Systemic Therapy For Hepatocellular Carcinoma Research Articles

Analysis of prognosis and background liver disease in non-advanced hepatocellular carcinoma in two decades.

Antiviral hepatitis and systemic therapies for hepatocellular carcinoma (HCC) remarkably progressed in the recent 10 years. This study aimed to reveal the actual transition and changes in the prognosis and background liver disease in non-advanced HCC in the past 20 years. This retrospectively recruited 566 patients who were diagnosed with non-advanced HCC from February 2002 to February 2022. The prognosis was analyzed by subdividing according to the diagnosis date (period I: February 2002-April 2009 and period Ⅱ: May 2009-February 2022). Patients in period II (n = 351) were significantly older, with lower albumin-bilirubin (ALBI) scores and alpha-fetoprotein (AFP) and more anti-viral therapy, systemic therapy, and hepatic arterial infusion chemotherapy as compared with those in period I (n = 215). The etiology ratio of the background liver disease revealed decreased hepatitis C virus from 70.6% to 49.0% and increased non-B, non-C from 17.7% to 39.9% from periods I to Ⅱ. The multivariate analysis revealed older age and higher ALBI score in Barcelona Clinic Liver Cancer (BCLC) 0/A stage, AFP of >20 ng/mL, and higher ALBI score in BCLC B stage as independent prognosis factors. Fine-Gray competing risk model analysis revealed that liver-related deaths significantly decreased in period II as compared to period I, especially for BCLC stage 0/A (HR: 0.656; 95%CI: 0.442-0.972, P = 0.036). The characteristics of patients with non-advanced HCC have changed over time. Appropriate background liver management led to better liver-related prognoses in BCLC 0/A.

The Liver Frailty Index predicts survival in systemic therapy for hepatocellular carcinoma: a multicentre prospective cohort study

The Liver Frailty Index predicts survival in systemic therapy for hepatocellular carcinoma: a multicentre prospective cohort study

Hepatocellular Carcinoma: Advances in Systemic Therapy.

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing over 90% of cases globally and ranking as the third leading cause of cancer-related death. This article reviews the evolving landscape of systemic therapies for advanced HCC, emphasizing recent advancements and their impact on patient outcomes. The advent of molecular targeted therapies has transformed HCC management, with sorafenib being the first FDA-approved molecular targeted therapy, setting a standard for a decade. However, recent breakthroughs involve the combination of atezolizumab and bevacizumab, demonstrating superior outcomes over sorafenib, leading to FDA approval in 2020. Another notable combination is tremelimumab and durvalumab, showing efficacy in a multinational phase III trial. Beyond these combinations, this article explores the role of other first-line treatments and subsequent therapies after progression. The evolving landscape of systemic therapies for HCC reflects a paradigm shift, with immunotherapy combinations emerging as key players alongside targeted therapies. This article highlights the complexity of treatment decisions, considering individual patient characteristics and disease etiology, and underscores the ongoing quest to optimize both systemic and local-regional therapies for improved long-term outcomes in HCC patients.

Understanding the efficacy of frontline therapies for hepatocellular carcinoma through etiologic stratification.

