Management Of Advanced Hepatocellular Carcinoma Research Articles

Precision combination therapies: shaping the future management of advanced hepatocellular carcinoma?

Precision combination therapies: shaping the future management of advanced hepatocellular carcinoma?

Immunotherapy responses in viral hepatitis-induced hepatocellular carcinoma: A meta-analysis.

e16223 Background: The advent of immunotherapy has ushered in a paradigm shift in the management of advanced hepatocellular carcinoma (HCC). The distinctive etiological profiles of HCC, characterized by HBV predominance in Asia and HCV/nonviral prevalence in the West, may impart intricacies in the immunological milieu, thereby influencing treatment outcomes. This meta analysis delves into the immunotherapeutic outcomes in patients with hepatitis-induced HCC. Methods: A systematic search was conducted by applying the Boolean logic (and/or) in PubMed (MEDLINE), Embase and Cochrane Library until February 3, 2024. This study investigates the outcomes of patients with HCC complicated by hepatic infection, focusing on overall survival (OS) and progression-free survival (PFS). A meta-analysis was conducted, combining data from 6 studies for OS and 5 studies for PFS. Statistical analyses were conducted using R (v.4.3.2., Vienna). Results: A total of 6 clinical trials pooling in 2958 patients were included in this meta analysis. For OS, the random effects model estimated the cumulative survival across the studies to be 18.3950 months (95% CI [16.3869; 20.4032]). Quantifying heterogeneity revealed a tau-squared value of 5.1789 and Higgins I-squared of 72.7% [41.2%; 87.3%]. The test of heterogeneity indicated significant variability among the studies (Q = 21.99, df = 6, p = 0.0012). For PFS, the random effects model estimated the combined progression-free survival to be 5.9906 months (95% CI [4.2889; 7.6923]). Quantifying heterogeneity revealed a tau-squared value of 3.4995 and Higgins I-squared of 95.4% [91.9%; 97.4%]. The test of heterogeneity indicated significant variability among the studies (Q = 87.66, df = 4, p < 0.0001). Conclusions: The intricate relationship between HCC, hepatic infection, and treatment outcomes necessitates tailored therapeutic strategies for this patient population. Unveiling the heterogeneity in our analysis prompts a comprehensive exploration of potential factors, spanning both biological variances and clinical parameters. This inquiry fuels scientific discourse, urging an in-depth investigation into the immunological nuances influencing therapeutic responses in hepatitis-induced HCC. By addressing these complexities, we can optimize patient care and advance our understanding of effective treatment modalities for this challenging disease.

Precise staging of advanced HCC promotes higher quality of personalized treatment management: Chinese experts consensus on precision diagnosis and management of advanced hepatocellular carcinoma (2023)

Precise staging of advanced HCC promotes higher quality of personalized treatment management: Chinese experts consensus on precision diagnosis and management of advanced hepatocellular carcinoma (2023)

Advances in Targeted Drug Resistance Associated with Dysregulation of Lipid Metabolism in Hepatocellular Carcinoma.

Hepatocellular carcinoma is the prevailing malignant neoplasm affecting the liver, often diagnosed at an advanced stage and associated with an unfavorable overall prognosis. Sorafenib and Lenvatinib have emerged as first-line therapeutic drugs for advanced hepatocellular carcinoma, improving the prognosis for these patients. Nevertheless, the issue of tyrosine kinase inhibitor (TKI) resistance poses a substantial obstacle in the management of advanced hepatocellular carcinoma. The pathogenesis and advancement of hepatocellular carcinoma exhibit a close association with metabolic reprogramming, yet the attention given to lipid metabolism dysregulation in hepatocellular carcinoma development remains relatively restricted. This review summarizes the potential significance and research progress of lipid metabolism dysfunction in Sorafenib and Lenvatinib resistance in hepatocellular carcinoma. Targeting hepatocellular carcinoma lipid metabolism holds promising potential as an effective strategy to overcome hepatocellular carcinoma drug resistance in the future.

First-Line Targeted Therapy for Hepatocellular Carcinoma: Role of Atezolizumab/Bevacizumab Combination.

