Effects of Branched-Chain Amino Acid (BCAA) Supplementation on the Progression of Advanced Liver Disease: A Korean Nationwide, Multicenter, Prospective, Observational, Cohort Study.

BACKGROUND AND AIMS: Clinical evidence for the benefits of branched-chain amino acids (BCAAs) is lacking in advanced liver disease. We evaluated the potential benefits of long-term oral BCAA supplementation in patients with advanced liver disease. METHODS: Liver cirrhosis patients with Child-Pugh (CP) scores from 8 to 10 were prospectively recruited from 13 medical centers. Patients supplemented with 12.45 g of daily BCAA granules over 6 months, and patients consuming a regular diet were assigned to the BCAA and control groups, respectively. The effects of BCAA supplementation were evaluated using the model for end-stage liver disease (MELD) score, CP score, serum albumin, serum bilirubin, incidence of cirrhosis-related events, and event-free survival for 24 months. RESULTS: A total of 124 patients was analyzed: 63 in the BCAA group and 61 in the control group. The MELD score (p = 0.009) and CP score (p = 0.011) significantly improved in the BCAA group compared to the control group over time. However, the levels of serum albumin and bilirubin in the BCAA group did not improve during the study period. The cumulative event-free survival was significantly improved in the BCAA group compared to the control group (HR = 0.389, 95% CI = 0.221-0.684, p < 0.001). CONCLUSION: Long-term supplementation with oral BCAAs can potentially improve liver function and reduce major complications of cirrhosis in patients with advanced liver disease.

Changes in the neutrophil-to-lymphocyte ratio predict the prognosis of patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND AND AIM: Although sorafenib is the first systemic therapy to show survival benefit for advanced hepatocellular carcinoma (HCC), its survival benefit is variable for HCC. Systemic inflammation may be associated with survival in HCC. We investigated the use of systemic inflammation markers, including neutrophil-to-lymphocyte ratio (NLR), in the prognosis of sorafenib-treated HCC patients. PATIENTS AND METHODS: We retrospectively analyzed data of 82 patients with advanced HCC who received sorafenib as the first-line treatment. Data on pretreatment and post-treatment (2-3 months after initiating sorafenib therapy, first tumor response evaluation day) clinical, laboratory, and tumor characteristics were collected. Survival-related prognostic factors were analyzed. RESULTS: Patients were mostly in the intermediate (12.2%) or advanced (87.8%) Barcelona Clinic Liver Cancer stages. Fifty-six (68.3%) patients had vascular invasion and 34 (41.5%) patients had extrahepatic disease. The median progression-free survival (PFS) and overall survival (OS) were 4.7 months [95% confidence interval (CI): 2.8-6.5 months] and 4.7 months (95% CI: 2.8-6.5 months). In multivariate analysis for OS, diarrhea (hazard ratio: 0.588; 95% CI: 0.348-0.993) and NLR decline (decreased compared with pretreatment) (hazard ratio: 0.479; 95% CI: 0.300-0.765) were independent factors of good OS. In the NLR decline group, the median PFS and OS were 7.1 and 7.3 months, respectively. In the NLR nondecline group, the median PFS and OS were 3.0 and 3.2 months, respectively. The difference in OS between the two groups was significant (P = 0.004). CONCLUSION: A change in NLR after sorafenib therapy was associated with a better prognosis in patients with advanced HCC.

A comparative study of sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function.

BACKGROUND/AIMS: Metronomic chemotherapy (MET) is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS) of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). METHODS: A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS. RESULTS: The median number of MET cycles was two (1-15). The OS values for the MET group and sorafenib group were 158 days (132-184) and 117 days (92-142), respectively (P=0.029). The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P=0.014) and Child-Pugh class B (HR=1.856, P=0.008). CONCLUSIONS: MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

New chemical treatment options in second-line hepatocellular carcinoma: what to do when sorafenib fails?

