Sorafenib versus nivolumab after lenvatinib treatment failure in patients with advanced hepatocellular carcinoma.

BACKGROUND AND AIM: An optimal sequential anti-hepatocellular carcinoma (HCC) agent that can be used after failed lenvatinib treatment has not been established. Here, we compared the outcomes of sorafenib and nivolumab as second-line agents after failed lenvatinib treatment in patients with advanced HCC. METHODS: Patients with advanced HCC who had received sorafenib or nivolumab as second-line agents after failed lenvatinib treatment were recruited from two Korean tertiary institutions between November 2018 and June 2020. RESULTS: The median age of the 60 participants (52 treated with sorafenib and eight treated with nivolumab) at baseline was 56.8 years. The demographic, laboratory and tumor variables, as well as lenvatinib treatment duration, were similar between the two groups. The median durations of sorafenib and nivolumab treatment were 1.2 and 2.6 months, respectively ( P = 0.164). Twenty-four (40.0%) patients died during the follow-up period (median, 15.8 months). The median overall survival (OS) of the study population was 5.8 months. The median OS of patients treated with sorafenib was significantly longer than the median OS of patients treated with nivolumab (8.7 vs. 3.0 months; P = 0.046). Sorafenib treatment (vs. nivolumab) was independently associated with a lower risk of mortality (hazard ratio = 0.194; 95% confidence interval, 0.053-0.708; P = 0.013). Worse Eastern Cooperative Oncology Group performance status, larger maximal tumor size, lymph node metastases and higher total bilirubin levels were independently associated with increased mortality risk (all P < 0.05). CONCLUSIONS: Lenvatinib-sorafenib sequential treatment resulted in significantly better survival did than lenvatinib-nivolumab sequential treatment in patients with advanced HCC. Larger studies are needed to validate our results.

New Evidence of Oral Branched-Chain Amino Acid Supplementation on the Prognosis of Patients With Advanced Liver Disease.

INTRODUCTION: Oral branched-chain amino acids (BCAAs) might benefit patients with advanced liver disease. We assess its effects on prognosis compared with control from the meta-analysis. METHODS: Study end points were development of hepatic encephalopathy (HE), hepatocellular carcinoma (HCC), mortality, and overall liver-related events (LREs). Risk ratios (RRs) and hazard ratios (HRs) were calculated using random effects model and heterogeneity using I 2 statistic. RESULTS: Twenty-eight studies were included in this meta-analysis; 1,578 and 1,727 patients in oral BCAAs and control groups, respectively. From studies using RRs as outcome measures, oral BCAAs were better in preventing HE and LRE than controls, with RRs 0.684 (95% confidence interval [CI] 0.497-0.941; P = 0.019) and 0.788 (95% CI 0.585-0.810; P < 0.001), respectively. Oral BCAAs had marginal effect on preventing HCC compared with control, with RR 0.791 (95% CI 0.619-1.011; P = 0.061); no significant difference in mortality was detected. From studies using HRs as outcome measures, oral BCAAs were superior to control in preventing LRE with adjusted HR 0.497 (95% CI 0.321-0.770; P = 0.002). In subgroups undergoing HCC resection, oral BCAAs had beneficial effect in preventing HE (RR 0.716, 95% CI 0.514-0.996; P = 0.047) and LRE (RR 0.716, 95% CI 0.595-0.860; P < 0.001). DISCUSSION: Oral BCAAs could afford clinical benefits in reducing HE and LRE risks, especially among patients undergoing HCC resection.

Co-administration of ursodeoxycholic acid with rosuvastatin/ezetimibe in a non-alcoholic fatty liver disease model.

