Treatment Of Advanced Hepatocellular Carcinoma Research Articles

Sorafenib combined with tarexib for first-line treatment of unresectable hepatocellular carcinoma and its predictive role and correlation with PD-L1 CTCs

BackgroundThis study aims to evaluate the safety efficacy of combining the PD-1 antibody Tirelizumab with Sorafenib in the treatment of advanced hepatocellular carcinoma. Additionally we are committed to investigating the relationship between circulating tumor cell (CTC) counts/PD-L1 expression the prognosis of patients with advanced hepatocellular carcinoma.MethodsThis study included 32 patients with unresectable primary liver cancer who received treatment with Tislelizumab in combination with Sorafenib. Tislelizumab was administered via intravenous injection at a dose of 200 mg every 3 weeks, while Sorafenib was given orally at a dose of 400 mg twice daily. Patients were evaluated every 3 cycles (9 weeks) to assess the safety and efficacy of the treatment regimen. Prior to enrollment, all patients underwent CTC counting and assessment of PD-L1 expression in circulating tumor cells. The primary endpoint was the objective response rate (ORR), evaluated by the investigator according to the RECIST v1.1 criteria. Secondary endpoints aimed to assess the relationship between circulating tumor cell (CTC) counts or programmed death ligand 1 (PD-L1) expression and the prognosis of patients with advanced hepatocellular carcinoma.ResultsAs of November 2022, a total of 32 patients have been enrolled in the study and received combination treatment. Among the 32 patients, 31 (96.8%) tested positive for circulating tumor cells (CTCs), with counts ranging from 1 to 45 and a median of 7 (3, 11). PD-L1-positive CTCs were detected in 25 patients (78.1%). All 32 patients were followed up for 2 to 14 months, with a median follow-up time of 6 months. Correlation analysis revealed that distant metastasis, vascular invasion, and the presence of more than 5 CTCs were significantly associated with PD-L1-positive CTCs. The one-year overall survival rates for patients with PD-L1-positive CTCs and those with PD-L1-negative CTCs were 78.5% vs 64.3% (P = 0.309). Additionally, the one-year overall survival rates for the group with rising CTC counts compared to the group with stable or declining counts were 34.3% vs 90% (P = 0.063).ConclusionThe combination of Tislelizumab and Sorafenib demonstrates promising antitumor activity in the first-line treatment of hepatocellular carcinoma, with a relatively high objective response rate (ORR) and acceptable safety profile. Baseline CTC PD-L1 positivity can serve as a predictive marker for selecting hepatocellular carcinoma patients for PD-1/PD-L1 blockade therapy, and dynamic measurement of CTC changes can be used to monitor treatment efficacy.

A case of complete remission by cabozantinib as an end-line treatment for advanced hepatocellular carcinoma.

Cabozantinib is a multi-kinase inhibitor targeting multiple tyrosine kinases. It improves overall survival and progression-free survival in patients previously treated with sorafenib for advanced hepatocellular carcinoma (HCC) compared to the placebo in the phase 3 CELESTIAL trial. A 71-year-old man presented to our hospital for treatment of HCC with chronic hepatitis C. He was refractory to sorafenib, lenvatinib, regorafenib, and ramucirumab and started atezolizumab and bevacizumab therapy in November 2020. After administering the second cycle on December 10, 2020, the patient was diagnosed with progressive disease in January 2021. Therefore, cabozantinib (60 mg/day) was initiated on January 14, 2021. As the grade 3 aspartate aminotransferase and alanine aminotransferase levels increased, grade 3 anorexia and a decline in performance status were observed in the first week, and cabozantinib was terminated. His performance status and anorexia gradually improved, and contrast-enhanced computed tomography (CT) in June 2021 showed complete remission (CR) according to the modified Response Evaluation Criteria in Solid Tumors. The patient did not show disease progression for 11 months without receiving any treatment for HCC. To the best of our knowledge, this is the first report of CR with cabozantinib in advanced HCC.