INTRODUCTION: There have been no therapies available for patients who experience disease progression after sorafenib treatment. Regorafenib inhibits multiple kinases involved in tumor proliferation and neoangiogenesis, which has produced a survival benefit in hepatocellular carcinoma (HCC) after sorafenib failure. Other active candidate agents are c-Met inhibitors and immune checkpoint inhibitors. Areas covered: This paper presents an updated summary of the preclinical and clinical experience with regorafenib, c-Met inhibitors (tivantinib, cabozantinib and tepotinib), and a checkpoint inhibitor (nivolumab, pembrolizumab) in HCC. The reported data were obtained from abstracts of international conferences and journal articles published up to August 2016 and found in a PubMed search. Expert opinion: Based on favorable data from preclinical and clinical trials, regorafenib, c-Met inhibitor, and checkpoint inhibitors are promising agents for HCC after sorafenib failure. However, further efforts to maximize the survival benefit and minimize adverse events of these drugs in the treatment of HCC are still necessary. Additionally, searching for predictors of good responders could allow these new drugs to be applied in personalized treatments of HCC.

Trends and Patterns of Hepatocellular Carcinoma Treatment in Korea.

Multiple therapeutic modalities are available for hepatocellular carcinoma (HCC) treatment. We aimed to evaluate the trends for HCC treatment in Korea. Recent trends and patterns in treatment modalities were assessed in HCC patients who first registered for the Health Insurance Review Assessment Service between 2008 and 2012. From 2009 to 2012, 57,690 patients were diagnosed with HCC. Transcatheter arterial chemoembolization (TACE) was the most common treatment modality for initial treatment. Curative treatment modalities like hepatic resection, liver transplantation, and local ablation therapy increased gradually. The 3 most common treatment modalities (hepatic resection, local ablation therapy, TACE) used after initial treatment in 2009 were studied. Following initial hepatic resection, 44.5% of patients required re-treatment. TACE was the most common modality (in 48.3% of cases), while 15.0% of patients received local ablation therapy. After local ablation therapy, 55.4% of patients were re-treated, wherein 45.0% of patients received TACE and 31.5% received local ablation therapy. Following initial TACE, 73.9% patients were re-treated, most commonly with TACE (57.7%) followed by local ablation therapy (12.8%). While there were no significant differences between the initial and re-treatment modalities, various multiple treatments followed the initial treatment. The treatment modalities were interchangeable.

Real-Life Experience of Sorafenib Treatment for Hepatocellular Carcinoma in Korea: From GIDEON Data.

PURPOSE: The purpose of this study is to report real life experiences of sorafenib therapy for hepatocellular carcinoma (HCC) in Korea, using a subset of data from GIDEON (Global Investigation of Therapeutic Decisions in HCC and of Its Treatment with Sorafenib; a large, prospective, observational study). MATERIALS AND METHODS: Between January 2009 and April 2012, a total of 497 patients were enrolled from 11 sites in Korea. Of these, 482 patients were evaluable for safety analyses. Case report forms of paper or electronic version were used to record safety and efficacy data from all patients. RESULTS: More patients of Child-Pugh A received sorafenib for > 8 weeks than did patients of Child-Pugh B (55.5% vs. 34.3%). Child-Pugh score did not appear to influence the starting dose of sorafenib, and approximately 70% of patients both in Child-Pugh A and B groups received the recommended initial daily dose of 800 mg (69.0% and 69.5%, respectively). The median overall survival (OS) and time to progression (TTP) were 8.5 months and 2.5 months. In Child-Pugh A patients, the median OS and TTP were 10.2 months and 2.5 months. The most frequent treatment-emergent drug-related adverse event was hand-foot skin reaction (31.7%), followed by diarrhea (18.0%). The incidence of treatment-emergent adverse events was similar in both Child-Pugh A (85.4%) and Child-Pugh B (84.8%) patients. CONCLUSION: Sorafenib was well tolerated by Korean HCC patients in clinical settings, and the safety profile did not appear to differ by Child-Pugh status. Survival benefit in Korean patients was in line with that of a previous pivotal phase III trial (SHARP).

Sorafenib in the treatment of recurrent hepatocellular carcinoma after liver transplantation: a report of four cases.

With an increasing number of patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT), tumor recurrence remains the main limiting factor for long-term survival. Although sorafenib is available for advanced HCC, there is still a lack of data on the use of sorafenib for treatment of recurrent HCC after LT. Here, we report on four cases of the use of sorafenib for treatment of recurrent HCC after LT. The median time of recurrence from LT was 4 months (range, 1-16 months). Two of the four evaluated patients showed stable disease, which was the best response and the duration of stabilization was 11 months and 5 months, respectively. One patient also experienced stable disease and remained in stable disease without sorafenib therapy for 29 months and the total duration of stabilization was 38 months. The remaining patient showed partial response but stopped treatment due to radiological tumor progression during treatment. Although all cases were high risk group for recurrence such as above Milan criteria, vascular invasion and tumor biology, clinical outcomes showed some good results. Therefore, sorafenib may be an acceptable treatment option for recurrent HCC after LT.

