Treatment Of Advanced Hepatocellular Carcinoma Research Articles

CRAFITY score as a predictive marker for refractoriness to atezolizumab plus bevacizumab therapy in hepatocellular carcinoma: a multicenter retrospective study

BackgroundAlthough atezolizumab plus bevacizumab (Atezo/Bev) therapy has been used as the preferred first-line treatment for advanced hepatocellular carcinoma (HCC), up to 26% of patients do not achieve disease control, suggesting alternative treatments might be more beneficial for such patients. We investigated key predictors for refractoriness to Atezo/Bev therapy, particularly in the first-line setting.MethodsWe retrospectively analyzed 302 patients with HCC who received Atezo/Bev therapy between October 2020 and September 2022 across nine hospitals in Japan. Refractoriness was defined as best overall response (BOR) of progressive disease or stable disease and a progression-free survival (PFS) of < 180 days (RECIST v1.1). Clinical benefit was defined as BOR of partial/complete response or stable disease with PFS of ≥ 180 days. Baseline characteristics and potential predictors, identified through literature review, were compared between these groups. Stratifications of overall survival (OS), and PFS were also assessed.ResultsRefractoriness was observed in 126 (41.7%) patients, while 154 (51.0%) achieved clinical benefit. Due to a significant association between the treatment line and refractory rate, the subsequent analysis focused on the first-line cohort (n = 214; 72 [33.6%] patients showed refractoriness). Among 13 potential predictors, the CRP and AFP in immunotherapy (CRAFITY) score had the best predictive performance, with refractory rates of 24.6%, 44.6%, and 57.9% in CRAFITY-0, 1, and 2 patients, respectively (p < 0.001). OS and PFS were also well-stratified by this scoring system.ConclusionsApproximately one-third of patients were refractory to first-line Atezo/Bev therapy. The CRAFITY score demonstrated superior performance in predicting refractoriness.

Effect of Biliary Drainage on the Prognosis of Patients with Hepatocellular Carcinoma and Bile Duct Invasion.

Bile duct invasion (BDI) is rarely observed in patients with advanced hepatocellular carcinoma (HCC), leading to hyperbilirubinemia. However, the efficacy of pretreatment biliary drainage for HCC patients with BDI and obstructive jaundice is currently unclear. Thus, the aim of this study was to assess the effect of biliary drainage on the prognosis of these patients. We retrospectively enrolled a total of 200 HCC patients with BDI from multicenter cohorts. Patients without obstructive jaundice (n=99) and those who did not undergo HCC treatment (n=37) were excluded from further analysis. Finally, 64 patients with obstructive jaundice (43 subjected to drainage and 21 not subjected to drainage) were included. Propensity score matching was then conducted. The biliary drainage group showed longer overall survival (median 10.13 months vs 4.43 months, p=0.004) and progression-free survival durations (median 7.00 months vs 1.97 months, p<0.001) than the non-drainage group. Multivariate analysis showed that biliary drainage was a significantly favorable prognostic factor for overall survival (hazard ratio, 0.42; p=0.006) and progression-free survival (hazard ratio, 0.30; p<0.001). Furthermore, in the evaluation of first response after HCC treatment, biliary drainage was beneficial (p=0.005). Remarkably, the durations of overall survival (p=0.032) and progression-free survival (p=0.004) were similar after propensity score matching. Biliary drainage is an independent favorable prognostic factor for HCC patients with BDI and obstructive jaundice. Therefore, biliary drainage should be contemplated in the treatment of advanced HCC with BDI to improve survival outcomes.

Clinical Effects and Safety of Intra-Arterial Infusion Chemotherapy with Lipiodol versus Intra-Arterial Infusion Chemotherapy Alone for Treatment of Advanced Hepatocellular Carcinoma

