Efficacy and Safety of TACE Combined with a Tyrosine Kinase Inhibitor for the Treatment of TACE-Refractory Hepatocellular Carcinoma: A Retrospective Comparative Study.

PURPOSE: Combining angiogenesis inhibitors may enhance therapeutic efficacy synergistically after TACE refractoriness. The purpose of this study was to compare the outcomes of transarterial chemoembolization (TACE) plus a tyrosine kinase inhibitor (TACE-TKI) with TKI only for patients with TACE-refractory hepatocellular carcinoma (HCC). METHODS: From January 2019 to March 2022, 101 HCC patients confirmed with TACE-refractory were retrospectively reviewed in the study. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were evaluated between groups. RESULTS: Fifty-two patients undergoing TACE-TKI, while 32 patients receiving TKI alone were included. The objective response rate (ORR) was higher in the TACE-TKI group compared with the TKI group (55.8% vs. 25.0%, P = 0.006). The median PFS in the TACE-TKI group was significantly longer than that in the TKI group (7.6 months vs. 4.9 months, P = 0.018). The median OS was non reach to statistical longer than that in the TKI alone group (19.5 months vs. 17.7 months, P = 0.055). Subgroup analysis showed that TACE-TKI treatment resulted in a significantly longer median PFS and OS for Barcelona Clinic Liver Cancer (BCLC) stage B patients (PFS 11.8 months vs. 5.1 months, P = 0.017; OS 30.3 months vs. 19.4 months, P = 0.022). CONCLUSION: For patients with TACE-refractory HCC, TACE-TKI appeared to be superior to TKI monotherapy with regard to tumor control and PFS. Furthermore, for the BCLC stage B subgroup, TACE-TKI therapy was superior to TKI monotherapy in both OS and PFS.

Efficacy and safety of tyrosine kinase inhibitors plus PD-1 inhibitor in patients with transarterial chemoembolization- refractory hepatocellular carcinoma: a two-center retrospective study.

Object: To investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs: sorafenib and lenvatinib) plus PD-1 inhibitor (camrelizumab) versus TKIs alone in transarterial chemoembolization-refractory (TACE-refractory) hepatocellular carcinoma (HCC). Materials and methods: Data of TACE-refractory HCC patients treated with TACE+TKIs+PD-1 inhibitor (TACE+TKIs+PD-1group) (n=57) or TACE+TKIs (TACE+TKIs group) (n=50) from January 2019 to January 2022 were retrospectively collected and analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups. Potential factors affecting OS and PFS were evaluated by univariate and multivariate analyses. Results: Compared with the TKIs group, both PFS and OS were prolonged in the TACE+TKIs+PD-1 group (median PFS: 7 months vs. 5 months, P=0.007; median OS: 17 months vs. 11 months, P=0.002). In multivariate analysis, tumor size and treatment were independent prognostic factors for PFS and OS. The incidence and severity of AEs related to the treatment between the two groups showed no significant difference. Conclusion: The treatment of TACE combined with TKIs plus camrelizumab demonstrated promising efficacy and safety in TACE-refractory HCC.

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.

Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy.

The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.

Drug-eluting Bead-Transcatheter Arterial Chemoembolization for Advanced Hepatocellular Carcinoma Refractory to Conventional Lipiodol-based Transcatheter Arterial Chemoembolization.

PURPOSE: To evaluate the potential of drug-eluting bead (DEB)-transcatheter arterial chemoembolization (TACE) as a treatment option for patients with refractory to conventional lipiodol-based TACE (c-TACE) especially with decreased liver function. PATIENTS AND METHODS: We retrospectively evaluated the treatment results of DEB-TACE for 89 HCC nodules in 27 patients with c-TACE refractory according to liver function. RESULTS: Although overall survival was significantly better in Child-Pugh A patients than in Child-Pugh B patients (median survival time, MST: 561 vs 347 days, p=0.031), progression-free survival was almost similar in both patients between Child-Pugh A and B (MST: 79 vs 87 days, p=0.534). Regarding antitumor response, the objective response rate (ORR) and disease-control rate (DCR) were 5.3/12.5% and 52.7/87.5% in Child-Pugh A/B, respectively. In each 89 HCC nodules, ORR and DCR were almost similar between Child-Pugh A and B (ORR, 20.3 vs 13.3%; DCR, 77.0 vs 73.3%, respectively). Adverse events of DEB-TACE were well-tolerated, and liver function was reserved during DEB-TACE procedures. CONCLUSION: DEB-TACE could be a therapeutic option for advanced HCC patients with c-TACE refractory and decreased liver function.

Efficacy and Safety of TACE Combined With Sorafenib Plus Immune Checkpoint Inhibitors for the Treatment of Intermediate and Advanced TACE-Refractory Hepatocellular Carcinoma: A Retrospective Study.