Lenvatinib, sintilimab combined interventional treatment vs bevacizumab, sintilimab combined interventional treatment for intermediate-advanced unresectable hepatocellular carcinoma.

Bevacizumab and sintilimab combined interventional treatment (BeSiIT) and L envatinib and sintilimab combined interventional treatment (LeSiIT) are two commonly used therapeutic regimens for intermediate-advanced hepatocellular carcinoma (HCC) in clinical practice. To compare the clinical efficacy and safety of BeSiIT and LeSiIT for the treatment of intermediate and advanced HCC. Patients diagnosed with intermediate-advanced HCC and initially treated with BeSiIT or LeSiIT in the Tianjin Medical University Cancer Institute and Hospital between February 2020 and July 2021 were included. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), conversion rate, and treatment-related adverse events. Total 127 patients met the inclusion criteria and were divided into BeSiIT and LeSiIT groups. Twenty-eight and fifty patients in the BeSiIT and LeSiIT groups, respectively, were assessed after 1:2 propensity score matching. PFS and OS rates were not significantly different between the two groups. No significant variations were noted in ORRs or DCRs according to the Response Evaluation Criteria in Solid Tumors (RECIST), and modified RECIST. BeSiIT group showed a better conversion rate than the LeSiIT group (P = 0.043). Both groups showed manageable toxicity profiles. Multivariate analysis showed that the independent factors associated with PFS were alpha-fetoprotein levels and carcinoembryonic antigen score. In intermediate-to-advanced HCC, the BeSiIT and LeSiIT groups exhibited acceptable toxicities and comparable PFS, OS, and ORR.

Drug-eluting beads chemoembolization combined with programmed cell death 1 inhibitor and lenvatinib for large hepatocellular carcinoma.

The combination of transarterial chemoembolization (TACE), lenvatinib, and programmed cell death 1 (PD-1) inhibitor has been widely used in the treatment of advanced hepatocellular carcinoma (HCC) and has achieved promising results. However, there are few studies comparing whether drug-eluting beads TACE (D-TACE) can bring more survival benefits to patients with large HCC compared to conventional TACE (C-TACE) in this triplet therapy. To compare the efficacy and adverse events (AEs) of triple therapy comprising D-TACE, PD-1 inhibitors, and lenvatinib (D-TACE-P-L) and C-TACE, PD-1 inhibitors, and lenvatinib (C-TACE-P-L) in patients with large HCC (maximum diameter ≥ 5 cm), and analyze the prognostic factors. Following a comprehensive review of our hospital's medical records, this retrospective study included 104 patients: 50 received D-TACE-P-L, and 54 received C-TACE-P-L. We employed Kaplan-Meier estimation to assess the median progression-free survival (PFS) between the two groups, utilized Cox multivariate regression analysis to identify prognostic factors, and applied the χ 2 test to evaluate AEs. The objective response rate (ORR) and median PFS were significantly higher in the D-TACE-P-L group compared to the C-TACE-P-L group (ORR: 66.0% vs 44.4%, P = 0.027; median PFS: 6.8 months vs 5.0 months, P = 0.041). Cox regression analysis identified treatment option, portal vein tumor thrombus, and hepatic vein invasion as protective factors for PFS. AEs were comparable between the two groups. D-TACE-P-L may have significantly better PFS and ORR for large HCC, while exhibiting similar AEs to C-TACE-P-L.

Demographics and Immunotherapy Efficacy for Advanced Hepatocellular carcinoma: A Systematic Review and Meta-Analysis of Phase III Clinical Trials

