIC non-responders. Conclusion Additional therapy with sorafenib could probably improve the prognosis of HAIC refractory patients. [ABSTRACT FROM AUTHOR]

Abstact Background and Aims To compare the tumor control and safety of stereotactic body radiation therapy ( SBRT) combined with transcatheter arterial chemoembolization ( TACE) for small, solitary, and hypervascular hepatocellular carcinoma ( HCC) with TACE alone. Methods Three hundred and sixty-five HCC patients who had solitary, ≤ 3 cm, and hypervascular nodule were treated with TACE. Among them, 30 patients followed by SBRT ( SBRT group) and 38 patients without additional therapy and previous HCC treatment (control group) were enrolled in this retrospective cohort study. Local tumor progression, complication, and disease-free survival were compared between these groups. Results There was no difference in clinical background between these groups. Complete response to therapy was noted in 29 (96.3%) patients of the SBRT group, and in only one (3.3%) patient of the TACE group ( P < 0.001). None of the patients developed acute hematologic toxicity of more than Common Terminology Criteria for Adverse Events Grade 3 during and after the treatment. Furthermore, none of the SBRT group developed radiation-induced liver damage. Disease-free survival of the 12 patients without previous HCC treatments in SBRT group was significantly superior to that in control group (15.7 months vs 4.2 months; P = 0.029). Conclusion The results indicated that SBRT combined with TACE is a safe and effective modality for locoregional treatment of small solitary primary HCC, and could be potentially a suitable option. [ABSTRACT FROM AUTHOR]

Background and Aim We compared the treatment response, survival, and safety to hepatic arterial infusion chemotherapy ( HAIC) in patients with advanced hepatocellular carcinoma ( HCC) according to Child- Pugh ( CP) score. Methods The study subjects were 249 patients with advanced HCC and CP class A and B who had been treated with HAIC. Patients were grouped according to CP score (5/6, 7 and 8/9) and their tumor response, tolerance, and survival were assessed. Results The median survival time ( MST) was 8.2, 9.7, 6.3, and 3.9 months for the whole group, patients with CP 5/6, 7 and 8/9, respectively ( P < 0.0001). Complete response ( CR) and partial response ( PR) were seen in 11 and 57 patients, respectively, with an overall response rate of 27.3%. The response rate was higher in patients with CP score 5/6 and 7, than CP 8/9 (30.5%, 28.2%, 13.8%). The dropout rate was significantly higher in patients with CP score 8/9 than the other two (8.0%, 12.8%, 33.3%, respectively). The survival rate was significantly better in patients who achieved CR/ PR than the others with CP score 5/6, 7. CP score 8/9 was an independent negative factor for response and survival. Conclusion Advanced HCC patients with CP score of 5/6 and 7 showed a better response to HAIC and better prognosis than those with CP score 8/9. [ABSTRACT FROM AUTHOR]

Objective: To compare the assessment of response and prognosis of patients to sorafenib treatment by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP). Methods: Sixty-six patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib were enrolled in this retrospective study. The response to treatment was evaluated by RECIST, mRECIST and changes in AFP and DCP. Results: The median survival time of all patients was 8.6 months. The median time to radiological progression was 3.3 months. The response rates [complete response (CR) + partial response (PR)] by RECIST and mRECIST were 3.0 and 9.0%, respectively, while the disease control rates [CR + PR + stable disease (SD)] were 50 and 50%, respectively. Assessment by mRECIST of overall survival provided a better stratification of the patients according to the response to treatment (p = 0.009) than RECIST (p = 0.09). Assessment of overall survival by a change in AFP ratio of ≤1 at 8 weeks was better than that of >1 at 8 weeks (p = 0.002). The DCP ratio was not useful for assessment of overall survival. Multivariate analysis identified mRECIST response (CR + PR + SD; p = 0.001), AFP ratio at 8 weeks (≤1; p = 0.046) and Child-Pugh A before treatment (p = 0.012) as significant and independent determinants of survival. The combination of AFP ratio at 8 weeks, assessment by mRECIST and Child-Pugh score before treatment allows stratification of prognosis of patients treated with sorafenib. Conclusion: The combination of mRECIST and AFP ratio is useful for the assessment of prognosis of patients with advanced HCC treated with sorafenib. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]