Impact of Early Lenvatinib Administration on Survival in Patients with Intermediate-Stage Hepatocellular Carcinoma: A Multicenter, Inverse Probability Weighting Analysis.

AIM/BACKGROUND: Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage hepatocellular carcinoma (HCC). In this study, we investigated the impact of early lenvatinib administration in patients with intermediate-stage HCC, especially those with tumors beyond the up-to-7 criteria. MATERIALS/METHODS: A total of 208 patients with intermediate-stage HCC whose initial treatment was early lenvatinib administration or TACE were enrolled. Multivariate overall survival analysis was performed in this cohort. In addition, the impact of early lenvatinib administration on survival in patients with HCC beyond the up-to-7 criteria was clarified using inverse probability weighting (IPW) analysis. RESULTS: The overall cumulative survival rates at 6, 12, 18, and 24 months were 94.4, 79.9, 65.8, and 50.1%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that HCC treatment with lenvatinib (hazard ratio [HR], 0.199; 95% confidence interval [CI], 0.077-0.517; p < 0.001), α-fetoprotein ≥100 ng/mL (HR, 1.687), Child-Pugh class B disease (HR, 1.825), and beyond the up-to-7 criteria (HR, 2.016) were independently associated with overall survival. The 6-, 12-, 18-, and 24-month cumulative survival rates were 96.0, 90.4, 65.7, and 65.7%, respectively, in patients treated with lenvatinib, and 94.1, 78.5, 65.3, and 48.4%, respectively, in patients who received TACE (p < 0.001). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that lenvatinib therapy was significantly associated with overall survival in patients with HCC beyond the up-to-7 criteria (HR, 0.230; 95% CI, 0.059-0.904; p = 0.035). CONCLUSIONS: Lenvatinib may be a suitable first-line treatment for patients with intermediate-stage HCC beyond the up-to-7 criteria.

Predictive Factors of Complete Response to Transarterial Chemoembolization in Intermediate Stage Hepatocellular Carcinoma beyond Up-To-7 Criteria.

AIM: To clarify the prognosis and identify predictors for obtaining a complete response (CR) by transarterial chemoembolization (TACE) in intermediate stage HCC beyond up-to-7 criteria. METHODS: Of the 120 patients with intermediate stage HCC who were treated by TACE as the initial treatment from February 2007 to January 2016, 72 finally matched the following inclusion criteria: beyond up-to-7 criteria; Child-Pugh score under 7; and no combined therapy within 4 weeks after the initial TACE. The CR rate and overall survival (OS) were evaluated. Logistic regression analysis was performed to identify predictors of CR. The deterioration of liver function after TACE was also evaluated. RESULTS: The CR rate was 56.9%, and the overall median survival time (MST) was 37.7 months. The MST was 38.7 months in the CR group and 28.0 months in the non-CR group (p = 0.018). HCC within up-to-11 criteria was the only predictor of CR. The CR rate and MST were 70.7% and 37.7 months, respectively, in patients with HCC within up-to-11 criteria and 38.7% and 32.7 months, respectively, in the patients beyond up-to-11 criteria. Deterioration of the Child-Pugh score after the initial TACE and the 2nd TACE occurred in 24.2% and 12.0%, respectively, and deterioration of the modified albumin-bilirubin (mALBI) grade occurred in 17.6% and 7.4%, respectively. CONCLUSION: TACE can achieve high CR rates with prolonged overall survival for intermediate stage HCC beyond up-to-7 criteria. The predictor of CR was within up-to-11 criteria. Deterioration of liver function was not severe, but requires caution. Multidisciplinary approach as additional treatment after TACE is important.

Optimizing Survival Benefit by Surgical Resection by the Seven-Eleven Criteria in Barcelona Clinic Liver Cancer Stage A/B Hepatocellular Carcinoma beyond the Milan Criteria.