491 Background: Despite significant advancements in recent years, hepatocellular carcinoma (HCC) treatment options remain limited for patients who progress on locoregional therapy. Given increasing interest in personalized cancer care for HCC, analysis was done to understand whether the etiology of HCC influenced the efficacy of four common first-line FDA approved systemic therapy regimens. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database from 1/1/2003 to 8/1/2021 with 3519 HCC patients who have received either atezolizumab-bevacizumab (AB), nivolumab, sorafenib, or lenvatinib as a first-line systemic therapy. Information on demographics (age, gender, sex race, ethnicity, ECOG, SES Index), cancer stage, and treatment type was collected. In addition, comorbidities of hepatitis B, hepatitis C, alcohol use, diabetes, and obesity were collected as surrogates for disease etiology: viral hepatic disease, alcohol induced hepatic dysfunction or non-alcoholic fatty liver disease (NAFLD). Patients with missing data in any of the population stratifying variables were excluded. Overall survival (OS), Progression-free-survival (PFS) and time to treatment discontinuation (TTTD) were analyzed for each systemic therapy stratified by etiology as endpoints. Kaplan-Meier (KM) univariate analysis was performed along with the log-rank test for the primary outcome. Multivariate analysis (MVA) was conducted on all three endpoints via cox proportional hazard model to adjust for possible covariates in the patient population. Results: After exclusion criteria, 548 patients with complete data were included (AB N=124, Sorafenib N=324, Lenvatinib N=61, Nivolumab N=39) with variable etiologic presence (hepatitis B N=14, hepatitis C N=50, alcohol use N=41, diabetes N=50, Obesity N=44). When comparing patients across all recorded systemic therapies stratified by the etiologic variables, there was no statistically significant difference in OS, PFS, or TTTD. When stratified by presence of Hepatitis B, patients treated with atezolizumab-bevacizumab trended towards improved outcomes but did not reach statistical significance (P = 0.064). Other treatments showed mixed results in relation to specific etiologies, but no clear trend in efficacy emerged. Conclusions: This early retrospective study suggests that systemic therapy for HCC is not significantly impacted by factors associated with the etiology of disease, such as hepatitis C, alcohol use, and obesity. However, small population sizes and potential nonrandom covariate missingness in this study may obscure effects. Future studies are needed to further elucidate this trend along with subpopulation effects of other systemic therapies.

Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis.

Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT). We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1. A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74). The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

Efficacy and features of balloon-occluded transarterial chemoembolization for hepatocellular carcinoma: a narrative review.

Systemic therapy for hepatocellular carcinoma (HCC) is recommended in transarterial chemoembolization (TACE)-refractory and unsuitable cases. In Japan, TACE is broadly classified into conventional TACE (C-TACE), balloon occluded TACE (B-TACE), and drug-eluting beads TACE. However, the type of TACE recommended for TACE-refractory or unsuitable cases has not been elucidated, and a targeted approach for individual cases and appropriate TACE selection is important. B-TACE is considered a valuable therapeutic option in the management of HCC. The technique involves the precise placement of a microcatheter with a balloon into the target hepatic artery, followed by selective occlusion of the hepatic artery, including tumor-feeding vessels, using the balloon. By leveraging the hemodynamic changes resulting from arterial occlusion, B-TACE enables effective accumulation of chemotherapeutic agents within the tumor. Incorporating B-TACE into the treatment strategy for HCC is of utmost importance. Therefore, this article provides an overview of the technique. A comprehensive review of all available literature in the English language through December 1, 2023 utilizing PubMed was conducted. In the intermediate stage, TACE and systemic therapy play complementary roles, and it is important to select a treatment strategy that considers tumor status and hepatic reserve. However, no study has investigated the various types of TACE in the treatment of such patients. Currently, TACE in Japan is broadly classified into C-TACE, B-TACE, and drug-eluting beads TACE (DEB-TACE). This article outlines the evolution of B-TACE for HCC. We identified retrospective and prospective studies evaluating B-TACE. In this review, we evaluate data on B-TACE for HCC. In the era of systemic therapy, B-TACE may play a complementary and synergy effect role.

Exploring potential predictive biomarkers through historical perspectives on the evolution of systemic therapies into the emergence of neoadjuvant therapy for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a type of liver cancer, ranks as the sixth most prevalent cancer globally and represents the third leading cause of cancer-related deaths. Approximately half of HCC patients miss the opportunity for curative treatment and are then limited to undergoing systemic therapies. Currently, systemic therapy has entered the era of immunotherapy, particularly with the advent of immune-checkpoint inhibitors (ICIs), which have significantly enhanced outcomes for patients with advanced HCC. Neoadjuvant treatment for HCC has become a possibility-findings from the IMbrave 050 trial indicated that ICIs offer the benefit of recurrence-free survival for high-risk HCC patients post-resection or local ablation. However, only a small fraction of individuals benefit from systemic therapy. Consequently, there is an urgent need to identify predictive biomarkers for treatment response and outcome assessment. This study reviewed the historical progression of systemic therapy for HCC, highlighting notable therapeutic advancements. This study examined the development of systemic therapies involving conventional drugs and clinical trials utilized in HCC treatment, as well as potential predictive biomarkers for advanced and/or locally advanced HCC. Various studies have revealed potential biomarkers in the context of HCC treatment. These include the association of dendritic cells (DCs) with a favorable response to neoadjuvant therapy, the presence of enriched T effector cells and tertiary lymphoid structures, the identification of CD138+ plasma cells, and distinct spatial arrangements of B cells in close proximity to T cells among responders with locally advanced HCC receiving neoadjuvant cabozantinib and nivolumab treatment. Furthermore, pathological response has been associated with intratumoral cellular triads consisting of progenitor CD8+ T cells and CXCL13+ CD4+ T helper cells surrounding mature DCs in patients receiving neoadjuvant cemiplimab for resectable HCC. Despite no widely recognized predictive biomarkers for HCC individualized treatment, we believe neoadjuvant trials hold the most promise in identifying and validating them. This is because they can collect multiple samples from resectable HCC patients across stages, especially with multi-omics, bridging preclinical and clinical gaps.