Introduction: This study aimed to assess the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) in 2 groups of patients: those who receive lipiodol (referred to as the lipiodol group) and those who do not receive lipiodol (referred to as the control group). Methods: From January 2016 through December 2023, 85 patients with advanced hepatocellular carcinoma were enrolled in this retrospective study. In total, 40 patients received HAIC with lipiodol, while 45 patients were given HAIC without lipiodol. The modified response evaluation criteria for solid tumors were used to evaluate the tumor response, which was assessed through an imaging study. The two groups were compared regarding their overall survival (OS), progression-free survival (PFS), and safety. Results: The outcomes between the lipiodol group and control group demonstrated no significant difference: the objective response rates (p = 0.066) were 32.5% and 15.6%; the disease control rates (p = 0.556) were 67.5% and 73.3%; the median OS times (p = 0.339) were 224 days and 398 days; the median PFS (p = 0.334) times were 191 days and 286 days in the lipiodol group and the control group, respectively. Adverse events also showed no significant difference between the two groups: elevation of total bilirubin (p = 0.834) rates were 40.0% and 37.8%; elevation of alanine aminotransferase (p = 0.191) percentages were 35.0% and 22.2%; and elevation of aspartate aminotransferase values (p = 0.058) were 65.0% and 44.4% in the lipiodol group and the control group, respectively. Conclusions: HAIC without lipiodol was non-inferior to HAIC with lipiodol in the clinical outcome.

Dual effects of targeting neuropilin-1 in lenvatinib-resistant hepatocellular carcinoma: inhibition of tumor growth and angiogenesis.

In the era of immunotherapy, lenvatinib (LEN) still holds an important position in the sequential treatment of advanced hepatocellular carcinoma (HCC). However, the sustained therapeutic effect of LEN is not sufficient, and there is a need to address the development of resistance. Neuropilin-1 (NRP1) is known to act as a coreceptor for epidermal growth factor receptor (EGFR), Met, and vascular endothelial growth factor receptor 2 (VEGFR2), which have been reported to be involved in LEN resistance. In this study, we used cell culture and in vivo xenograft models to evaluate the contribution of NRP1 in the acquisition of LEN resistance in HCC as well as the potential of NRP1 as a therapeutic target. LEN resistance increased EGF/EGFR and hepatocyte growth factor (HGF)/Met signaling in liver cancer cells and VEGFA/VEGFR2 and HGF/Met signaling in vascular endothelial cells, thereby promoting cell proliferation, cell migration, and angiogenesis. We found that activation of NRP1 is essential for the enhancement of these signaling. In addition, NRP1 inhibition combined with LEN therapy synergistically improved the antitumor effects against LEN-resistant HCC, indicating that NRP1 is an attractive therapeutic target.NEW & NOTEWORTHY We demonstrated that neuropilin-1 (NRP1) was an essential coreceptor mediating the activation of multiple signaling pathways in the acquisition of resistance to lenvatinib (LEN) in HCC. The addition of NRP1 inhibition to LEN had a synergistic antitumor effect on LEN-resistant HCC in culture and in vivo xenograft models.

974P Surufatinib combined with anti-PD-1/PD-L1 antibody in the second-line or monotherapy in third-line treatment of advanced hepatocellular carcinoma: A single-arm, open-label, multi-center phase II study

974P Surufatinib combined with anti-PD-1/PD-L1 antibody in the second-line or monotherapy in third-line treatment of advanced hepatocellular carcinoma: A single-arm, open-label, multi-center phase II study

LBA38 Iparomlimab and tuvonralimab (QL1706) with bevacizumab and/or chemotherapy in first-line (1L) treatment of advanced hepatocellular carcinoma (aHCC): A randomized, open-label, phase II/III study (DUBHE-H-308)

LBA38 Iparomlimab and tuvonralimab (QL1706) with bevacizumab and/or chemotherapy in first-line (1L) treatment of advanced hepatocellular carcinoma (aHCC): A randomized, open-label, phase II/III study (DUBHE-H-308)

Drug-eluting bead transarterial chemoembolization combined with apatinib/camrelizumab for the treatment of advanced hepatocellular carcinoma with hepatic arterioportal shunts.