Introduction: Immune checkpoint inhibitors (ICIs) are fundamental in treating advanced hepatocellular carcinoma (HCC). Considering previous reports implied varied responses among patient subgroups, such as patients with different hepatitis etiologies, we planned this meta-analysis to identify specific populations that might derive greater survival benefits from ICIs as a first-line treatment. Methods: We conducted a comprehensive search in PubMed and the Cochrane Library for phase III clinical trials comparing ICIs and multikinase inhibitors (MKIs) as first-line therapies for advanced HCC. We extracted and synthesized hazard ratios (HRs) for overall survival (OS) across different patient subgroups mainly using the random effect model. Results: Our analysis included nine phase III trials involving ICIs, either alone or in combination with other treatments, compared with MKIs. The synthesized HRs for patients with hepatitis B virus, hepatitis C virus, and nonviral etiologies were 0.74, 0.77, and 0.86, respectively, showing no significant differences (p = 0.13). Such finding remained when we only analyzed clinical trials with positive results. HRs consistently favored ICIs across various demographics such as age, sex, geographic region, performance status, alpha-fetoprotein levels, and disease stage or extent. Notably, patients with extrahepatic spread showed a trend towards better outcomes (HR 0.73) compared to those without (HR 0.85, p = 0.07). Conclusion: The efficacy of ICIs as a first-line treatment for advanced HCC was consistent across diverse patient subgroups, regardless of hepatitis etiology or other demographic factors. These findings do not support using these characteristics to determine the use of ICI therapy in advanced HCC.

Human GM-CSF/IL-3 enhance tumor immune infiltration in humanized HCC patient-derived xenografts

Background & AimsResponses to immunotherapies in hepatocellular carcinoma (HCC) are suboptimal with no biomarkers to guide patient selection. “Humanized” mice represent promising models to address this deficiency but are limited by variable chimerism and underdeveloped myeloid compartments. We hypothesized that expression of human GM-CSF and IL-3 increases tumor immune cell infiltration, especially myeloid-derived cells, in humanized HCC patient-derived xenografts (PDXs). Material and MethodsNOG (NOD/Shi-scid/IL-2Rγnull) and NOG-EXL (huGM-CSF/huIL-3 NOG) mice conditioned with Busulfan underwent i.v. injection of human CD34+ cells. HCC PDX tumors were then implanted subcutaneously (SQ) or orthotopically (OT). Following serial blood sampling, mice were euthanized at defined tumor sizes. Tumor, blood, liver, and spleen were analyzed by flow cytometry and immunohistochemistry. ResultsHumanized NOG-EXL mice demonstrated earlier and increased human chimerism compared to humanized NOG mice (82.1% vs 43.8%, p<0.0001) with increased proportion of human monocytes (3.2% vs 1.1%, p=0.001) and neutrophils (0.8% vs 0.3%, p=0.02) in circulation. HCC tumors in humanized NOG-EXL mice had increased human immune cell infiltration (57.6% vs 30.2%, p=0.04), noting increased regulatory T cells (14.6% vs 6.8%, p=0.04), CD4+ PD-1 expression (84.7% vs 32.0%, p<0.01), macrophages (1.2% vs 0.6%, p=0.02), and neutrophils (0.5% vs 0.1%, p<0.0001). No differences were observed in tumor engraftment or growth latency in SQ tumors, but OT tumors required implantation at two rather than four weeks post-humanization for successful engraftment. Finally, utilizing adult bone marrow instead of fetal livers enabled partial HLA-matching to HCC tumors but required more CD34+ cells. ConclusionsHuman GM-CSF and IL-3 expression in humanized mice resulted in features more closely approximating the immune microenvironment of human disease, providing a promising model for investigating critical questions in immunotherapy for HCC. Impact and ImplicationsThis study introduces a unique mouse model at a critical point in the evolution of treatment paradigms for patients with hepatocellular carcinoma (HCC). Immunotherapies have become first line treatment for advanced HCC; however, response rates remain low with no clear predictors of response to guide patient selection. In this context, animal models that recapitulate human disease are greatly needed. Leveraging xenograft tumors derived from patients with advanced HCCs and a commercially available immunodeficient mouse strain that expresses human GM-CSF and IL-3, we demonstrate a novel but accessible approach for modeling the HCC tumor microenvironment.

