Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma.

BACKGROUND: Lenvatinib combined with pembrolizumab showed a promising result in an early phase study for hepatocellular carcinoma (HCC). The efficacy and safety of lenvatinib plus pembrolizumab for patients with unresectable HCC (uHCC) beyond the first-line setting were unclear. METHODS: Seventy-one consecutive patients who received lenvatinib plus pembrolizumab for uHCC were prospectively enrolled. Effect of lenvatinib combinations on Albumin-Bilirubin (ALBI) score and factors associated with progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: Of the 71 cases, 58 (81.7%) were in BCLC C. There were 44 (62%) for the first-line systemic treatment, and 27 (38%) had experienced targeted therapy or nivolumab treatment. The objective response rate and disease control rate (DCR) were 34.1% and 84.1% for the first-line setting, and 18.5% and 70.4% for systemic therapy-experienced cases (Response Evaluation Criteria in Solid Tumors version 1.1, RECIST v1.1), respectively. The mean ALBI score was stable during the treatment course. After a median of 9.3 months of follow-up, the median PFS was 9.3 months versus 4.4 months, and the median OS was not estimable yet versus 12 months for Child-Pugh A versus B patients, respectively. Prior nivolumab failure was the only significant factor associated with poorer PFS (HR = 3.253, p = 0.004). Child-Pugh class B (HR = 2.646, p = 0.039) and prior nivolumab failure (HR = 3.340, p = 0.014) were independent factors for poorer OS in multivariate analysis. CONCLUSIONS: A high DCR was observed by lenvatinib/pembrolizumab combination without adverse effect on ALBI score for systemic therapy-naïve and -experienced uHCC. Suboptimal response to prior nivolumab-failed patients requires further exploration.

Radiological features and outcomes of combined hepatocellular-cholangiocarcinoma in patients undergoing surgical resection.

BACKGROUND/PURPOSE: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer. Preoperative diagnosis of cHCC-CCA is difficult, and outcome of cHCC-CCA is obscured. Our study aimed to investigate the clinicopathological and radiological features of cHCC-CCA and compare their outcomes with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS: From August 2010 to December 2017, 891 patients undergoing liver tumor resection in Taipei Veterans General Hospital, including 30 patients with pathology-proven cHCC-CCA, 819 HCC, and 42 ICC were retrospectively reviewed. Radiological features of contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) in patients with cHCC-CCA were reevaluated by a radiologist. Factors association with disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: The mean age of cHCC-CCA, HCC and ICC was similar. Hepatitis B virus infection was prevalent in patients with cHCC-CCA (22/30, 73.3%). Most (70%) of the cHCC-CCA had atypical radiological pattern of HCC and belonged to classic type in pathological features. cHCC-CCA and ICC had worse DFS, but the 5-year OS of cHCC-CCA was substantial adequate after surgery. Of the 891 patients, male gender, advanced T stage, multiple tumor number, alpha-fetoprotein (AFP) level >20 ng/ml, cHCC-CCA, and ICC were factors associated with poor DFS in multivariable analysis. Older age, T stage 3 or 4, presence of macrovascular invasion, AFP >20 ng/mL, cHCC-CCA, and ICC were factors significantly associated with OS. CONCLUSION: cHCC-CCA is associated with high risk of recurrence following surgical resection as compared with HCC. Closely post-operative monitoring is highly recommended.

Analyzing risk factors and developing a stratification system for hepatocellular carcinoma recurrence after interferon-free direct-acting antiviral therapy in chronic hepatitis C patients.