Background: Ursodeoxycholic acid (UDCA), statins, and ezetimibe (EZE) have demonstrated beneficial effects against non-alcoholic fatty liver disease (NAFLD). We investigated the efficacy of the combination of UDCA and the mix of rosuvastatin (RSV)/EZE in the treatment of NAFLD. Methods: NAFLD mouse models were developed by injecting thioacetamide, fasting, and high-carbohydrate refeeding, high-fat diet, and choline-deficient L-amino acid-defined high-fat diet (CDAHFD). Low-dose UDCA (L-UDCA; 15 mg/kg) or high-dose UDCA (H-UDCA; 30 mg/kg) was administered with RSV/EZE. We also employed an in vitro model of NAFLD developed using palmitic acid-treated Hepa1c1c7 cells. Results: Co-administration of RSV/EZE with UDCA significantly decreased the collagen accumulation, serum alanine aminotransferase (ALT) levels, and mRNA levels of fibrosis-related markers than those observed in the vehicle group in thioacetamide-treated mice (all P < 0.01). In addition, in the group fasted and refed with a high-carbohydrate diet, UDCA/RSV/EZE treatment decreased the number of apoptotic cells and serum ALT levels compared with those observed in the vehicle group (all P < 0.05). Subsequently, H-UDCA/RSV/EZE treatment decreased the number of ballooned hepatocytes and stearoyl-CoA desaturase 1 (SCD-1) mRNA levels (P = 0.027) in the liver of high-fat diet-fed mice compared with those observed in the vehicle group. In the CDAHFD-fed mouse model, UDCA/RSV/EZE significantly attenuated collagen accumulation and fibrosis-related markers compared to those observed in the vehicle group (all P < 0.05). In addition, UDCA/RSV/EZE treatment significantly restored cell survival and decreased the protein levels of apoptosis-related markers compared to RSV/EZE treatment in palmitic acid-treated Hepa1c1c7 cells (all P < 0.05). Conclusion: Combination therapy involving UDCA and RSV/EZE may be a novel strategy for potent inhibition of NAFLD progression.

The effect of pharmacological treatment and lifestyle modification in patients with nonalcoholic fatty liver disease: An umbrella review of meta-analyses of randomized controlled trials.

Nonalcoholic fatty liver disease (NAFLD) is a liver disease that affects approximately 25% of the world's population, and various treatments have been applied for NAFLD patients. We compared the effectiveness of each intervention conducted to treat NAFLD by evaluating meta-analyses of pharmacological interventions and lifestyle modification including diet and exercise. We searched Pubmed/Medline, Embase, and Cochrane Library and included meta-analyses of randomized controlled trials investigating the effects of pharmacological intervention and lifestyle modification on NAFLD. The quality of included meta-analyses was evaluated by AMSTAR-2. If the effect size was expressed as mean difference, it was converted to standardized mean difference based on the random-effects model. A total of 1694 meta-analyses were identified, and 27 meta-analyses were eventually included in the review. Regarding pharmacological interventions, there was a high strength of evidence for the ALT reduction effect of silymarin on inactive controls (SMD = 0.88, p < 0.01, seven trials, 518 participants). Meanwhile, it was confirmed that appropriate diet and exercise were important in reducing liver fat (SMD = 1.51, p < 0.01, 12 trials, 765 participants). This umbrella review assessed the effects of pharmacological interventions and lifestyle modifications in the treatment of NAFLD. The results of this review can be utilized for clinical decisions when treating NAFLD patients.

Predictive Performance of CAGE-B and SAGE-B Models in Asian Treatment-Naive Patients Who Started Entecavir for Chronic Hepatitis B.

BACKGROUND & AIMS: Cirrhosis and age (CAGE-B) and stiffness and age (SAGE-B) models assess the risk of hepatocellular carcinoma (HCC) development in white patients with chronic hepatitis B (CHB) undergoing sustained antiviral therapy (AVT). Herein, we checked the predictive performance of these models in Asian patients with CHB. METHODS: We reviewed 734 treatment-naive patients with CHB who started entecavir between 2006 and 2011 and were followed up for more than 5 years without HCC development during AVT. The predictive performance of CAGE-B and SAGE-B models was calculated using area under the receiver operating characteristic curves (AUROCs). RESULTS: Median liver stiffness assessed using transient elastography after 5 years of AVT was 6.8 kPa. Median CAGE-B and SAGE-B models after 5 years of AVT were 7.0 and 6.0, respectively. More than 5 years after AVT initiation, 66 patients (9.0%) developed HCC. The AUROCs of the CAGE-B and SAGE-B models were 0.764 and 0.785 after 7 years and 0.799 and 0.802 after 10 years of AVT, respectively. The cumulative incidence of HCC was significantly higher in the high-risk groups according to CAGE-B and SAGE-B risk stratification than in the medium- and low-risk groups (P < .05 in all cases). The SAGE-B model showed a higher likelihood ratio (χ2) (76.2 vs 71.4) and linear trend (χ2) (74.1 vs 58.6) than the CAGE-B model, whereas the CAGE-B model showed higher Akaike information criteria (64.3 vs 50.3). CONCLUSIONS: Both SAGE-B and CAGE-B showed acceptable performance in predicting HCC after 5 years of AVT in Asian patients with CHB.