Questionnaire survey of Japanese board-certified expert hepatobiliary and pancreatic surgeons and instructors on the surgical indications for hepatocellular carcinoma.

Recent advancements in systemic therapy for hepatocellular carcinoma (HCC) necessitate the establishment of resectability criteria for advanced HCC. A questionnaire survey sought to clarify the perspectives of Japanese expert hepatobiliary surgeons regarding surgical indications for HCC. Thirty-one questions were used to determine when surgery is strongly recommended (resectable: R) or not recommended (unresectable: UR). A total of 351 responses were obtained. While 64.7% of the respondents considered solitary tumors as being R, irrespective of size, opinions diverged on the upper limit of the number of tumors/tumor size for R: (1) up to three nodules with no size limit (27.9%), (2) up to three nodules ≤5 cm in diameter each (21.4%) and (3) up to three nodules ≤3 cm in diameter each (19.4%). Vp1, Vp2, Vp3, and Vp4 were considered as being R by 90.9%, 70.7%, 39.0%, and 8.0% of respondents, respectively. Half of the respondents indicated they would consider resection even for cases with extrahepatic spread under limited conditions. The current views of Japanese expert surgeons on the resectability criteria for HCC were clarified for the first time. The findings could serve as a basis for preparing expert consensus statements on the resectability criteria for HCC.

Sorafenib Resistance Contributed by IL7 and MAL2 in Hepatocellular Carcinoma Can Be Overcome by Autophagy-Inducing Stapled Peptides.

Drug resistance poses a great challenge in systemic therapy for hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms associated with resistance to anti-cancer drugs, such as Sorafenib, remain unclear. In this study, we use transposon insertional mutagenesis to generate Sorafenib-resistant HCC cell lines in order to identify potential drug resistant causative genes. Interleukin 7 (IL7) and mal, T cell differentiation protein 2 (MAL2) were identified as candidate genes that promote survival by activating JAK/STAT and PI3K/AKT signaling pathways. Sorafenib-resistant cells exhibited higher clonogenic survival and lower drug sensitivity due to IL7 and MAL2 upregulation. Higher anti-apoptotic effect, clonogenic survival and increased PI3K/AKT/STAT3 activities were observed in IL7 and MAL2 co-overexpressing cells compared with controls or cells overexpressing IL7 or MAL2 individually. Given the critical role of MAL2 in endocytosis, we propose that MAL2 might facilitate the endocytic trafficking of IL7 and its cognate receptors to the plasma membrane, which leads to upregulated JAK/STAT and PI3K/AKT signaling pathways and Sorafenib resistance. Additionally, our previous studies showed that an autophagy-inducing stapled peptide promoted the endolysosomal degradation of c-MET oncogene and overcame adaptive Sorafenib resistance in c-MET+ HCC cells. In this study, we demonstrate that these stapled peptides readily induced autophagy and inhibited the proliferation of both wild-type and Sorafenib-resistant HCC cells co-overexpressing both IL7 and MAL2. Furthermore, these peptides showed synergistic cytotoxicity with Sorafenib in drug-resistant HCC cells co-overexpressing both IL7 and MAL2. Our studies suggest that targeting autophagy may be a novel strategy to overcome IL7/MAL2-mediated Sorafenib resistance in HCC.