BACKGROUND: The introduction of direct-acting antiviral agents (DAAs) has revolutionized the therapeutic landscape of chronic hepatitis C (CHC), however real-world data on the risk factors of hepatocellular carcinoma (HCC) recurrence following DAA treatment in CHC-HCC patients are limited in Taiwan. We aimed to evaluate the therapeutic efficacy of DAAs in Taiwanese patients with prior hepatitis C virus (HCV)-induced HCC and identify the posttreatment risk factors for HCC recurrence. METHODS: Between January 2017 and August 2021, 208 CHC-HCC patients underwent DAA treatment at Taipei Veterans General Hospital. Among them, 94 patients met the inclusion criteria (Barcelona clinic liver cancer [BCLC] stage 0/A after treatment with complete radiological response) for analysis. Comprehensive demographic, clinical, and laboratory data were collected before and after DAA treatment. The primary outcome was HCC recurrence post-DAA treatment, and independent variables were assessed using multivariate Cox proportional hazards models. RESULTS: The mean age of the enrolled patients was 75.9 ± 8.9 years; 44.7% were male, and 94.7% were Child-Pugh class A. Before DAA treatment, 31.9% experienced HCC recurrence. The median follow-up after DAA treatment was 22.1 months (interquartile range, 8.6-35.9 months). After treatment, 95.7% of the patients achieved a sustained virological response (SVR 12 ), but HCC recurrence occurred in 54.3%. Cumulative HCC recurrence rates after treatment were 31.1% at 1 year, 57.3% at 3 years, and 68.5% at up to 5.69 years. Multivariate analysis revealed that prior HCC recurrence before DAA treatment (hazard ratio [HR] = 3.15, p = 0.001), no SVR 12 after treatment (HR = 6.829, p = 0.016), 12-week posttreatment alpha-fetoprotein (AFP) level >10 ng/mL (HR = 2.34, p = 0.036), and BCLC A3 lesions (two or three nodules without any tumor exceeding 3 cm) (HR = 2.31, p = 0.039) were independent risk factors for HCC recurrence. We further developed a risk stratification system based on these significant independent factors. CONCLUSION: This investigation underscores the critical influence of factors such as prior HCC recurrence, successful attainment of SVR 12 , posttreatment AFP level, and specific tumor characteristics in determining the risk of HCC recurrence after treatment with DAAs. Our proposed innovative risk stratification system may not only contribute to enhanced personalized care but also holds the potential to optimize treatment outcomes.

Radiologic Patterns Determine the Outcomes of Initial and Subsequent Transarterial Chemoembolization in Intermediate-Stage Hepatocellular Carcinoma.

Introduction: Outcomes of transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (HCC) are diverse because of the heterogeneity of tumor burden. Radiologic pattern is one criterion for determining whether TACE is unsuitable. However, additional evidence is required. This study determined the influence of radiologic morphology on the outcomes of initial and subsequent TACE. Methods: From January 2007 to September 2021, 633 treatment-naive patients with HCC with intermediate-stage HCC undergoing TACE were retrospectively enrolled. Of these patients, 386 patients received repeated TACE. The radiological features of HCC were evaluated by two radiologists and classified into encapsulated nodular type, simple nodular type with extranodular growth, confluent multinodular type, and infiltrative type. The objective response rate (ORR) and survival rate after initial and subsequent TACE among various radiologic morphologies were compared. Results: After initial TACE, encapsulated nodular type HCC had the highest ORR (58%), followed by extranodular type (45.8%), confluent multinodular type (29%), and infiltrative type (19.5%). Notably, radiologic pattern was highly associated with tumor burden. Tumor burden and radiologic morphology were significantly associated with ORR and overall survival (OS) in the multivariate analysis. In 386 patients with subsequent TACE, encapsulated nodular type HCC had the highest ORR (48.7%), followed by extranodular type (37.3%), confluent multinodular type (26.2%), and infiltrative type (10%). In the multivariate analysis, radiologic features were significant independent predictors of ORR and OS after receiving subsequent TACE. Conclusion: Radiologic patterns determine the outcomes of initial and subsequent TACE. Systemic therapy should be considered for patients with intermediate-stage HCC with unfavorable radiologic patterns.

Determinants of Survival and Post-Progression Outcomes by Sorafenib-Regorafenib Sequencing for Unresectable Hepatocellular Carcinoma.

The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure.

Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are promising agents for unresectable hepatocellular carcinoma (uHCC), but lack effective biomarker to predict outcomes. The gut microbiome can modulate tumor response to immunotherapy, but its effect on HCC remains unclear. METHODS: From May 2018 to February 2020, patients receiving ICI treatment for uHCC were prospectively enrolled; their fecal samples were collected before treatment. The fecal microbiota and metabolites were analyzed from 20 patients with radiology-proven objective responses (OR) and 21 randomly selected patients with progressive disease (PD). After March 2020, 33 consecutive Child-Pugh-A patients were recruited as a validation cohort. Additionally, feces from 17 healthy volunteers were collected for comparison of background microbes. RESULTS: A significant dissimilarity was observed in fecal bacteria between patients with OR and patients with PD before immunotherapy. Prevotella 9 was enriched in patients with PD, whereas Lachnoclostridium, Lachnospiraceae, and Veillonella were predominant in patients with OR. Ursodeoxycholic acid and ursocholic acid were significantly enriched in the feces of patients with OR and strongly correlated with the abundance of Lachnoclostridium. The coexistence of Lachnoclostridium enrichment and Prevotella 9 depletion significantly predicted better overall survival (OS). In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p<0.001). CONCLUSIONS: Fecal microbiota and bile acids were associated with outcomes of immunotherapy for uHCC. These findings highlight the potential role of gut microbiota and metabolites as biomarkers to predict outcomes of ICI-treated HCC.