Purpose: The study aims to retrospectively investigate the efficacy and safety of sorafenib combined with transarterial chemoembolization (TACE) (TACE+Sor) vs. TACE combined with sorafenib plus immune checkpoint inhibitors (TACE+Sor+ICIs) in treating intermediate and advanced TACE-refractory hepatocellular carcinoma (HCC). Materials and Methods: This study was approved by the ethics committee of Lisui Hospital, Zhejiang University, China. From January 2016 to June 2020, 51 eligible patients with intermediate or advanced TACE-refractory HCC received TACE+Sor (n = 29) or TACE+Sor+ICIs (n = 22). The differences in tumor response, adverse events (AEs), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Factors affecting PFS and OS were determined by Cox regression. Results: The disease control rate was higher in the TACE+Sor+ICIs group than in the TACE+Sor group (81.82 vs. 55.17%, P = 0.046). Compared with the TACE+Sor group, PFS and OS were prolonged in the TACE+Sor+ICIs group (median PFS: 16.26 vs. 7.30 months, P < 0.001; median OS: 23.3 vs. 13.8 months, P = 0.012). Multivariate analysis showed that BCLC stage, alpha-fetoprotein and treatment were independent factors of PFS; BCLC, Child-Pugh class, ablation after disease progression and treatment were independent predictive factors of OS. Four patients in the TACE+Sor+ICIs group and three patients in the TACE+Sor group suffered from dose reduction or interruption (18.18 vs. 10.34%, P = 0.421). The incidence of ICI-related AEs in the TACE+Sor+ICIs group was well-controlled. Conclusion: The therapeutic schedule of TACE+Sor+ICIs demonstrated efficacy and safety in intermediate and advanced TACE-refractory HCC.

Prediction of Prognosis of Intermediate-Stage HCC Patients: Validation of the Tumor Marker Score in a Nationwide Database in Japan.

BACKGROUND/AIM: Adequate assessment of transcatheter arterial chemoembolization (TACE)-refractory status has become more important for switching treatment in intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) patients treated with TACE. The usefulness of a previously proposed tumor marker score for predicting prognosis of BCLC-B HCC patients treated with TACE was investigated. METHODS: Using a nationwide database, we examined the records of 1,306 naïve BCLC-B HCC with Child-Pugh A who were treated from 2001 to 2007, after excluding those with missing data (hepatic function or tumor markers) or cases with a single large tumor. Alpha-fetoprotein (AFP) ≥100 ng/mL, fucosylated AFP (AFP-L3) ≥10%, and des-gamma-carboxy prothrombin ≥100 mAU/mL were markers used to define positive cases. The number of positive tumor markers was used as a prognostic score, and its predictive value was evaluated in a retrospective manner. RESULTS: Median survival time became shorter along with increased score (0, 1, ≥2 = 4.8, 3.8, 3.2 years, respectively; p < 0.01). Tumor marker score (≥2; hazard ratio [HR] 1.675, 95% confidence interval [CI] 1.372-2.044, p < 0.001), serum levels of albumin (≥3.5 g/dL; HR 0.726, 95% CI 0.528-0.997, p = 0.048), and up-to-7 criteria (HR 1.673, 95% CI 1.400-2.000, p < 0.001) were significant prognostic factors for death in the Cox hazard multivariate analysis. CONCLUSION: Tumor marker score had a useful predictive prognostic value in BCLC-B HCC treated with TACE. Especially in patients with a tumor marker score of 2 or greater, a poor therapeutic response should be expected, and appropriate judgement of TACE-refractory status is necessary.

Efficacy and safety of TACE in combination with sorafenib for the treatment of TACE-refractory advanced hepatocellular carcinoma in Chinese patients: a retrospective study.

BACKGROUND: Transarterial chemoembolization (TACE) and sorafenib (SOR) are well-established treatments for hepatocellular carcinoma (HCC). This study evaluates the efficacy and safety of SOR combined with TACE in the treatment of patients with TACE-refractory, advanced-stage HCC. METHODS: This retrospective study included 61 patients with TACE-refractory advanced HCC. Patients were divided into TACE + SOR (n=30) and TACE (n=31) treatment groups. Patient demographic and clinical characteristics, overall survival (OS), time to progression (TTP), disease control rate (DCR), and adverse events (AEs) were compared between the two groups. RESULTS: Compared with TACE alone, the 5-year OS and TTP were prolonged in the TACE + SOR group (median OS: 17.9 vs 7.1 months, P<0.001; median TTP: 9.3 vs 3.4 months, P<0.001). Multivariate analysis showed that Child-Pugh class A (hazard ratio [HR], 0.234; 95% confidence interval [CI], 0.092-0.595), Eastern Cooperative Oncology Group performance status 1 (HR, 0.355; 95% CI, 0.153-0.826), alpha-fetoprotein <400 ng/mL (HR, 0.349; 95% CI, 0.177-0.689), and TACE + SOR treatment (HR, 0.151; 95% CI, 0.071-0.322) were independent, positive predictive factors of OS. CONCLUSION: The OS and TTP in the combined treatment group were significantly improved when compared with the TACE group. However, no significant difference in DCR was found between these two groups. While no AEs occurred in the TACE group, two patients in the TACE + SOR group experienced severe AEs which were effectively mitigated by lowering the dose of SOR. Thus, SOR in combination with TACE is a safe and effective treatment for advanced-stage, prior-TACE-resistant HCC.

A Case of Achieving Complete Remission with Stereotactic Body Radiation Therapy in Patients with Hepatocellular Carcinoma with Macrovascular Invasion after Repeated Transarerial Chemoembolization

Transarterial chemoembolization (TACE) is the worldwide procedure performed for patients with various stage hepatoceullar carcinoma (HCC), but is not yet considered as curative treatment because of relatively high local recurrence rate. Moreover, many clinicians frequently experience treatment failure (incomplete necrosis or stage progression etc.) after repeated TACE, but no clear guidelines have been recommended about salvage treatment modalities for this situation. Recently, studies for combination of radiation therapy and TACE for HCC with TACE refractoriness have been tried and reported better therapeutic efficacy. Based on above suggestions, we herein offer our experience of a patient with macrovascular invasion developed after repeated TACE that achieve complete remission by stereotactic body radiation therapy. Further study, maybe regarding a combination of locoregional and systemic therapy, is necessary on how to manage HCC patients with TACE refractoriness.