Update on systemic therapy for hepatocellular carcinoma

Update on systemic therapy for hepatocellular carcinoma

Outcomes of Patients with Child-Pugh B and Unresectable Hepatocellular Carcinoma Undergoing First-Line Systemic Treatment with Sorafenib, Lenvatinib, or Atezolizumab Plus Bevacizumab

Introduction: Systemic therapy is recommended for patients with Child-Pugh A in hepatocellular carcinoma (HCC). We analyzed the outcomes of a cohort of patients with HCC who received either sorafenib (Sor), lenvatinib (Len) or atezolizumab plus bevacizumab (Atezo + Bev) as first-line systemic therapy for HCC, with the aim of identifying prognostic factors for survival. Methods: A total of 825 patients with advanced HCC and Child-Pugh A or B received either Sor, Len or Atezo + Bev as first-line systemic therapy. Liver function was assessed according to the Child-Pugh score and the modified albumin-bilirubin (mALBI) grade. Results: Prognosis was analyzed according to liver function such as Child-Pugh classifications, scores, and mALBI grades that worsened with a decline in liver function (p <0.001 for all). A Child-Pugh score of 7 was a factor significantly associated with OS. In patients with a Child-Pugh score of 7, an mALBI grade of 3 was an independent predictor of OS. In Child-Pugh B patients with HCC, receiving Atezo + Bev was identified as a factor associated with PFS. Conclusion: Determining the hepatic reserve of patients with unresectable HCC might be useful for identifying patents suitable for systemic treatment for HCC. Atezo + Bev might prolong the PFS of patients with a Child-Pugh score of 7.

Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence

BackgroundNovel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy.MethodsWe applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a prospective clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response at the time of resection.ResultsST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer-associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell marker expression suggesting strong activity of these cells. HCC-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to the tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic responses, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by HCC-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient.ConclusionsThese data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.

P53 and VEGF are promising biomarkers for sorafenib efficacy in an experimental model of NASH-related HCC.

The efficacy of systemic therapy for hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is poorly understood. In this study we evaluated the effects of sorafenib based on the expression of molecular markers related to major hepatocarcinogenesis pathways and angiogenesis in a NASH-related HCC model. Forty male rats were submitted to NASH-HCC induction through the combination of a high-fat and choline deficient diet and diethylnitrosamine (100mg/L) administration in the drinking water for 13 and 16weeks. After the induction period, the rats received daily gavage administration of saline solution (control) or Sorafenib (5mg/kg/day) for 3weeks. Thereafter, the animals were euthanized and samples from liver nodules were collected for histopathological analysis and immunohistochemical assessment of HEP-PAR-1, glutamine-synthetase, VEGF, survivin, β-catenin and p53. A semi-quantitative score was used for VEGF, survivin and β-catenin analysis. For p53, the percentage of positive cells was determined. Results were processed by Wilcoxon's test or Student's t-test. Both protocols efficiently induced HCC, most of them being moderately to poorly differentiated. Sorafenib-treated animals showed a decreased expression of VEGF and p53 in HCCs generated at 13weeks when compared to control animals (p = 0.03; p = 0.04, respectively). No significant difference in β-catenin and survivin were observed. There was a significant decrease in VEGF and p53 expression when comparing the two control groups (13 vs. 16weeks, p < 0.01). p53 and VEGF are promising biomarkers for assessment of efficacy of Sorafenib, whereas survivin and β-catenin were not found useful. Decreased immunohistochemical expression of p53 and VEGF in the 16week control group may indicate a different metabolic status of HCC.