Transarterial chemoembolization using drug eluting beads for the treatment of hepatocellular carcinoma: Now and future.

Transarterial chemoembolization (TACE) using doxorubicin-eluting beads (DEBs) have been introduced as a novel device which ensures more sustained and tumor-selective drug delivery and permanent embolization compared to conventional TACE with lipiodol. Studies highlighting the use of TACE with DEBs for the treatment of hepatocellular carcinoma (HCC) have shown similar or better results compared to conventional TACE with lipiodol. TACE with DEBs is increasingly being performed interchangeably with conventional TACE. This review assessed the characteristics, clinical outcomes and future direction of TACE with DEBs compared to conventional TACE.

Clinical course of sorafenib treatment in patients with hepatocellular carcinoma.

OBJECTIVE: Sorafenib has been shown to improve survival of patients with advanced hepatocellular carcinoma (HCC). However, its tolerance in clinical practice has not been well evaluated, and whether sorafenib should be continued in cases of tumor progression or intolerance has not been established. The authors retrospectively assessed sorafenib tolerability, and evaluated the clinical course in patients who showed progression during sorafenib treatment. MATERIAL AND METHODS: Between March 2008 and July 2010, 80 patients with advanced HCC were treated with sorafenib. RESULTS: With a median of 78.5 days of treatment, 15% discontinued sorafenib due to adverse events. The duration was significantly longer in patients with Child-Pugh class A liver function (233 ± 240 days) than in those with Child-Pugh class B (100 ± 136 days; p = 0.006). The overall progression rate was 53% (43/80), with a median time to progression of 105 days (95% confidence interval, 59-150 days). After progression, 14 patients received conservative care only (group 1), 14 continued sorafenib monotherapy (group 2), 6 changed to treatment without sorafenib (group 3) and 9 underwent additional treatment with concomitant sorafenib (group 4). Survival after progression was significantly better in groups 2, 3 and 4 than in group 1 (p = 0.001). CONCLUSIONS: Sorafenib was tolerable for most patients in clinical practice and may be continued in patients who show progression during sorafenib therapy. However, it was less well tolerated in patients with Child-Pugh class B liver function and should be used with caution in these patients.

Sorafenib in liver cancer.

INTRODUCTION: With growing knowledge of the molecular pathway of carcinogenesis, targeted therapies have become the 'blue ocean' of cancer treatment. sorafenib is an oral multikinase inhibitor that targets Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) (Raf/MEK/ERK) and several tyrosine kinases (VEGFR-2, VEGFR-3, PDGFR-ß) that has shown efficacy in hepatocellular carcinoma (HCC). AREAS COVERED: An updated summary of the preclinical and clinical experience with sorafenib in HCC is presented in this paper. Data are based on abstracts from international conferences and journal articles found in a PubMed search of literature published up to December 2011. EXPERT OPINION: Based on favorable data from preclinical and clinical trials, sorafenib has been approved as a standard therapy in advanced HCC. However, further efforts to understand the additional roles of sorafenib in the treatment of HCC are still necessary. Data for sorafenib will guide the development of new drugs for the treatment of HCC.

Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy.

JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors.

A randomized comparative study of high-dose and low-dose hepatic arterial infusion chemotherapy for intractable, advanced hepatocellular carcinoma.