Application and Impact of Antiviral Therapy for Patients with HBV-Related Hepatocellular Carcinoma Receiving Sorafenib and Lenvatinib Treatment.

Overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) has improved in the era of multi-line sequential therapy. The application of antiviral therapy and its impact on survival for patients with HBV-related HCC needs to be reassessed. The aim of this study was to evaluate the application and impact of antiviral therapy on survival for patients with HBV-related HCC receiving tyrosine kinase inhibitor (TKI) therapy. Patients with advanced HBV-related HCC treated with sorafenib or lenvatinib as first-line therapy with (n = 377) and without (n = 182) nucleos(t)ide analogue (NUC) therapy were retrospectively enrolled. Prognostic factors of OS were evaluated. Secular trends in the increased application of NUC therapy and improved survival were observed in the last decade. The HBV reactivation rate in patients without NUC therapy was 6.6%. By multivariate analysis, baseline low HBV viral load, achieving undetectable HBV DNA after TKI therapy, and ability to receive second-line therapy were found to be independent predictors of OS. In subgroup patients with NUC therapy, starting NUC before TKI was associated with a better OS. In conclusion, the application of antiviral therapy for patients with HBV-related HCC receiving TKI therapy has increased over time. Achieving complete virological suppression may contribute to a better OS in patients with advanced HBV-related HCC.

Direct-acting antivirals for patients with chronic hepatitis C and hepatocellular carcinoma in Taiwan.

BACKGROUND/PURPOSE: The treatment of chronic hepatitis C (CHC) has evolved from interferon (IFN)-based therapy to direct acting antivirals (DAAs). The effect of antiviral treatment on outcome of hepatocellular carcinoma (HCC) patients with CHC has not been well analyzed in Taiwan. METHODS: From April 2015 to May 2018, 199 HCC patients with CHC undergoing DAAs treatment, including 127 having prospectively longitudinal observation, were enrolled. Among them, 107 BCLC 0/A patients achieving curative treatment of HCC were further compared with a historical cohort of 42 HCC patients experienced pegylated interferon (Peg-IFN) plus ribavirin for CHC after curative treatment. RESULTS: The sustained virological response (SVR) rates were 95.0% in BCLC stage 0/A (114/120), 97.1% in BCLC B (68/70), and 77.8% in BCLC C (7/9). The median recurrence-free survivals (RFS) between the DAA and IFN arms were of no difference by counting either from antiviral treatment (29.3 mo vs 39.2 mo, p = 0.764) or from curative treatment (65.8 mo vs 44.0 mo, p = 0.130), respectively. Achievement of SVR was the key independent factor associated with RFS and overall survival. The pattern of recurrence was also similar between the DAA and IFN arms. For intermediate stage HCC patients, the median time to tumor progression was 9.2 months from the initiation of DAA therapy, and 90% of patients maintained in BCLC B till 12 months after the DAA treatment. CONCLUSIONS: The SVR is high within BCLC B HCV-HCC patients by DAAs treatment. The risk of HCC recurrence and progression is not increased by DAAs.

Redefining Tumor Burden in Patients with Intermediate-Stage Hepatocellular Carcinoma: The Seven-Eleven Criteria.