Úloha imunoterapie pri liečbe hepatocelulárneho karcinómu

Hepatocellular carcinoma (HCC) represents the most common primary liver malignancy, accounting for approximately 75–80% of all liver cancer cases. The global incidence of hepatocellular carcinoma is increasing due to rising rates of underlying diseases, creating a significant cancer burden and a significant clinical challenge due to its often late presentation and limited effective treatment options. Immune checkpoint inhibitors have revolutionized the treatment approach in various malignancies. In the treatment of advanced hepatocellular carcinoma, immunotherapy has proven to be more effective than tyrosine kinase inhibitors, which have been a treatment option for a decade. Clinical trials such as the HIMALAYA and IMbrave150 have demonstrated significant survival benefits, showing superior efficacy compared to sorafenib. Despite these promising results, not all HCC patients respond to immunotherapy equally. There is a need to search for reliable prognostic and predictive biomarkers that can help predict which patients are most likely to benefit from immunotherapy, thereby personalizing treatment and improving outcomes. The purpose of this article is to provide a summary of clinical trials on immunotherapy for various stages of hepatocellular carcinoma.

Current perspectives on the pharmacological treatment of advanced hepatocellular carcinoma: a narrative review

Current perspectives on the pharmacological treatment of advanced hepatocellular carcinoma: a narrative review

N6‐methyladenosine reader YTHDF3‐mediated zinc finger protein 41 inhibits hepatocellular carcinoma progression by transcriptional repression of Snail

AbstractAdvanced metastasis of hepatocellular carcinoma (HCC) significantly contributes to high death rates among patients. The efficiency of targeted therapies and chemotherapeutic agents shows individual variability. Therefore, there is no effective treatment for advanced HCC. Zinc finger proteins (ZFPs) are known to be crucial in various tumors, especially on HCC. In our study, we verified that ZFP41 could suppress the progression and metastasis of HCC through in vitro and in vivo experiments. During the past years, N6‐methyladenine (m6A) regulation has also been increasingly reported in HCC. To investigate whether ZFP41 could be regulated via m6A methylation, our results showed that YTHDF3 bound to the mRNA of ZFP41 and degrade it. Subsequently, to further elucidate the function of ZFP41, we identified Snail, a well‐known oncogenic molecule, through RNA‐seq. As a canonical component in the epithelial‐to‐mesenchymal transition (EMT) pathway, Snail plays a pivotal role and is a critical marker for tumor invasion and metastasis. Our results showed ZFP41 could inhibit Snail and the EMT pathway through its transcriptional repression. In conclusion, our study revealed that ZFP41 is a potential prognostic element for patients with HCC, and targeting ZFP41 might be used for translational clinical applications as a promising therapeutic target.

PH-sensitive adriamycin hydrochloride and oxaliplatin dual-loaded microspheres synergistically enhance local injections effect of hepatocellular carcinoma

Chemotherapy is the primary palliative treatment for advanced hepatocellular carcinoma (HCC). However, the systemic delivery is associated with the drawbacks including a high risk of adverse effects and a low efficacy. Therefore, local injection therapy may be beneficial. Nevertheless, the existing local drug-carrying microspheres(DOBM)have the characteristics of low loading and abrupt release, can not simultaneously load two drugs, and may cause unnecessary toxicity. In this study, we created the dual-loaded bovine serum albumin (BSA) microspheres (also known as DOBM), which were hollow and contained both oxaliplatin (OXA) and Adriamycin hydrochloride (DOX). In addition, this pH-sensitive drug delivery method exhibited a high drug loading capacity and was promising in breaking through biological barriers, making it a viable option for the treatment of HCC through local implantation. Based on physiochemical evaluation of BSA microspheres, they had a porous structure which was close to the surface. Adriamycin and oxaliplatin were successfully added to the surface of BSA microspheres. According to in vitro experimental results, the growth of human HCC (HCC-LM3 and PLC/PRF/5) cell lines was significantly inhibited by DOBM. Furthermore, in the subcutaneous PLC/PRF/5 HCC model, DOBM played an essential role in tumor development and change in the tumor microenvironment.