Hepatocellular carcinoma (HCC) is an aggressive malignancy accounting for 90% of primary liver malignancies. Therapeutic options for HCC are primarily based on the baseline functional status, the extent of disease at presentation and the underlying liver function that is clinically evaluated by the Barcelona-Clinic Liver Cancer system and Child–Pugh score. In patients with advanced HCC, the United States Food and Drug Administration (US-FDA) approved systemic therapies include the combination of atezolizumab–bevacizumab, sorafenib, and lenvatinib in the first line setting while cabozantinib, regorafenib, ramucirumab (in patients with alfa-fetoprotein [AFP] > 400 ng/mL), pembrolizumab, nivolumab, and nivolumab-ipilimumab combination are reserved for patients who progressed on sorafenib. European Medical Agency (EMA) approved the use of atezolizumab–bevacizumab, sorafenib, and lenvatinib in the first line setting, while cabozantinib, regorafenib, and ramucirumab (in patients with alfa-fetoprotein [AFP] > 400 ng/mL) are approved for use in patients that progressed on first-line therapy. In the first line setting, sorafenib demonstrated a median overall survival (OS) benefit of 3 months as compared to that of best supportive care in randomized phase III trials, while lenvatinib was shown to be non-inferior to sorafenib. Recently, phase 3 studies with immunotherapeutic agents including atezolizumab plus a bevacizumab combination and tremelimumab plus durvalumab combination demonstrated a better OS and progression free survival (PFS) compared to sorafenib in the first-line setting, making them attractive first-line options in advanced HCC. In this review, we outlined the tumorigenesis and immune landscape of HCC in brief and discussed the role and rationale of combining immunotherapy and anti-VEGF therapy. We further expanded on potential limitations and the future directions of immunotherapy in combination with targeted agents in the management of advanced HCC.

Hepatocellular Carcinoma: Pick the Winner-Tyrosine Kinase Inhibitor Versus Immuno-oncology Agent-Based Combinations.

The treatment landscape for advanced hepatocellular carcinoma has changed dramatically over the past 4 years. We now have numerous options for patients in frontline, second-line, and beyond. The most significant impact has been the introduction of immunotherapy into our treatment paradigms. We now have regimens that induce consistent double-digit objective response rates and markedly improve overall survival (OS) with favorable side effect profiles. The combination of atezolizumab and bevacizumab has demonstrated that the combination of targeting programmed death-ligand 1 and the vascular endothelial growth factor axis can improve outcomes versus sorafenib in the IMBrave150 study. Results from the COSMIC-312 study evaluating the multikinase vascular endothelial growth factor receptor, hepatocyte growth factor receptor, and AXL tyrosine kinase receptor inhibitor cabozantinib in combination with atezolizumab improved progression-free survival versus sorafenib, but at this time, there is no improvement in OS and response rates were lower than expected. Additional data with similar combinations are awaited on the basis of encouraging early-phase data. In addition, the combination of cytotoxic T-lymphocyte-associated protein 4 and programmed cell death-1/programmed death-ligand 1 targeting is yielding similar promising early results, and the phase III HIMALAYA study met its primary end points of improving OS versus sorafenib for durvalumab plus tremelimumab and demonstrated noninferiority for single-agent durvalumab as well. However, this combination did not improve progression-free survival and objective response rates with this combination did not seem significantly different from that with single-agent durvalumab. Although there are still knowledge gaps in this rapidly changing landscape, we will address some of the important questions relevant to making therapeutic decisions in the management of advanced hepatocellular carcinoma in the modern era on the basis of our current knowledge of the safety and efficacy of these evolving regimens. The goal is to provide clinicians with the knowledge needed to optimize outcomes for their patients.

Novel Perspectives in Immune Checkpoint Inhibitors and the Management of Non-Alcoholic Steatohepatitis-Related Hepatocellular Carcinoma

Simple SummaryHepatocellular carcinoma (HCC) is a huge worldwide healthcare burden. The incidence of non-viral causes of hepatocellular carcinoma, such as non-alcoholic steatohepatitis (NASH), is rising. The introduction of immune checkpoint inhibitors (ICI) has led to a paradigm shift in the systemic treatment of HCC. However, not all patients can benefit from ICI. Recent studies have suggested that the response to ICI may allude to the underlying aetiology of HCC, such as NASH. Our review aims to summarise the latest evidence of ICI in advanced HCC, elaborates on the controversy surrounding the use of ICI in NASH-HCC, and discusses potential biomarkers that can be used to predict responses to ICI in advanced HCC.Immune checkpoint inhibitors have revolutionised the systemic treatment of advanced hepatocellular carcinoma. Although phase III trials, testing single agent nivolumab and pembrolizumab, failed to meet their primary endpoints, the combination of atezolizumab and bevacizumab has demonstrated a remarkable objective response and unprecedented survival benefits, replacing sorafenib as the standard first-line treatment for advanced hepatocellular carcinoma. Despite these successes observed in immune checkpoint inhibitors in the management of advanced hepatocellular carcinoma, not all patients responded to treatment, which has led to the search of risk factors and biomarkers that could predict the response to immune checkpoint inhibitors. Recent translational studies have begun to shed light on the impact of an underlying liver disease, namely NASH, which might affect the response to immune checkpoint inhibitors. In addition, antidrug-antibody and gene expression assays have demonstrated promises in predicting the response to immune checkpoint inhibitors. In this article, we will provide an overview of the use of ICI in the management of advanced HCC, review the evidence that surrounds the recent controversy regarding NASH-HCC, and discuss potential biomarkers that predict the response to immune checkpoint inhibitors.

Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation: A retrospective analysis.

410 Background: Lenvatinib is approved for use in patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, its clinical outcomes in patients experiencing HCC recurrence after liver transplantation (LT), remain unclear. Further, despite of immunotherapeutic advances (atezolizumab plus bevacizumab, pembrolizumab, and nivolumab) in the management of advanced HCC, patients with prior LT are not benefited because of the risk of allograft rejection, and they are also excluded in the most prospective clinical trials for novel agents. Thus, we investigated the efficacy and safety of lenvatinib treatment in patients with recurrent HCC after LT. Methods: This single center, retrospective study included 22 patients with recurrent HCC after LT who received lenvatinib at the Asan Medical Center, South Korea, between November 2019 and March 2021. Lenvatinib was given 12mg/day for bodyweight ≥ 60 kg or 8 mg/day for bodyweight < 60 kg. Response and adverse events (AEs) were graded according to RECIST v1.1 and NCI CTCAE v5.0. Results: The median age was 58 years (range, 20-69) and 95.5% (n = 21) were male. Most common etiology of HCC was hepatitis B (n = 18, 81.8%). The median time to recurrence after LT was 6.6 months (95% CI, 4.2-9.1 months). Prior to systemic therapy, transarterial embolization (TACE) (n = 12, 54.5%) was the most commonly used therapy for recurred HCC after LT. At the time of lenvatinib initiation, 95.5% (n = 21) of the patients were Child-Pugh A with 15 (68.2%) and 7 (31.8%) patients classified as ALBI grades 1 and 2, respectively. All patients were at BCLC stage C and lenvatinib was administered as first-line (n = 19) and second-line (n = 3) therapy. The objective response rate (ORR) was 13.6%. With a median follow-up duration of 5.2 months (range, 1.7-14.5 months), the median progression-free survival (PFS) was 6.6 months (95% CI: 3.6-9.5 months) and overall survival (OS) was 14.5 months (95% CI: not assessable). The 6-month PFS and OS rates were 59.8% and 88.8%, respectively. Patients with ALBI grade 2 showed significantly poorer OS [11.1 months (95% CI: not assessable)] compared to patients with ALBI grade 1 [14.5 months (95% CI: not assessable)] ( p= 0.011). AEs were hypertension (n = 8, 36.4%), thrombocytopenia (n = 7, 31.8%), and fatigue (n = 6, 27.3%). Conclusions: Lenvatinib was effective and showed manageable toxicities in patients with recurrent HCC after LT. These outcomes are comparable to those from the pivotal REFLECT trial where patients with LT were excluded. Better baseline liver function (ALBI grade 1) at lenvatinib initiation correlated with better survival outcomes.

POSA16 An Umbrella Review on the Effectiveness of Systemic Treatments for the Management of Advanced Hepatocellular Carcinoma

This umbrella review of systematic literature reviews (SLRs) and meta-analyses (MAs) aims to identify and synthesize currently available knowledge on the effectiveness of systemic treatments for advanced hepatocellular carcinoma (HCC). It addresses three research questions: (1) What is the clinical efficacy of systemic therapies used in patients with advanced HCC? (2) What are the most serious adverse events relating to those therapies? (3) What is the quality of the available evidence?

Clinical Implication of E2F Transcription Factor 1 in Hepatocellular Carcinoma Tissues.