Treatment efficacy by hepatic arterial infusion chemotherapy vs. sorafenib after liver-directed concurrent chemoradiotherapy for advanced hepatocellular carcinoma.

BACKGROUND: We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC). METHODS: Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates. RESULTS: The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group. CONCLUSIONS: The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.

Lenvatinib is independently associated with the reduced risk of progressive disease when compared with sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: Recently, lenvatinib demonstrated non-inferiority to sorafenib in terms of overall survival (OS) in a randomized phase III study that was conducted at 154 sites in 20 countries. Here, we investigated treatment outcomes and safety of lenvatinib compared with sorafenib and identified independent predictors of poor outcomes, including shorter progression-free survival (PFS) and OS in Korean patients with unresectable hepatocellular carcinoma (HCC). METHODS: Patients with advanced HCC treated with lenvatinib or sorafenib at Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine between October 2018 to October 2019 were considered eligible. Response evaluation was performed according to the modified Response Evaluation Criteria in Solid Tumors. RESULTS: The lenvatinib arm had a significantly lower proportion of patients who received prior anti-HCC treatments (47.7% vs 78.7%; P < 0.001) than those in the sorafenib arm. Univariate analysis showed that ECOG 1 (vs 0), serum albumin, alpha-fetoprotein (AFP), previous anti-HCC treatments, and lenvatinib (vs sorafenib) were significant predictors of progressive disease (all P < 0.05). In the subsequent multivariate analysis, ECOG 1 (vs 0) (hazard ratio [HR] = 4.721, 95% confidence interval [CI] 1.371-16.259; P = 0.014), higher AFP level (HR = 1.000, 95% CI 1.000-1.000; P = 0.015), and lenvatinib treatment (vs sorafenib) (HR = 0.461, 95% CI 0.264-0.804; P = 0.006) independently predicted a higher probability of progressive disease. CONCLUSIONS: Patients treated with lenvatinib demonstrated significantly longer PFS than those treated with sorafenib. Furthermore, no significant differences were observed in mortality rates between the two groups, which indicated that lenvatinib is non-inferior to sorafenib in terms of OS.

Efficacy and Safety of Liver-Directed Concurrent Chemoradiotherapy and Sequential Sorafenib for Advanced Hepatocellular Carcinoma: A Prospective Phase 2 Trial.

PURPOSE: Although sorafenib as a standard of care for advanced hepatocellular carcinoma (HCC) prolongs overall survival (OS), its efficacy is limited owing to its unsatisfactory objective response and marginal survival benefit. To counter these limitations, we designed a single-arm, phase II trial with liver-directed concurrent chemoradiotherapy (LD-CCRT) and sequential sorafenib treatment in patients with advanced HCC. METHODS AND MATERIALS: We enrolled advanced HCC patients diagnosed between 2014 and 2017 who were ineligible for curative treatment. During the first and last 5 days of 5-week radiation therapy, concurrent hepatic arterial infusion with 5-fluorouracil (500 mg/d) and leucovorin (50 mg/d) through an implanted port was administered 4 weeks after initiation of LD-CCRT and sequential sorafenib treatment (400 mg, twice daily). The primary endpoint was OS. This trial has been registered at clinicaltrials.gov. RESULTS: Among the enrolled patients (n = 47), objective response rates 4 weeks after LD-CCRT and during/up to sorafenib maintenance were 44.7% and 53.2%, respectively. Overall, 9 patients (19.1%) underwent curative resection or transplantation after down staging. The median radiation dose was 60 Gy. The median OS was 24.6 months for the entire cohort and 13.0 months for the subgroup with tumor invasion into the main portal trunk or its first branch, whereas the median progression-free survival for the cohort and subgroup was 6.8 and 5.6 months, respectively. The most frequent treatment-related adverse events were diarrhea (36.2%) and hand-foot skin reaction (34%), which were manageable with conservative treatment. CONCLUSIONS: LD-CCRT and sequential sorafenib treatment provided favorable OS and progression-free survival with good tolerability. Tumor reduction using an initial LD-CCRT enabled down staging, subsequent curative treatment, and long-term survival in about 20% of the patients with advanced HCC. However, further randomized trials are required to confirm these results.