Clinical significance of upregulated Rho GTPase activating protein 12 causing resistance to tyrosine kinase inhibitors in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major health challenge with high incidence and poor survival rates in China. Systemic therapies, particularly tyrosine kinase inhibitors (TKIs), are the first-line treatment for advanced HCC, but resistance is common. The Rho GTPase family member Rho GTPase activating protein 12 (ARHGAP12), which regulates cell adhesion and invasion, is a potential therapeutic target for overcoming TKI resistance in HCC. However, no studies on the expression of ARHGAP12 in HCC and its role in resistance to TKIs have been reported. To unveil the expression of ARHGAP12 in HCC, its role in TKI resistance and its potential associated pathways. This study used single-cell RNA sequencing (scRNA-seq) to evaluate ARHGAP12 mRNA levels and explored its mechanisms through enrichment analysis. CellChat was used to investigate focal adhesion (FA) pathway regulation. We integrated bulk RNA data (RNA-seq and microarray), immunohistochemistry and proteomics to analyze ARHGAP12 mRNA and protein levels, correlating with clinical outcomes. We assessed ARHGAP12 expression in TKI-resistant HCC, integrated conventional HCC to explore its mechanism, identified intersecting FA pathway genes with scRNA-seq data and evaluated its response to TKI and immunotherapy. ARHGAP12 mRNA was found to be highly expressed in malignant hepatocytes and to regulate FA. In malignant hepatocytes in high-score FA groups, MDK-[integrin alpha 6 (ITGA6) + integrin β-1 (ITGB1)] showed specificity in ligand-receptor interactions. ARHGAP12 mRNA and protein were upregulated in bulk RNA, immunohistochemistry and proteomics, and higher expression was associated with a worse prognosis. ARHGAP12 was also found to be a TKI resistance gene that regulated the FA pathway. ITGB1 was identified as a crossover gene in the FA pathway in both scRNA-seq and bulk RNA. High expression of ARHGAP12 was associated with adverse reactions to sorafenib, cabozantinib and regorafenib, but not to immunotherapy. ARHGAP12 expression is elevated in HCC and TKI-resistant HCC, and its regulatory role in FA may underlie the TKI-resistant phenotype.

Apatinib plus hepatic arterial infusion of oxaliplatin and raltitrexed for hepatocellular carcinoma with extrahepatic metastasis: phase II trial

Most patients with advanced hepatocellular carcinoma (HCC) ultimately experience tumor progression after first-line systemic therapies. Systemic therapy is generally recommended as second-line treatment for advanced HCC in the major guidelines. Combining apatinib with hepatic arterial infusion chemotherapy (HAIC) likely drives synergistic activity on advanced HCC with extrahepatic metastasis. This phase II trial (ChiCTR2000029082) aimed to assess efficacy and safety of this combination in patients with HCC with extrahepatic metastasis who have progressed after first-line systemic therapies. The primary end point was the objective response rate (ORR). The secondary endpoints were progress-free survival (PFS), disease control rate (DCR), 6- and 12-month survival rates, overall survival (OS), and adverse events (AEs). Thirty-nine patients received oral treatment with apatinib, and hepatic artery infusion oxaliplatinplus raltitrexed. Per RECIST v1.1, the ORR and DCR was 53.8% and 89.7% in the patients population, respectively. The median PFS and OS was 6.2 months and 11.3 months, respectively. The 6- and 12-month survival rates were 81.7% and 44.1%, respectively. All AEs were manageable by medication or dose modifications. Apatinib plus HAIC for second-line therapy in advanced HCC with extrahepatic metastasis shows promising efficacy and manageable toxicities.