BACKGROUND AND AIMS: For patients with intermediate-stage hepatocellular carcinoma (HCC), the definition of high tumor burden remains controversial. This study aimed to compare the prognostic value of different criteria of tumor burden in patients with intermediate-stage HCC undergoing transarterial chemoembolization (TACE). METHODS: From 2007 to 2019, 632 treatment-naive patients with intermediate-stage HCC undergoing TACE were retrospectively enrolled. We compared different criteria of tumor burden in discriminating radiologic response and survival, including up-to-7, up-to-11, 5-7, 7 lesions criteria, and newly proposed 7-11 criteria. RESULTS: The proportions of patients classified as high tumor burden were varied by different criteria. Among the 5 criteria, 7-11 criteria have the best performance to discriminate complete response (CR) and overall survival (OS) after TACE. In patients with low, intermediate, and high tumor burden classified by 7-11 criteria, the CR rate was 21, 12, and 2.5%, respectively (p < 0.001), and the median OS was 33.1, 22.3, and 11.9 months, respectively (p < 0.001). By multivariate analysis, 7-11 criteria were significantly associated with CR (intermediate vs. high burden, odds ratio = 4.617, p = 0.002; low vs. high burden, odds ratio = 8.675, p < 0.001) and OS (intermediate vs. high burden, hazard ratio = 0.650, p < 0.001; low vs. high burden, hazard ratio = 0.520, p < 0.001). Seven to 11 criteria also had the lowest corrected Akaike information criteria, highest homogeneity value, and highest area under the receiver operating characteristic curve in predicting 1-, 2-, and 3-year mortality among all criteria. CONCLUSION: Conventional definitions of tumor burden were not optimal for patients with intermediate HCC. The new 7-11 criteria had the best discriminative power in predicting radiologic response and survival in patients with intermediate-stage HCC undergoing TACE.

Effect of Transarterial Chemoembolization on ALBI Grade in Intermediate-Stage Hepatocellular Carcinoma: Criteria for Unsuitable Cases Selection.

Transarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC). We aimed to identify unsuitable cases who were at risk of ALBI-grade migration by TACE. Consecutive 531 BCLC-B HCC patients undergoing TACE were reviewed, and factors associated with ALBI-grade migration were analyzed. There were 129 (24.3%) patients experienced acute ALBI-grade migration after TACE, and 85 (65.9%) out of the 129 patients had chronic ALBI-grade migration. Incidences of acute ALBI-grade migration were 13.9%, 29.0% for patients within or beyond up-to-7 criteria (p < 0.001) and 20.0%, 36.2% for patients within or beyond up-to-11 criteria (p < 0.001), respectively. HBV infection, tumor size plus tumor number criteria were risk factors associated with acute ALBI-grade migration. Bilobar tumor involvement was the risk factor of chronic ALBI-grade migration in patients with acute ALBI-grade migration. Up-to-eleven (p = 0.007) performed better than up-to-seven (p = 0.146) to differentiate risk of dynamic ALBI score changes. Moreover, ALBI-grade migration to grade 3 has adverse effect on survival. In conclusion, tumor burden beyond up-to-eleven was associated with ALBI-grade migration after TACE, indicating that up-to-eleven can select TACE-unsuitable HCC patients who are at risk of liver function deterioration.

Comparable benefits of HCV eradication by direct acting antivirals and interferon-based therapy in patients with hepatocellular carcinoma undergoing surgical resection.

Whether direct-acting antivirals (DAA) provide comparable survival benefit with interferon (IFN)-based therapy remains unclear. The aim of this study was to compare the outcomes after achieving SVR by IFN-based and DAA therapy after resection of HCV-related hepatocellular carcinoma (HCC). Consecutive 285 patients receiving curative resection for HCV-related HCC were retrospectively enrolled, including 103 (36.1%) and 69 (24.2%) patients with IFN-based and DAA therapy, respectively. Factors associated with recurrence, overall survival (OS) and hepatic decompensation-free survival were evaluated. The SVR rate of DAA was 95.7% in HCC patients. During a median follow-up period of 49.6 months, 102 (35.8%) patients died and 63 (24%) developed hepatic decompensation. By multivariate analysis, SVR by DAA or IFN-based therapy was not associated with early or late HCC recurrence. Achieving SVR (by IFN-based therapy: HR=0.321, P<0.001; by DAA: HR=0.396, P=0.011), BCLC stage B-C (HR=1.914, P=0.024), FIB-4 score >3.25 (HR=1.664, P=0.016) and microvascular invasion (HR=1.603, P=0.048) were independent predictors of OS. Achieving SVR (by IFN-based therapy: HR=0.295, P<0.001; by DAA: HR=0.193, P=0.002), BCLC stage B-C (HR=2.975, P=0.001), GGT >70 U/L (HR=1.931, P=0.015) and cirrhosis (HR=2.035, P=0.007) were independent predictors of decompensation-free survival. The benefit of achieving SVR was consistently observed in cirrhotic and non-cirrhotic patients, and in patients with and without HCC recurrence. In conclusion, achieving SVR by either DAA or IFN-based therapy provide comparable and significant reduction of mortality and hepatic decompensation after surgical resection of HCV-related HCC. DAA therapy should be prescribed for all HCC patients after curative surgical resection.