To evaluate the efficacy and safety of drug eluting bead transarterial chemoembolization (D-TACE) combined with apatinib/camrelizumab in patients with advanced hepatocellular carcinoma (HCC) and hepatic arterioportal shunts (APSs). From January 2021 to December 2022, the consecutive medical records of patients with advanced HCC and APS receiving D-TACE combined with apatinib/camrelizumab were reviewed for eligibility. Overall survival (OS), progression-free survival (PFS), tumour response, and adverse events (AEs) were assessed. A total of 23 patients were included in this study, with a median follow-up of 11 months (range, 2-26 months). Eight patients (34.8%) achieved partial response; 13 (56.5%), stable disease; and 2 (8.7%), progressive disease. The objective response and disease control rates were 34.8% and 91.3%, respectively. The OS and PFS rates were 11 and 7 months, respectively. Multivariate analysis indicated that the tumour number was an independent prognostic factor for PFS. AEs occurred in 19 patients after oral apatinib treatment and in 8 patients after camrelizumab treatment. No treatment-related death occurred during the study period. D-TACE combined with apatinib/camrelizumab showed meaningful efficacy and controllable AEs in these patients, making it a promising treatment option. (1) We investigated a new treatment strategy for patients with advanced HCC and hepatic APS and (2) D-TACE combined with apatinib/camrelizumab demonstrated meaningful efficacy and manageable AEs, making it a promising treatment option.

Research Progress on Anti-angiogenesis Drugs in Hepatocellular Carcinoma

Primary liver cancer is the sixth most prevalent cancer worldwide and ranked in third for cancer-related mortality rate. Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers. High vascularization of HCC implies the significance of angiogenesis in the development and pathogenesis of HCC. Several angiogenic pathways have been identified as being dysregulated in HCC, highlighting potential therapeutic targets for the treatment of HCC. In 2007, sorafenib was approved as the standard first-line treatment for advanced HCC, catapulting the therapeutic approach of HCC into the avenue of targeted therapy. In recent years, the approval of several novel targeted drugs and the progress in combination of immunotherapy and targeted therapies provide more alternatives for the treatment of HCC. The progress of anti-angiogenesis therapies in HCC over the past few decades is reviewed and the future prospect of anti-angiogenesis therapy for HCC is also discussed.

Patient and physician expectations regarding disease and treatment of advanced HCC: The prospective PERCEPTION1 study

BackgroundWe aim to explore patient expectations regarding their treatments and prognosis in comparison to physicians' assessments in patients with advanced hepatocellular carcinoma (HCC) receiving systemic treatments. MethodsWe prospectively enrolled 205 patients in France and Belgium with BCLC B/C HCC receiving systemic treatment (NCT04823754). Patients completed a 28-question survey and Hospital Anxiety and Depression Scale (HADS), while physicians filled a 17-question survey after the initial consultation. Univariate and multivariate models were used to assess factors associated with concordant patient-physician responses, HADS, predicted (by physicians) and observed overall survival. ResultsPatients had a median age of 68 years with 75% of BCLC C HCC; 86.3% received atezolizumab/bevacizumab. 60% of patients didn't discuss life expectancy with the physician. 63% of the patients believed they had a life expectancy > 5 years. Among shared questions between patients and physicians, 36.4% of concordance was observed; major differences centered on life expectancy with patients more optimistic than physicians. A lower patient-physician concordance was seen with shorter-consultations (p=0.003), female physicians (p=0.02), BCLC C (p=0.03) and >100 HCC patients/year per physician (p=0.008). Compared to France, patients from Belgium have more satisfaction about the consultation (p<0.001) but were less optimistic about life expectancy. Using HADS, 52% of the patients have anxiety/depression that was correlated with AFP (p=0.03). The predicted median overall survival by physician was 18 months versus 13 months for the observed overall survival (weak correlation, ρ=0.31). ConclusionExpectations regarding systemic treatments for advanced HCC differ significantly between patients and physicians, showing notable variations across countries. Impact and implicationsThis multicentric prospective study, conducted in France and Belgium, focuses on patients with advanced HCC undergoing systemic treatments. The findings of our study underscore the disparities in expectations regarding systemic treatments for advanced HCC between patients and physicians, revealing also significant variations between France and Belgium. These results suggest the need for targeted interventions aimed at enhancing patients' comprehension of their disease and fostering better communication between patients and physicians Clinical trial numberNCT04823754