A survey on transarterial chemoembolization refractoriness and a real-world treatment pattern for hepatocellular carcinoma in Korea.

BACKGROUND/AIMS: Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC), but there is much controversy about TACE refractoriness. The aim of this study was to identify trends in the actual clinical application of TACE and recognition of TACE refractoriness by Korean experts. METHODS: In total, 17 questionnaires on TACE refractoriness were administered to 161 clinicians via an online survey. Multiple answers were allowed for some questions. RESULTS: Most clinicians agreed that there is a need for standardization of TACE application through specific scoring systems (n=124, 77.0%). TACE refractoriness was predominantly expected by participants when recurrences were detected within 1 month (n=70, 43.5%), there were 4 to 6 tumors (n=77, 47.8%), the maximal tumor size was 3-5 cm (n=49, 30.4%), and when there was insufficient tumor necrosis despite TACE being repeated more than three times (n=78, 48.4%). Overall, sorafenib therapy (n=137) and radiotherapy (n=114) were preferred when repeated TACE was considered ineffective. CONCLUSION: Treatment of HCC is often based on the clinical judgment of clinicians because of the heterogeneity among individuals. Experts need to continue discussions on the standardization and sub-classification of HCC treatment guidelines in Korea.

Transarterial Chemoembolization in Treatment-Naïve and Recurrent Hepatocellular Carcinoma: A Propensity-Matched Outcome Analysis.

OBJECTIVES: Transarterial chemoembolization (TACE) improves the survival of patients with hepatocellular carcinoma (HCC); however, TACE treatment outcomes of patients with treatment-naïve HCC (TN-HCC) and those with recurrent HCC after curative resection (R-HCC) have not yet been compared. METHODS: We recruited 448 patients with TN-HCC, and 275 patients with R-HCC treated with TACE as first-line anti-cancer treatment. RESULTS: At first TACE, patients with TN-HCC showed a significantly lower proportion of male gender (74.9% vs. 84.3%), higher proportion of liver cirrhosis (61.9% vs. 49.3%), higher aspartate aminotransferase (median 48 vs. 31 IU/L), alanine aminotransferase (median 38 vs. 26 IU/L), alpha-fetoprotein (AFP) (median 96.6 vs. 7.7 ng/mL), and total bilirubin (mean 1.0 vs. 0.8 mg/dL) levels, longer prothrombin time (median 1.05 vs. 1.01 international normalized ratio), higher tumor number (mean 2.1 vs. 1.7), larger tumor size (median 3.1 vs. 1.6 cm), and lower proportion of Barcelona Clinic Liver Cancer stage 0-A (55.6% vs. 71.9%) than patients with R-HCC (all P < 0.05). Multivariate analysis showed that TACE for TN-HCC (vs. R-HCC) was an independent predictor of mortality (hazard ratio, 1.328; P = 0.024) with AFP level and tumor number (all P < 0.05). However, treatment outcomes between TN-HCC and R-HCC became statistically similar after propensity score-matched (PSM) analysis using liver cirrhosis, tumor size, and multiple tumors (P < 0.05). CONCLUSIONS: Based on the similar TACE treatment outcomes observed with the PSM analysis, the current TACE treatment guideline for patients with TN-HCC might similarly be applied for patients with R-HCC.

Reproducibility of European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients treated with sorafenib.

BACKGROUND & AIMS: The European Association for the Study of the Liver criteria and the modified Response Evaluation Criteria in Solid Tumors are used for assessing the treatment outcomes of hepatocellular carcinoma. We investigated the inter- and intra-observer reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients with advanced hepatocellular carcinoma treated with sorafenib. METHODS: A total of 99 patients with treatment-naive advanced hepatocellular carcinoma receiving sorafenib were included. The κ-values for the inter- and intra-observer agreement of the treatment response were calculated. RESULTS: Inter-observer agreement for baseline tumour number was excellent, as reflected by the high κ-value. The κ-statistics showed "excellent" concordance between the 2 sets of measurements by observer A regarding the overall responses using the European Association for the Study of the Liver criteria (κ = .948, agreement rate = 84.8%) and modified Response Evaluation Criteria in Solid Tumors (κ = .944, agreement rate = 83.8%; all P < .001). In addition, high κ-values indicated concordance between the first sets of measurements by observers A and B (κ = .991 by the European Association for the Study of the Liver criteria and .988 by modified Response Evaluation Criteria in Solid Tumors, all P < .001). When agreements in radiological overall responses between the 2 sets of measurements by observer B and between the second sets of measurements by observers A and B were calculated, similar results regarding high κ-values (>.8) were obtained. CONCLUSIONS: The reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in assessing treatment outcomes was high in patients with advanced hepatocellular carcinoma treated with sorafenib.