PURPOSE: Hepatic arterial infusion chemotherapy (HAIC) has been reported to be effective in patients with advanced hepatocellular carcinoma (HCC). METHODS: In this multicenter, prospective, open-labeled, clinical trial, we randomly assigned 68 patients with advanced HCC to receive either low-dose [n = 32, 5-fluorouracil (FU), 170 mg/m(2) and cisplatin, 7 mg/m(2) on days 1-5] or high-dose HAIC (n = 36, 5-FU, 500 mg/m(2) on days 1-3 and cisplatin, 60 mg/m(2) on day 2) every 4 weeks via an implantable port system. RESULTS: A total of 207 cycles of HAIC was given to the 68 patients. Overall, 6 patients (8.8%) achieved a partial response and 21 patients (30.9%) had stable disease. The objective response rate (CR + PR) was significantly improved in the high-dose group compared to the low-dose group (16.7% vs. 0%, P = 0.024). The median time to disease progression and overall survival were slightly prolonged in the high-dose group compared to the low-dose group (median survival, 193 vs. 153 days; P = 0.108; median time to disease progression, 145 vs. 90 days; P = 0.095). Multivariate analysis showed that tumor response to treatment [P = 0.007, RR 2.27 (95% CI, 1.248-4.132)] was the only factor associated with overall survival. All adverse events were tolerable and successfully managed in both treatment groups. CONCLUSIONS: Both HAIC regimens are safe and effective in patients with advanced HCC. High-dose HAIC achieves a better tumor response compared to low-dose HAIC.

A comparative study of high-dose hepatic arterial infusion chemotherapy and transarterial chemoembolization using doxorubicin for intractable, advanced hepatocellular carcinoma.

BACKGROUND/AIMS: Transarterial chemoembolization (TACE) has long been used as a palliative therapy for unresectable hepatocellular carcinoma (HCC). High-dose hepatic arterial infusion chemotherapy (HAIC) has showed favorable outcomes in patients with intractable, advanced HCC. The aim of this study was to compare the effectiveness and safety of high-dose HAIC and conventional TACE using doxorubicin for advanced HCC. METHODS: The high-dose HAIC group comprised 36 patients who were enrolled prospectively from six institutions. The enrollment criteria were good liver function, main portal vein invasion (including vascular shunt), infiltrative type, bilobar involvement, and/or refractory to prior conventional treatment (TACE, radiofrequency ablation, or percutaneous ethanol injection), and documented progressive disease. Patients received 5-fluorouracil (500 mg/m(2) on days 1~3) and cisplatin (60 mg/m(2) on day 2 every 4 weeks) via an implantable port system. In the TACE group, 31 patients with characteristics similar to those in the high-dose HAIC group were recruited retrospectively from a single center. Patients underwent a transarterial infusion of doxorubicin every 4~8 weeks. RESULTS: Overall, 6 patients (8.9%) achieved a partial response and 20 patients (29.8%) had stable disease. The objective response rate (complete response+partial response) was significantly better in the high-dose HAIC group than in the TACE group (16.7% vs. 0%, P=0.030). Overall survival was longer in the high-dose HAIC group than in the TACE group (median survival, 193 vs. 119 days; P=0.026). There were no serious adverse effects in the high-dose HAIC group, while hepatic complications occurred more often in the TACE group. CONCLUSIONS: High-dose HAIC appears to improve the tumor response and survival outcome compared to conventional TACE using doxorubicin in patients with intractable, advanced HCC.

The impact of hepatitis B viral load on recurrence after complete necrosis in patients with hepatocellular carcinoma who receive transarterial chemolipiodolization: implications for viral suppression to reduce the risk of cancer recurrence.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high tendency for recurrence after radical treatment. Apart from tumor and liver function parameters, little is known about the role of hepatitis B virus (HBV) factors in the recurrence of HCC. The objective of this study was to identify the potential relation between viral load and HCC recurrence in patients undergoing transarterial chemolipiodolization. METHODS: This was a cohort study of 62 consecutive patients who had HBV-related HCC and achieved complete necrosis with transarterial chemolipiodolization. Risk factors, including viral load for posttreatment recurrence, were analyzed. RESULTS: Overall, 32 of 62 patients (51.6%) developed a recurrence during the study period (7.2-37.5 months). Multivariate analysis established Child-Pugh Class B (P = .014), multiple tumors (P = .013), and high viral load (HBV DNA levels >10(5) copies/mL) at complete necrosis (P = .001) as independent risk factors for recurrence. On both univariate and multivariate analyses, high viral load at the time of complete necrosis was identified as the strongest factor for recurrence; moreover, its statistically significant effects still were observed even when conducting the analyses separately for both local recurrence (P = .018) and distant recurrence (P = .009). CONCLUSIONS: Among individuals who underwent transarterial chemolipiodolization, high HBV viral load at complete necrosis was among the most important risk factors for posttreatment recurrence, irrespective of the locational pattern of recurrence. The current findings underscored the need for future work that tests the applicability of antiviral therapy to reduce the risk of HCC recurrence in this setting.