Autophagy modulation attenuates sorafenib resistance in HCC induced in rats

Hepatocellular carcinoma (HCC) has risen as the villain of cancer-related death globally, with a usual cruel forecasting. Sorafenib was officially approved by the FDA as first-line treatment for advanced HCC. Despite the brilliant promise revealed in research, actual clinical results are limited due to the widespread appearance of drug resistance. The tumor microenvironment (TME) has been correlated to pharmacological resistance, implying that existing cellular level strategies may be insufficient to improve therapy success. The role of autophagy in cancer is a two-edged sword. On one hand, autophagy permits malignant cells to overcome stress, such as hypoxic TME and therapy-induced starvation. Autophagy, on the other hand, plays an important role in damage suppression, which can reduce carcinogenesis. As a result, controlling autophagy is certainly a viable technique in cancer therapy. The goal of this study was to investigate at the impact of autophagy manipulation with sorafenib therapy by analyzing autophagy induction and inhibition to sorafenib monotherapy in rats with HCC. Western blot, ELISA, immunohistochemistry, flow cytometry, and quantitative-PCR were used to investigate autophagy, apoptosis, and the cell cycle. Routine biochemical and pathological testing was performed. Ultracellular features and autophagic entities were observed using a transmission electron microscope (TEM). Both regimens demonstrated significant reductions in chemotherapeutic resistance and hepatoprotective effects. According to the findings, both autophagic inhibitors and inducers are attractive candidates for combating sorafenib-induced resistance in HCC.

Efficacy of hepatic arterial infusion chemotherapy and its combination strategies for advanced hepatocellular carcinoma: A network meta-analysis

BACKGROUND With the rapid progress of systematic therapy for hepatocellular carcinoma (HCC), therapeutic strategies combining hepatic arterial infusion chemotherapy (HAIC) with systematic therapy arised increasing concentrations. However, there have been no systematic review comparing HAIC and its combination strategies in the first-line treatment for advanced HCC. AIM To investigate the efficacy and safety of HAIC and its combination therapies for advanced HCC. METHODS A network meta-analysis was performed by including 9 randomized controlled trails and 35 cohort studies to carry out our study. The outcomes of interest comprised overall survival (OS), progression-free survival (PFS), tumor response and adverse events. Hazard ratios (HR) and odds ratios (OR) with a 95% confidence interval (CI) were calculated and agents were ranked based on their ranking probability. RESULTS HAIC outperformed Sorafenib (HR = 0.55, 95%CI: 0.42-0.72; HR = 0.51, 95%CI: 0.33-0.78; OR = 2.86, 95%CI: 1.37-5.98; OR = 5.45, 95%CI: 3.57-8.30; OR = 7.15, 95%CI: 4.06-12.58; OR = 2.89, 95%CI: 1.99-4.19; OR = 0.48, 95%CI: 0.25-0.92, respectively) and transarterial chemoembolization (TACE) (HR = 0.50, 95%CI: 0.33-0.75; HR = 0.62, 95%CI: 0.39-0.98; OR = 3.08, 95%CI: 1.36-6.98; OR = 2.07, 95%CI: 1.54-2.80; OR = 3.16, 95%CI: 1.71-5.85; OR = 2.67, 95%CI: 1.59-4.50; OR = 0.16, 95%CI: 0.05-0.54, respectively) in terms of efficacy and safety. HAIC + lenvatinib + ablation, HAIC + ablation, HAIC + anti- programmed cell death 1 (PD-1), and HAIC + radiotherapy had the higher likelihood of providing better OS and PFS outcomes compared to HAIC alone. HAIC + TACE + S-1, HAIC + lenvatinib, HAIC + PD-1, HAIC + TACE, and HAIC + sorafenib had the higher likelihood of providing better partial response and objective response rate outcomes compared to HAIC. HAIC + PD-1, HAIC + TACE + S-1 and HAIC + TACE had the higher likelihood of providing better complete response and disease control rate outcomes compared to HAIC alone. CONCLUSION HAIC proved more effective and safer than sorafenib and TACE. Furthermore, combined with other interventions, HAIC showed improved efficacy over HAIC monotherapy according to the treatment ranking analysis.

Phase Ib trial of durvalumab plus tremelimumab in combination with particle therapy in patients with advanced hepatocellular carcinoma with macrovascular invasion: DEPARTURE trial.