Prognostic factors of sorafenib therapy in hepatocellular carcinoma patients with failure of transarterial chemoembolization.

BACKGROUND: There is no approved therapy for patients with failed transarterial chemoembolization (TACE) and progression of hepatocellular carcinoma. We aimed to investigate the efficacy and prognostic factors in patients with TACE failure who received sorafenib rescue therapy. METHODS: We investigated 54 patients who met the criteria of TACE failure as defined by the international guidelines of Europe and Japan. Sorafenib was used as a rescue therapy. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier methods, and multivariate analysis was performed to find prognostic factors. RESULTS: The patients were followed for a median 5.5 months, and the median duration of sorafenib administration was 3.3 months. The presence of main (or lobar) portal vein invasion (PVI) (3.7 versus 8.4 months, p = 0.004), dose reduction of sorafenib (4.0 versus 8.8 months, p = 0.002) and Child-Pugh class B (5.3 versus 8.9 months, p = 0.004) were associated with shorter OS compared to the presence of segmental PVI (or absence of macroscopic vascular invasion, MVI), full dosage of sorafenib and Child-Pugh class A, respectively. The presence of main (or lobar) PVI was associated with poorer PFS compared to the presence of segmental PVI (or absence of MVI) (2.1 versus 3.8 months p = 0.010). CONCLUSIONS: Sorafenib is a potential rescue therapy in patients with TACE failure. However, the clinical benefits need to be further evaluated for patients with main (or lobar) PVI or those treated with reduced doses of sorafenib.

Substitution at rt269 in Hepatitis B Virus Polymerase Is a Compensatory Mutation Associated with Multi-Drug Resistance.

The emergence of compensatory mutations in the polymerase gene of drug resistant hepatitis B virus (HBV) is associated with treatment failure. We previously identified a multi-drug resistant HBV mutant, which displayed resistance towards lamivudine (LMV), clevudine (CLV), and entecavir (ETV), along with a strong replication capacity. The aim of this study was to identify the previously unknown compensatory mutations, and to determine the clinical relevance of this mutation during antiviral therapy. In vitro mutagenesis, drug susceptibility assay, and molecular modeling studies were performed. The rtL269I substitution conferred 2- to 7-fold higher replication capacity in the wild-type (WT) or YMDD mutation backbone, regardless of drug treatment. The rtL269I substitution alone did not confer resistance to LMV, ETV, adefovir (ADV), or tenofovir (TDF). However, upon combination with YMDD mutation, the replication capacity under LMV or ETV treatment was enhanced by several folds. Molecular modeling studies suggested that the rtL269I substitution affects template binding, which may eventually lead to the enhanced activity of rtI269-HBV polymerase in both WT virus and YMDD mutant. The clinical relevance of the rtL269I substitution was validated by its emergence in association with YMDD mutation in chronic hepatitis B (CHB) patients with sub-optimal response or treatment failure to LMV or CLV. Our study suggests that substitution at rt269 in HBV polymerase is associated with multi-drug resistance, which may serve as a novel compensatory mutation for replication-defective multi-drug resistant HBV.

Clinical outcomes and prognostic factors of patients with advanced hepatocellular carcinoma treated with sorafenib as first-line therapy: a Korean multicenter study.

BACKGROUND AND AIM: Sorafenib is recommended as a standard treatment for advanced hepatocellular carcinoma (HCC). The efficacy and safety of sorafenib as a first-line therapy in Korean patients with advanced HCC were investigated. METHODS: From 2007 to 2012, 86 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) treated with sorafenib as a first-line therapy were enrolled from five tertiary hospitals. Predictors of overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS: The median age was 59.5 years, and 71 (82.6%) were males; 57 (66.3%) patients were in Child-Pugh class A. The median OS and PFS were 5.0 (range 4.0-5.9) and 3.2 (range 2.6-3.7) months, respectively. Regarding OS, Child-Pugh class A (6.0 vs 2.8 months), tumor diameter < 5 cm (6.0 vs 4.3 months), baseline α-fetoprotein < 200 ng/mL (5.8 vs 4.1 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (5.9 vs 4.0 months) were independent favorable predictors (all P < 0.05). Similarly, regarding PFS, Child-Pugh class A (4.3 vs 2.1 months), tumor diameter < 5 cm (3.9 vs 2.8 months), baseline α-fetoprotein < 200 ng/mL (5.6 vs 2.8 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (4.5 vs 2.6 months) were independent favorable predictors (all P < 0.05). All toxicities during sorafenib treatment were manageable. CONCLUSIONS: Because the efficacy of sorafenib seems marginal in Korean patients with treatment-naïve HCC, how to select candidates with favorable outcomes should be further investigated.