High-throughput screening identified pacritinib as a promising therapeutic approach to overcome lenvatinib resistance in hepatocellular carcinoma by targeting IRAK1

Lenvatinib resistance presents a significant challenge in the clinical management of advanced hepatocellular carcinoma (HCC). To address this issue, we established lenvatinib resistant HCC cells and performed high-throughput screening using FDA-approved anti-cancer drug library. Through quantitative selective drug sensitivity scoring (sDSS), pacritinib, a well-known JAK inhibitor, emerged as the top candidate, displaying the highest sDSS score among 219 compounds. We further demonstrated that pacritinib reduced the viability of a panel of HCC cell lines in a dose-dependent manner, while exhibiting minimal effects on normal liver cells. Interestingly, pacritinib, but not other JAK inhibitors such as ruxolitinib, upadacitinib, or filgotinib, acted synergistically with lenvatinib in HCC cells. In lenvatinib-resistant HCC cells, pacritinib significantly decreased proliferation and induced apoptosis. Rescue studies using IL-1 receptor-associated kinase 1 (IRAK1) overexpression and knockdown revealed that pacritinib's effects are mediated through IRAK1, with minimal impact on normal liver cells. In a xenograft model of lenvatinib-resistant HCC, oral administration of pacritinib significantly reduced tumor size without affecting body weight. Immunohistochemical analysis of tumor sections revealed that pacritinib reduced Ki67 staining and phosphorylated IRAK1. Our findings suggest that pacritinib may be a promising therapeutic option for the treatment of advanced HCC, particularly in patients who have developed resistance to lenvatinib.

Synergistic activity of Enterococcus Faecium-induced ferroptosis via expansion of IFN-γ+CD8+ T cell population in advanced hepatocellular carcinoma treated with sorafenib

ABSTRACT The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-γ production and an increased proportion of IFN-γ+CD8+ T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-γ+CD8+ T cells to secrete IFN-γ, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.

Second-line treatment patterns and outcomes in advanced HCC after progression on atezolizumab/bevacizumab

Background and AimsAtezolizumab/bevacizumab (A/B) is now a standard first-line (1L) treatment for advanced hepatocellular carcinoma (aHCC), but the optimal second-line (2L) regimen is not known. We evaluated real world treatment patterns and outcomes to investigate factors associated with post-progression survival (PPS). MethodsIn this multicenter, international, retrospective study, we examined clinical characteristics and outcomes of patients with aHCC who progressed on 1L A/B. The primary outcome of PPS was defined as time from first radiographic progression on A/B to death. Results406 patients alive after progression on 1L A/B were included in the final analysis. 45.3% (n=184) received best supportive treatment (BST) and 54.7% (n=222) continued active systemic treatment. In the 2L, 155 patients were treated with tyrosine kinase inhibitors (TKIs), 45 with immune checkpoint inhibitor (IO)-based regimens, and 3 had missing data. Median PPS of the whole cohort (mPPS) was 6.0 months (95% CI: 5.2-7.2). On multivariate Cox regression analysis, absence of portal vein tumor thrombus, ECOG <2, and continued active treatment were predictors of better PPS. mPPS was significantly longer for patients who continued active treatment versus BST (9.7 vs 2.6 months; HR 0.41, p<0.001). In the 2L setting, patients treated with TKIs had a numerically shorter mPPS compared to those treated with IO (8.4 vs 14.9 months; HR 1.37, p=0.256). ConclusionsContinuation of active therapy after A/B progression was independently associated with better survival even after adjusting for baseline disease characteristics. mPPS with IO-based therapy exceeded a year, suggesting that IO continuation post-progression may retain benefit. The precise sequencing of TKI and IO regimens warrants further investigation.

The Trend of the Treatment of Advanced Hepatocellular Carcinoma: Combination of Immunotherapy and Targeted Therapy.

Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy.

Triple combination of hepatic arterial infusion chemotherapy, immune checkpoint inhibitors, and tyrosine kinase inhibitors for treatment of advanced hepatocellular carcinoma: more robust evidence is still needed.

Triple combination of hepatic arterial infusion chemotherapy, immune checkpoint inhibitors, and tyrosine kinase inhibitors for treatment of advanced hepatocellular carcinoma: more robust evidence is still needed.