Evaluation of cardiovascular toxicity of the atezolizumab and bevacizumab combination

Introduction: The combination of atezolizumab, an immune checkpoint inhibitor (ICI), and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, is the first choice for systemic therapy in hepatocellular carcinoma. Immune-related cardiovascular toxicity—myocarditis and pericarditis—are known to occur during ICI treatment. By contrast, VEGF inhibitors (VEGFIs) cause cardiovascular complications such as hypertension and heart failure. Thus, different cardiovascular toxicities have been recognized for ICIs and VEGFIs, but the impact of their combination remains unclear. Here, we aimed to investigate the cardiovascular toxicity profile of atezolizumab in combination with bevacizumab using the World Health Organization adverse event reporting database—VigiBase.Methods: We analyzed data included in VigiBase till December 2022. To evaluate the frequency of reports related to atezolizumab, bevacizumab, and their combinations for 21 adverse events, we calculated the reporting odds ratio and information component. Analyses of the fatality of various cardiovascular toxicities associated with the use of each drug were performed.Results: The database included 84,951, 10,595, and 2,092 reports of treatment with bevacizumab, atezolizumab, and their combination, respectively. The disproportionality signal of hypertension, arterial embolism and thrombosis, supraventricular tachyarrhythmias, heart failure, myocarditis, hemorrhage-related clinical events, venous embolism and thrombosis, cardiomyopathy, respiratory failure with combination regimen of atezolizumab and bevacizumab was detected. Signals of these adverse events were also detected treatment with either atezolizumab or bevacizumab alone. Venous embolism and thrombosis exhibited the highest fatality rate in the two drug combination (12.82%) relative to those of atezolizumab (6.19%) and bevacizumab (4.54%).Discussion: Cardiovascular toxicity, owing to the combination of atezolizumab and bevacizumab, was similar to that of each single agent, and no new safety concerns were observed. Caution should be exercised when combining the two drugs since the fatality rate of thromboembolism increases with combination treatment.

Pretreatment Proteinuria Predicts the Prognosis of Patients Receiving Systemic Therapy for Unresectable Hepatocellular Carcinoma.

Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.

Personalized treatment for hepatocellular carcinoma in the era of targeted medicine and bioengineering.

Hepatocellular carcinoma (HCC) is a major global health burden, causing approximately 8.3 million deaths each year, and it is the third leading cause of cancer-related death worldwide, with a relative 5-year survival rate of around 18%. Due to the advanced stage of diagnosis in most patients, systemic treatment based on targeted therapy has become the only feasible option. Genomic studies have established a profile of molecular alterations in hepatocellular carcinoma with potentially actionable mutations, but these mutations have yet to be translated into clinical practice. The first targeted drug approved for systemic treatment of patients with advanced hepatocellular carcinoma was Sorafenib, which was a milestone. Subsequent clinical trials have identified multiple tyrosine kinase inhibitors, such as Lenvatinib, Cabozantinib, and Regorafenib, for the treatment of hepatocellular carcinoma, with survival benefits for the patient. Ongoing systemic therapy studies and trials include various immune-based combination therapies, with some early results showing promise and potential for new therapy plans. Systemic therapy for hepatocellular carcinoma is complicated by the significant heterogeneity of the disease and its propensity for developing drug resistance. Therefore, it is essential to choose a better, individualized treatment plan to benefit patients. Preclinical models capable of preserving in vivo tumor characteristics are urgently needed to circumvent heterogeneity and overcome drug resistance. In this review, we summarize current approaches to targeted therapy for HCC patients and the establishment of several patient-derived preclinical models of hepatocellular carcinoma. We also discuss the challenges and opportunities of targeted therapy for hepatocellular carcinoma and how to achieve personalized treatment with the continuous development of targeted therapies and bioengineering technologies.

Unresectable Hepatocellular Carcinoma: A Review of New Advances with Focus on Targeted Therapy and Immunotherapy

With an expected incidence of more than 1 million cases by 2025, liver cancer remains a problem for world health. With over 90% of cases, hepatocellular carcinoma (HCC) is the most prevalent kind of liver cancer. In this review, we presented the range of experimental therapeutics for patients with advanced HCC, the successes and failures of new treatments, areas for future development, the evaluation of dose-limiting toxicity in different drugs, and the safety profile in patients with liver dysfunction related to the underlying chronic liver disease. In addition to the unmet demand for biomarkers to guide treatment decisions and the burgeoning fields of immunotherapy and systemic therapy in hepatocellular carcinoma, the development of old and new drugs, including their failures and current advancements, has been reviewed. This review aims to evaluate the updated optimal clinical treatment of unresectable hepatocellular carcinomas in clinical practice, mainly through targeted therapy. Although surgical treatment can significantly enhance the survival probability of early and intermediate-stage patients, it is unsuitable for most HCC patients due to a lack of donors. Due to their severe toxicity, the few first-line anti-HCC drugs, such as sorafenib, are often reserved for advanced HCC patients for whom other therapies have failed. The second-line drugs are usually alternatives for patients with intolerance or resistance. Consequently, the ongoing growth of possible preclinical drugs and studies on miRNAs, lncRNAs, and numerous other signaling pathway targets for developing novel drugs may introduce additional treatment prospects for HCC.

Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis?

Atezolizumab plus bevacizumab has recently been approved as a new first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). We performed a real-world study to evaluate the impact of the IMbrave150 trial inclusion criteria on the safety and efficacy of treatment outside of clinical trials. We analyzed patients treated with atezolizumab plus bevacizumab for unresectable HCC from four different countries. No specific inclusion and exclusion criteria were applied, except for the absence of previous systemic therapies for HCC. The entire population was split into two groups according to concordance with the inclusion criteria as reported in the IMbrave150 trial in 'IMbrave150-in' and 'IMbrave150-out' patients, and safety and efficacy in the two groups of patients were evaluated. Overall, 766 patients were included in the analysis: 561/766 (73%) in the 'IMbrave150-in' group and 205/766 (27%) in the 'IMbrave150-out' group. Median overall survival (OS) and median progression-free survival (PFS) were 16.3 versus 14.3 months (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.35-0.65; p<0.0001] and 8.3 versus 6.0 months (HR 0.79, 95% CI 0.63-0.99; p=0.0431) in 'IMbrave150-in' and 'IMbrave150-out' patients, respectively. Multivariate analysis confirmed that patients included in the 'IMbrave150-in' group had significantly longer OS compared with patients included in the 'IMbrave150-out' group (HR 0.76, 95% CI 0.47-0.97; p=0.0195). In 'IMbrave150-in' patients, the albumin-bilirubin (ALBI) grade was not associated with OS, whereas in 'IMbrave150-out' patients, those with ALBI grade 1 reported a significant benefit in terms of OS compared with those with ALBI grade 2 (16.7 vs. 5.9 months; HR 4.40, 95% CI 2.40-8.08; p>0.0001). No statistically significant differences were reported in the 'IMbrave150-in' and 'IMbrave150-out' groups in terms of safety profile. Adherence to the IMbrave150 trial inclusion criteria favorably impacts the prognosis of patients receiving atezolizumab plus bevacizumab. Among patients who did not meet the IMbrave150 inclusion criteria, those with ALBI grade 1 could benefit from the treatment.

The Roles of Epigenetic Regulation and the Tumor Microenvironment in the Mechanism of Resistance to Systemic Therapy in Hepatocellular Carcinoma.

Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC.

Real world data of systemic therapy for hepatocellular carcinoma in Japan: HERITAGE study.

510 Background: Currently 6 regimens are available for advanced hepatocellular carcinoma (HCC) in Japan, including atezolizumab plus bevacizumab (AB), sorafenib (S), and lenvatinib (L) for first-line treatment and regorafenib (R), ramucirumab (RAM), and cabozantinib (C) for the second-line treatment. In real-world clinical practice, the number of combinations of treatment sequences is enormous. We have launched a nationwide registry of systemic therapy for HCC named Hepatoma Registry of Integrating and Aggregating Electric Health Records (HERITAGE). Methods: The HERITAGE is linked to the nationwide follow-up survey of the Japan Liver Cancer Association; cases treated with systemic therapy between 2015 and 2022 were included in the current study. Information on treatment efficacy and duration was collected and registered on each treatment regimen. Results: As of June 2022, 6,400 treatment lines (S 2,319, L 2559, AB 768, R 406, RAM 251, C 71) in 4,307 cases were enrolled. The response rates, disease control rates, and median treatment duration of each sequence of regimens are shown in the table. The 1st line regimen, S, L, and AB, were also used as the second and later lines in Japan and found as effective as if used as the 1st line treatment. Limitation: No adjustments for clinical conditions were performed. Conclusions: We have demonstrated the efficacy of various treatment sequences in a sufficient number of cases. Clinical trial information: UMIN000046567 . [Table: see text]