34 Background: The HIMALAYA trial established the combination of durvalumab and tremelimumab (STRIDE) as first-line treatment for advanced hepatocellular carcinoma (HCC). Carbon ion radiotherapy (C-ion RT) allows precise tumor targeting while sparing nearby normal tissue. Our strategy used C-ion RT to target a key tumor with macrovascular invasion (MVI) for disease management and potential MVI control, complemented by STRIDE. Recognising that C-ion RT stimulates immune responses, we posited that merging C-ion RT with STRIDE might enhance therapeutic effects. We present updated data of additional follow-up. Methods: This is a Phase Ib, multicenter study evaluating durvalumab with particle beam radiotherapy in HCC patients with MVI (Cohort A) and STRIDE (Cohort B). Both cohorts began with patients resistant to standard treatments. After safety confirmation, the study expanded to include therapy-naïve patients, totaling 15. C-ion RT begins after day 8 of the first cycle, following the initial drug dose. The relative biological effectiveness weighted dose is set at 60 Gy in four fractions over one week, targeting one representative intrahepatic nodule with MVI. The primary endpoint is adverse event rates, including dose limiting toxicity (DLT), with secondary endpoints on progression free survival (PFS) and overall survival (OS) (jRCT2031210046). This analysis of OS was conducted from the additional follow-up data from the primary analysis. Results: From July 2021 to January 2023, 15 advanced HCC patients were enrolled in our study (Cohort A: 3, Cohort B: 12). Four in Cohort B were systemic therapy-naïve. All cases confirmed MVI radiologically; with tumor invasion observed in the main portal vein for 4 patients and in the inferior vena cava for one. DLT evaluations in 3 from each cohort showed no incidents. While Cohort A had no adverse events, 4 patients in Cohort B (26.7%) experienced serious treatment-related adverse events. The median PFS was a significant 4.67 months (95%CI, 1.35–6.64). At the clinical cut-off date of March 31, 2024, 10 OS events were observed. The median OS was 10.4 months (95% CI, 5.6–15.2), and the 6- and 12-month OS rates were 66.7% and 46.7%, respectively. Conclusions: The safety of STRIDE in combination with particle therapy has been confirmed in advanced HCC with MVI. This combination, especially the irradiation of tumors with MVI using C-ion RT, holds promise in managing prognostic determinant tumors and potentially enhancing OS. Clinical trial information: jRCT2031210046 .

Incidence of hand-foot syndrome with protein kinase inhibitors in advanced hepatocellular carcinoma patients who received atezolizumab-bevacizumab combination.

Treatment of advanced HepatoCellular Carcinoma (HCC) is based on first-line (L1) combination of atezolizumab and high-dose (HD) bevacizumab while second-line (L2) refers one antiangiogenic protein kinase inhibitors (aaPKI). This prolonged antiangiogenic pressure let us to observe an increasing occurrence of Hand-Foot Syndromes (HFS) in patients receiving aaPKI after HD bevacizumab combination. This study reports observations and discussions about the evidence and hypothesis that could be made. Patients who received the L1 combination from September 1st 2020 to December 31st 2022 to identify L2 aaPKI. Demographic, biological, oncological data and occurrence of HFS were collected. In addition were collected the number of L1 combination cycles, type of aaPKI, and delay between last L1 cycle and L2 initiation. This study had a purely exploratory purpose, so no statistical analysis was planned. 17 patients received an aaPKI after the L1 HD bevacizumab combination with a median time of 26 days from last L1 cycle to L2 start. Five patients experienced HFS including grade 3 (n = 2) with sorafenib and cabozantinib. The HFS occurred with a median delay of 23 days (IQR: 21-28) from aaPKI start. Three patients experienced aaPKI-related dose-limiting toxicity. Proportion of patients experienced HFS in our cohort did not differ from pivotal trials data and the sample size do not allow to conclude. Hypotheses include timing of aaPKI start in HCC treatment, vascular toxicity at aaPKI start after HD bevacizumab discontinuation instead combination, patient-related outcome for a better understanding of these aaPKI-related HFS post HD bevacizumab.

Analysis of efficacy and safety for the combination of tislelizumab and regorafenib in advanced hepatocellular carcinoma: A prospective clinical study.

Programmed death receptor 1 (PD-1) monoclonal antibody has been approved for the first and second-line treatments of hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of tislelizumab + regorafenib as a second-line treatment option for advanced HCC. Treatment-related adverse events (TRAEs) were the primary endpoints in this clinical trial comprising 28 patients with advanced HCC. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). According to the mRECIST 1.1 evaluation criteria, the ORR was 28.6%. Complete and partial response were observed in 3 and 5 patients, respectively; stable disease was observed in 12 patients (DCR, 71.4%). The median PFS was 6.4 months. The incidence of grade 1-2 and 3-4 TRAEs was 57.1% and 39.3%, respectively. This study suggests that tislelizumab + regorafenib can be used as a second-line treatment for advanced HCC.