Background: To date, the clinical management of advanced hepatocellular carcinoma (HCC) patients remains challenging and the mechanisms of E2F transcription factor 1 (E2F1) underlying HCC are obscure. Materials and Methods: Our study integrated datasets mined from several public databases to comprehensively understand the deregulated expression status of E2F1. Tissue microarrays and immunohistochemistry staining was used to validate E2F1 expression level. The prognostic value of E2F1 was assessed. In-depth subgroup analyses were implemented to compare the differentially expressed levels of E2F1 in HCC patients with various tumor stages. Functional enrichments were used to address the predominant targets of E2F1 and shedding light on their potential roles in HCC. Results: We confirmed the elevated expression of E2F1 in HCC. Subgroup analyses indicated that elevated E2F1 level was independent of various stages in HCC. E2F1 possessed moderate discriminatory capability in differentiating HCC patients from non-HCC controls. Elevated E2F1 correlated with Asian race, tumor classification, neoplasm histologic grade, eastern cancer oncology group, and plasma AFP levels. Furthermore, high E2F1 correlated with poor survival condition and pooled HR signified E2F1 as a risk factor for HCC. Enrichment analysis of differentially expressed genes, coexpressed genes, and putative targets of E2F1 emphasized the importance of cell cycle pathway, where CCNE1 and CCNA2 served as hub genes. Conclusions: We confirmed the upregulation of E2F1 and explored the prognostic value of E2F1 in HCC patients. Two putative targeted genes (CCNE1 and CCNA2) of E2F1 were identified for their potential roles in regulating cell cycle and promote antiapoptotic activity in HCC patients.

How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma.

Simple SummaryHCC is a very aggressive disease and patients diagnosed in an advanced/metastatic setting obtain poor survival outcomes with standard treatments. In recent years, the introduction of immunotherapy strategies, such as immune checkpoint inhibitors as single agents and in combination with already approved local and systemic treatments, has strongly changed the therapeutic landscape of HCC. Soon, the discovery of novel potential immune targets, together with the understanding of potential biomarkers of resistance, will help to better define novel treatment opportunities for patients with HCC.Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child–Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care.

Clinical efficacy and safety of proton beam or photon radiation in combination with immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma.

e16113 Background: Management of advanced hepatocellular carcinoma (HCC) remains a challenge. IMbrave150, a pivotal trial reported impressive overall survival benefit using combination strategy of atezolizumab and bevacizumab compared to sorafenib. We wonder the efficacy and safety when combining radiotherapy with immune checkpoint inhibitors (ICIs), which radiation might provide better local treatment and possible trigger abscopal effect. The aim of this study is retrospectively reporting the real-world efficacy and tolerability of proton beam or photon radiation plus ICIs in patients with advance stage HCC. Methods: We retrospectively reviewed all BCLC stage C HCC patients who have received combination therapy with ICIs plus proton or photon therapy with well documented basic characteristics and prompt treatment efficacy evaluation between 1st of January 2016 to 31st of October 2019 at a single medical center in Taiwan. 20 patients had ICIs plus proton and 32 patients had ICIs plus photon were included for analysis. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier estimator. Results: Baseline characteristics were generally similar between ICIs plus proton or ICIs plus photon, while most patients in proton group did not receive prior systemic treatment and had less local therapies prior ICIs combine with radiotherapy. Median follow-up time was 10.7 months. The median Progression free survival (PFS) was not reached in ICIs plus proton group and 3.6 months (95% CI 2.7-4.6) in ICIs plus photon group (P = 0.007). The median OS was not reach in ICIs plus proton group and 12.1months (95% CI 6.4-17.7) in ICIs plus photon group (P = 0.007). Comparing ICIs plus proton group versus photon group, objective tumor response is 50% versus 9%, disease control rate is 80% versus 47% in each group. During follow-up, 7 patients (35%) in proton group achieved complete remission (CR). There was difference in radiation filed, 19 patients (95%) in proton group and 15 patients (47%) in photon group targeted on liver tumors, and more patient received > 50Gy treatment dose in proton group compared to photon group (90% versus 20%). Proton group has lower failure rate in both inner- or out-field compared to photon group. Grade 1 to grade 2 skin-dermatological and gastrointestinal toxicity remained the most frequent reported adverse events in both groups. There are only one therapy related grade 3 dermatitis in ICIs plus proton group and one grade 3 hepatitis, one grade 5 pneumonitis in ICIs plus photon group. Conclusions: This study reported real-world efficacy and safety of ICIs in combination with proton or photon therapy. Most adverse events were manageable. The combination of ICIs and proton therapy has impressive CR rate and OS benefit. Further prospective randomized trial is warranted for confirm our finding.

Non-surgical management of advanced hepatocellular carcinoma: A systematic review by Cancer Care Ontario.

Hepatocellular carcinoma (HCC) is a global health problem, accounting for 4.7% of all new cancer cases and 8.2% of all cancer deaths worldwide in 2018. Resection and transplantation are the only modalities that offer a cure for HCC; however, most patients are diagnosed at an advanced stage, precluding these curative treatments. A number of local (ie, ablative therapies) and/or local-regional therapies (ie, chemo-embolization) are used and followed by systemic therapy for advanced or progressive disease. Other treatments are available, but their efficacy compared with these standards is not well known. Literature searches (1/2000 to 1/2020 or 1/2005 to 1/2020, depending on the specific systematic review question) were conducted, including MEDLINE, Embase and the Cochrane Database of Systematic Reviews. Over 30,000 articles were identified. In total, 49 studies were included in the systematic review. There is no evidence to support the addition of sorafenib to any local or regional therapy. First-line systemic therapy options for unresectable or metastatic HCC include sorafenib, lenvatinib, and atezolizumab + bevacizumab. Regorafenib or cabozantinib provide survival benefits when given as second-line treatment.