Introduction: Optimal treatment of hepatocellular carcinoma (HCC) beyond the Milan criteria is in debate. We aimed to identify candidates for surgical resection (SR) in Barcelona Clinic Liver Cancer (BCLC)-A/B HCC beyond the Milan criteria with survival benefit. Methods: Patients with BCLC-A/B HCC beyond the Milan criteria at the National Taiwan University Hospital during 2005 and 2019 were screened, and those who received transarterial chemoembolization (TACE) or SR were consecutively included. The tumor burden was classified by the seven-eleven criteria into low (≤7), intermediate (7-11), or high (>11). Multivariable Cox proportional hazard regression analysis was used for outcome prediction. Results: Overall, 474 patients who received SR (n = 247) and TACE (n = 227) were enrolled. Patients who underwent SR were significantly younger with better liver reserve. There were 76 (31%) and 129 (57%) deaths in the SR and TACE groups after a median follow-up of 3.9 and 2.1 years, respectively. The seven-eleven criteria could distinguish median overall survival (OS) among low (n = 149), intermediate (n = 203), and high (n = 122) tumor burden groups (7.7 vs. 6.9 vs. 2.8 years, respectively, p < 0.001). Patients receiving SR had a significantly higher median OS compared with TACE in those with intermediate (8.2 vs. 2.6 years, p < 0.001) and high (5.6 vs. 1.5 years, p = 0.001) tumor burden. After adjustment for age, sex, and liver reserve, SR was predictive for better OS in intermediate (adjusted hazard ratio [aHR]: 0.45, 95% confidence interval [CI]: 0.27-0.75) and high tumor burden groups (aHR: 0.54, 95% CI: 0.32-0.92). The survival benefit of SR especially confines to patients within 3 tumors. Conclusions: In patients with BCLC-A/B HCC beyond the Milan criteria with tumor burden beyond the up-to-7 criteria but within 3 tumors, SR has better OS than TACE and should be considered in resectable patients.

Treatment Strategy for Intermediate-Stage Hepatocellular Carcinoma: Transarterial Chemoembolization, Systemic Therapy, and Conversion Therapy.

Transarterial chemoembolization (TACE) has been standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, all intermediate-stage HCC patients did not benefit from TACE treatment because intermediate-stage HCC encompasses a wide variety of HCCs. Owing to remarkable progress in systemic therapy, including molecular-targeted therapy for advanced-stage HCC, the standard treatment of HCC has recently shifted to systemic therapy. However, it remains controversial as to which treatment should be initially performed for intermediate-stage HCC. In addition, although curative treatment can be considered when the tumor shrinks, the timing of conversion therapy remains uncertain. This review summarizes the advances of HCC treatment and discusses treatment strategies for intermediate-stage HCC.

Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma.

Introduction: Several clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034). Methods: Patients with unresectable HCC were randomized to a TACE plus sorafenib group (N = 80) or a TACE alone group (N = 76). Patients in the combination treatment 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 progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607-1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466-0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria. Conclusions: In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034.

Extended criteria for liver transplantation in hepatocellular carcinoma. A retrospective, multicentric validation study in Belgium.

BACKGROUND: Recent studies indicate that a group of patients with cirrhosis receiving a liver transplantation for hepatocellular cancer (HCC) beyond the Milan Criteria (MC) can achieve a similar outcome compared to patients within these criteria. This study aims to investigate the value of the Asan critera (AC), up-to-7 criteria (UT7), French alpha-foetoprotein (AFP) model and Metroticket 2.0 (MT2.0) model compared to the MC. METHODS: 526 patients transplanted for non-metastatic HCC were analyzed. Patient groups within and beyond MC and extended criteria were determined according to radiological assessment and AFP value at listing. RESULTS: Overall survival (OS) and recurrence (RR) rates were similar between patients within MC and all extended criteria. Five-year OS within MC was 71.3% compared to 70.9% for AC, 71.4% for UT7, 69.7% for AFP-model and 71.0% for MT2.0 criteria. Five-year RR within MC was 12.3% compared to 13.5% for AC, 13.0% for UT7, 14.3% for AFP-model and 13.2% for MT2.0 criteria. Patients beyond MC but within the extended criteria had tendency towards higher recurrence. CONCLUSIONS: All validated extended criteria (AC, UT7, AFP-model and MT2.0) could be proposed as alternatives to the MC with similar outcome. Prospective data are awaited to assess recurrence beyond MC.