Efficacy and safety of HAIC combined with tyrosine kinase inhibitors versus HAIC monotherapy for advanced hepatocellular carcinoma: a multicenter propensity score matching analysis.

This study aimed to assess the clinical efficacy and safety of the combined approach involving hepatic arterial infusion chemotherapy (HAIC) and tyrosine kinase inhibitors (TKIs) for the treatment of advanced hepatocellular carcinoma (HCC). In this multicenter retrospective study conducted from January 2020 to December 2023, we reviewed advanced HCC patients who were treated either with HAIC alone or with a combination of HAIC and TKIs. To address initial disparities between the two groups, we employed propensity score matching (PSM). Tumor response evaluation was performed following RECIST 1.1 criteria. We compared survival outcomes, including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), between the two treatment groups. Safety assessments were conducted for all patients. Following the eligibility review, 138 patients underwent combined treatment with HAIC and TKIs (HT group), while 198 patients received HAIC monotherapy (HA group) and met the inclusion criteria for enrollment in this study. After PSM, 107 patients were assigned to each group. The HT group exhibited a longer median OS (18.0 versus 8.8 months; hazard ratio [HR], 0.52, p < 0.001) compared to the HA group. Median PFS was also longer in the HT group, although without statistical significance (6.0 versus 4.7 months; HR, 0.85, p = 0.265). The HT group demonstrated a higher ORR (41.1% versus 25.2%; p = 0.020). No significant differences were observed between the two groups in the incidence of all adverse events (AEs) or grade 3/4 AEs (any grade: 81.2% for HT versus 78.8% for HA, p = 0.68; grade 3/4: 18.1% for HT versus 13.6% for HA, p = 0.29). Importantly, all AEs were manageable and acceptable. Notably, no grade 5 AEs occurred in either group. Combination therapy involving HAIC and TKIs effectively prolonged survival in advanced HCC patients. It represented a preferable alternative to HAIC monotherapy, with manageable safety.

Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression

Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.

Anticancer Activity of Delta-Tocotrienol in Human Hepatocarcinoma: Involvement of Autophagy Induction.

(1) Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Surgical resection, tumor ablation, and liver transplantation are curative treatments indicated for early-stage HCC. The management of intermediate and advanced stages of pathology is based on the use of systemic therapies which often show important side effects. Vitamin E-derivative tocotrienols (TTs) play antitumoral properties in different tumors. Here, we analyzed the activity of delta-TT (δ-TT) on HCC human cell lines. (2) We analyzed the ability of δ-TT to trigger apoptosis, to induce oxidative stress, autophagy, and mitophagy in HepG2 cell line. We evaluated the correlation between the activation of autophagy with the ability of δ-TT to induce cell death. (3) The data obtained demonstrate that δ-TT exerts an antiproliferative and proapoptotic effect in HCC cells. Furthermore, δ-TT induces the release of mitochondrial ROS and causes a structural and functional alteration of the mitochondria compatible with a fission process. Finally, δ-TT triggers selective autophagy process removing dysfunctional mitochondria. Inhibition of autophagy reversed the cytotoxic action of δ-TT. (4) Our results demonstrate that δ-TT through the activation of autophagy could represent a potential new approach in the treatment of advanced HCC.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with tyrosine kinase inhibitors and immune checkpoint inhibitors in the treatment of advanced hepatocellular carcinoma with portal vein tumor thrombosis in the main trunk.

To evaluate the efficacy and safety of mFOLFOX-based hepatic arterial infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) in the treatment of advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). This retrospective study included patients who received mFOLFOX-based HAIC combined with TKIs and ICIs from January 2021 to January 2023. The primary outcome was the objective response rate of PVTT response, and the secondary outcomes were 6-month, 1-year survival rate, overall survival (OS), and corresponding adverse events and complications were also evaluated. PVTT responses were assessed using ITK-SNAP software. A total of 37 patients were included in the analysis, 18.92% achieved a complete response and 56.76% achieved a partial response in PVTT response. The objective response rate (ORR) of PVTT was 75.68%. The 6-month survival rate was 89%, the 1-year survival rate was 66%, and the median OS was 15.8 months. In univariate analysis, Child-Pugh score (P=0.010) was important factor for predicting OS; in multivariate analysis, Child-Pugh score (P=0.015, HR= 3.089, 95%CI: 1.250-7.633) was the important factor for predicting OS. In terms of adverse reactions, the most common adverse reactions associated with HAIC are pain and thrombocytopenia associated with oxaliplatin. FOLFOX-based HAIC combined with TKIs and ICIs induced an objective response rate of 75.68% in PVTT. FOLFOX-based HAIC combined with TKIs and ICIs provides more treatment options for PVTT.