Efficacy of sorafenib monotherapy versus sorafenib-based loco-regional treatments in advanced hepatocellular carcinoma.

BACKGROUND: Although sorafenib is accepted as the standard of care in advanced hepatocellular carcinoma (HCC), its therapeutic benefit is marginal. Here, we aimed to compare the efficacy and safety of sorafenib monotherapy (S-M) and sorafenib-based loco-regional treatments (S-LRTs) in advanced HCC. METHODS: From 2007 to 2012, 290 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) with S-M (n = 226) or S-LRTs (n = 64) were reviewed retrospectively. Survival outcomes and treatment-related toxicities between two groups were analyzed. RESULTS: Variables related to tumor burden and liver function were similar between the groups (all P > 0.05). Within the entire population, the S-LRTs group had both longer median overall survival (OS) (8.5 vs 5.5 months, P = 0.001) and progression-free survival (PFS) (5.3 vs 3.0 months, P = 0.002) than the S-M group. Furthermore, the S-LRTs group had longer Os than the S-M group in a subgroup with neither extrahepatic spread (EHS) nor regional nodal involvement (RNI) (18.0 vs 7.8 months, P = 0.019) and in a subgroup with EHS and/or RNI (8.3 vs 4.8 months, P = 0.028). In addition, the S-LRTs group had longer PFS than the S-M group in the subgroup with neither EHS nor RNI (9.6 vs 3.2 months, P = 0.027). TREATMENT: Related toxicity was similar between two groups. CONCLUSION: Combined use of sorafenib and LRTs may provide better treatment outcomes without significantly increasing treatment-related toxicities, even in patients with EHS and/or RNI. Therefore, addition of active LRTs might be considered, if feasible.

Applicability of BCLC stage for prognostic stratification in comparison with other staging systems: single centre experience from long-term clinical outcomes of 1717 treatment-naïve patients with hepatocellular carcinoma.

BACKGROUND: The most informative staging system regarding survival outcomes for treatment-naïve hepatocellular carcinoma (HCC) remains debated. We evaluated prognostic values of Barcelona Clinic Liver Cancer (BCLC) stage compared with other staging systems, and identified discrepancies between treatment options chosen in Korean clinical practice and BCLC guidelines. METHODS: Between 2003 and 2008, 1717 prospectively enrolled patients with treatment-naïve HCC were analysed. Prognostic ability of each staging system was assessed using time-dependent receiver-operating characteristic (ROC) curves. RESULTS: The most common aetiology was hepatitis B virus (1238, 72.1%); 167 (9.8%) patients were classified as BCLC stage 0, 526 (30.6%) as A, 333 (19.4%) as B, 608 (35.4%) as C and 83 (4.8%) as D. Median overall survival was 22.5 months, and 1-, 2-, 3-, 4-, and 5-year survival rates were 62.6, 48.3, 39.9, 34.7, and 29.3% respectively. Of six staging systems, BCLC had the highest area under ROC (AUROC; 0.821) for overall survival, followed by JIS (0.809), Tokyo score (0.771), CLIP (0.746), CUPI (0.701) and GRETCH (0.685) system. In both subgroups stratified according to treatment strategy (curative vs. palliative), BCLC also showed the best AUROCs (curative, 0.708/palliative, 0.807) for overall survival. Regarding discrepancies between treatment options chosen in our cohort and BCLC guidelines, more than half with very early/early-stage HCC underwent transarterial chemoembolization, rather than resection or local ablative therapy; most of those with advanced-stage HCC received intra-arterial chemotherapy-based treatments rather than sorafenib. CONCLUSION: BCLC was the best long-term prognostic model for treatment-naïve HCC in a large-scale Korean cohort. However, treatment modalities did not exactly match BCLC paradigm.