Combining liver-directed and immunotherapy in advanced hepatocellular carcinoma: A review and future directions

Hepatocellular carcinoma (HCC) is a highly morbid tumor with diverse genomic heterogeneity that poses a major therapeutic barrier. Systemic immunotherapy is often considered in the treatment of advanced HCC, but immunotherapy has been limited by high rates of resistance and immune evasion. Newer studies have explored the combination of locoregional treatments (LRTs), a common approach to intermediate-stage HCC or as a bridge to transplant, with immunotherapy. This review explores the current evidence regarding combination systemic immunotherapy with locoregional transarterial, ablation, and histotripsy modalities, as well as leading theories on the mechanism of their synergistic effects. Combinations of transarterial or ablative therapy with multikinase (MKIs) or immune checkpoint inhibitors (ICIs) have been linked to prolonged survival and delayed tumor progression/recurrence, though treatment-induced adverse effects remain an important consideration. Ablation and histotripsy may augment the efficacy of immunotherapy through the abscopal effect, in which subsequent immune response to local tumor destruction may enhance immunogenic cell death, even in satellite, untreated lesions. Newer management strategies may utilize circulating tumor DNA (ctDNA) for improved surveillance and early detection of recurrence.

New advances in the treatment of intermediate and advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, affecting millions of people worldwide. Due to the complexity and variability of the disease, there are major challenges in the treatment of HCC in its intermediate and advanced stages; despite advances in various treatment modalities, there are still gaps in our understanding of effective therapeutic strategies. Key findings from several studies have shown that the combination of immunotherapy and targeted therapy has a synergistic anti-tumor effect, which can significantly enhance efficacy with a favorable safety profile. In addition, other studies have identified potential biomarkers of therapeutic response, such as tumor protein 53 (TP53) and CTNNB1 (encoding β-conjugated proteins), thus providing personalized treatment options for patients with intermediate and advanced hepatocellular carcinoma. The aim of this article is to review the recent advances in the treatment of intermediate and advanced HCC, especially targeted immune-combination therapy, chimeric antigen receptor T cell therapy (CAR-T cell therapy), and gene therapy for these therapeutic options that fill in the gaps in our knowledge of effective treatment strategies, providing important insights for further research and clinical practice.

Efficacy and safety of transcatheter arterial chemoembolization followed by hepatic arterial infusion chemotherapy combined with TKI and PD-1 inhibitors as first-line treatment for advanced hepatocellular carcinoma

To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) followed by hepatic arterial infusion chemotherapy (HAIC) combined with TKI drugs and PD-1 inhibitors as the first-line treatment for advanced hepatocellular carcinoma (HCC). We retrospectively analyzed the data of 70 patients with advanced HCC treated in the Department of Oncology of Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine between July, 2020 and June, 2023. 23 of the patients received TACE combined with HAIC and TKI (TACE+HAIC+ TKI group) and 47 received TACE combined with HAIC, PD-1 inhibitors and TKI (TACE+HAIC+PD-1+TKI group). The clinical characteristics, laboratory test results, efficacy, outcomes and adverse events of the patients were compared between the two groups. The TACE+HAIC+TKI and TACE+HAIC+PD-1+TKI groups had significantly different objective remission rates (ORR; 60.87% vs 36.17%, P=0.031), comparable disease control rates (95.65% vs 93.62%, P=0.068), and different median progression-free survival (PFS) time (10.2 vs 11.8 months, P=0.003) and median overall survival (OS) time (15.7 vs 19.5 months, P=0.035). After propensity score matching (PSM), the median PFS and OS time of the two groups was 10.1 vs 14.5 months (P= 0.024) and 14.2 vs 21.2 months (P=0.221), respectively. The 1-year PFS rates of the 2 groups were 24.0% vs 52.2%, and the 1-, 2-and 3-year OS rates were 72.3% vs 93.1%, 23.9% vs 63.8%, and 23.9% vs 36.5%, respectively. The incidence of proteinuria was significantly higher in TACE+HAIC+PD-1+TKI group than in TACE+HAIC+TKI group (21.28% vs 0, P=0.025), but the incidences of grade 3-4 treatment-related adverse events were all similar between the two groups. The first-line treatment with TACE+HAIC+PD-1+TKI is safe and effective for advanced HCC and can significantly prolong the survival of the patients.