A real-world study of tyrosine kinase inhibitors plus anti-PD-1 immunotherapy with or without chemoembolization for hepatocellular carcinoma patients with main portal vein invasion.

Although systemic therapies are recommended for hepatocellular carcinoma (HCC) patients with main portal vein (MPV) invasion and preserved liver function, the outcome is limited. In the real-world, chemoembolization is a commonly used local treatment for advanced HCC. To evaluate whether the additional chemoembolization treatment yields survival benefits compared to systemic therapy for HCC patients with MPV invasion and preserved liver function (Child-Pugh score ≤ B7) in a real-world study from multiple centers. Between January 2020 and December 2022, 91 consecutive HCC patients with MPV invasion who received either systemic medical therapy (i.e., tyrosine kinase inhibitors (TKIs) plus anti-PD-1 immunotherapy, S group, n = 43) or in combination with chemoembolization treatment (S-T group, n = 48) from five centers were enrolled in the study. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS) and treatment response. Adverse events (AEs) related to treatment were also recorded. Survival curves were constructed with the Kaplan-Meier method and compared using the log-rank test. The baseline characteristics were comparable between the two groups. The mean number of chemoembolization sessions per patient was 2.1 (range 1-3). The median OS was 10.0months and 8.0months in the S-T group and S group, respectively (P = 0.254). The median PFS between the two groups was similar (4.0months vs. 4.0months, P = 0.404). The disease control rate between the S-T and S groups were comparable (60.4% vs. 62.8%, P = 0.816). Although no chemoembolization-related deaths occurred, 13 grade 3-4 AEs occurred in the S-T group. The results of the real-world study demonstrated that additional chemoembolization treatment did not yield survival benefits compared to TKIs plus anti-PD-1 immunotherapy for the overall patients with advanced HCC and MPV invasion.

Efficacy and safety of apatinib plus immune checkpoint inhibitors and transarterial chemoembolization for the treatment of advanced hepatocellular carcinoma

PurposeThe evidence of apatinib plus immune checkpoint inhibitors (ICIs) and transarterial chemoembolization (TACE) for treating advanced hepatocellular carcinoma (HCC) is limited. This study aimed to compare the treatment efficacy and safety of apatinib plus ICIs and TACE with apatinib plus TACE in these patients.MethodsThis study retrospectively enrolled 90 patients with advanced HCC treated with apatinib plus TACE (A-TACE group, n = 52) or apatinib plus ICIs and TACE (IA-TACE group, n = 38).ResultsThe objective response rate was numerically higher in IA-TACE group compared with A-TACE group without statistical significance (57.9% vs. 36.5%, P = 0.055). Disease control rate was not different between groups (86.8% vs. 76.9%, P = 0.248). Progression-free survival (PFS) was improved in IA-TACE group compared with A-TACE group (P = 0.018). The median PFS (95% confidence interval) was 12.5 (8.7–16.3) months in IA-TACE group and 8.5 (5.6–11.4) months in A-TACE group. Overall survival (OS) was also prolonged in IA-TACE group compared with A-TACE group (P = 0.007). The median OS (95% confidence interval) was 21.1 (15.8–26.4) months in IA-TACE group and 14.3 (11.5–17.1) months in A-TACE group. By multivariate Cox regression model, IA-TACE was independently associated with prolonged PFS (hazard ratio = 0.539, P = 0.038) and OS (hazard ratio = 0.447, P = 0.025). Most adverse events were not different between groups. Only the incidence of reactive cutaneous capillary endothelial proliferation was higher in IA-TACE group compared with A-TACE group (10.5% vs. 0.0%, P = 0.029).ConclusionApatinib plus ICIs and TACE may be an effective and safe treatment for patients with advanced HCC, but further large-scale studies are needed for verification.