Safety and Effectiveness of Hepatic Arterial Infusion Chemotherapy Combined With Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma in BCLC Stage C

Background: To assess the safety and efficacy of a combination therapy consisting of hepatic arterial infusion chemotherapy (HAIC) of Oxaliplatin, Fluorouracil, and Leucovorin (FOLFOX), tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) (TRIPLET) for patients with advanced hepatocellular carcinoma (HCC) in BCLC Stage C. Methods: This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients. 22 patients with initial presentation or recurrent HCC in BCLC Stage C received HAIC plus TKI plus ICI (TRIPLET) treatment from April 1, 2019, to April 30, 2020. The primary endpoint was objective response. The second endpoint were survival outcomes and safety. Findings: The best overall response was 59.1% per RECIST 1.1 and 81.8% per mRECIST. The median duration of response was 9.83 months per mRECIST. The DCR was 100% per both RECIST and mRECIST. Complete response (CR) was achieved in 7 patients (31.8%) per mRECIST. The median overall progression free survival (PFS) time in the cohort was 11.17 months (95% CI 5.87 - 16.46) per mRECIST. The estimated 6- and 12-month overall PFS rates were 82.7% and 42.7%, respectively. The estimated 6- and 12-month OS rates were 93.8% and 93.8%, respectively. Grade 3 adverse events occurred in 15 patients (68.2%) and were all reversible. Grade 4 adverse events occurred in 4 patients (18.2%) all with transient bone marrow suppression. Conclusion: HAIC plus TKI plus ICI (TRIPLET) has promising survival benefits in the management of advanced hepatocellular carcinoma in BCLC Stage C with tolerable safety. Funding Statement: This work was supported by the Guangzhou Science and Technology Program, civic technology research plan (No. 201903010037). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: The informed consent was obtained from all patients. All patients were followed up under the hospital ethics committee approval of SYSUCC (B2020-243-01). The principles of the Declaration of Helsinki were followed.

New frontiers in endovascular therapies for locally advanced hepatocellular carcinoma.

Hepatocellular carcinoma is the most common primary malignant liver tumour and is a leading cause of death worldwide. Despite the advent of screening programmes, most cases of hepatocellular carcinoma are diagnosed late (in an advanced stage) which precludes curative treatments such as surgery and ablation. Therefore, intra-arterial locoregional treatments now play a central role in the management of advanced hepatocellular carcinoma, such treatments ranging from trans-arterial chemo-embolisation to the more recently developed trans-arterial radio-embolisation technique. In this essay, we discuss the state of the art of intra-arterial treatment for locally advanced hepatocellular carcinoma and the future directions for such treatment.

Systemic targeted and immunotherapy for advanced hepatocellular carcinoma.

The activity of targeted agents and immunotherapy in the management of advanced hepatocellular carcinoma (HCC) is reviewed. The first drug approved by the Food and Drug Administration for advanced HCC, sorafenib, was approved in 2007. Regorafenib, the second drug, was approved 10 years later. Six additional drugs have been approved since. Targeted agents and checkpoint inhibitors are the only agents approved for systemic therapy of advanced HCC. Sorafenib and lenvatinib are approved as first-line agents, with regorafenib, cabozantinib, ramucirumab, nivolumab (used alone or with ipilimumab), and pembrolizumab approved for patients who have received prior sorafenib therapy. Most patients in phase 3 studies had Child-Pugh class A cirrhosis, and data on the use of these agents in patients with more advanced hepatic dysfunction are limited. All of the targeted agents improve survival in patients with advanced disease. Median overall survival durations of up to 12.3 and 13.6 months were reported with use of sorafenib and lenvatinib, respectively, in phase 3 trials. Overall survival durations of 10.6, 10.2, and 9.2 months have been achieved with use of regorafenib, cabozantinib, and ramucirumab as second-line therapy after sorafenib. A median overall survival of 13.2 months was reported in 1 cohort of a dose-expansion study of nivolumab in which all patients received prior sorafenib therapy. Median survival durations of 12.9 months and 13.9 months were reported with use of pembrolizumab in patients with a history of sorafenib therapy. The most common adverse effects associated with targeted agents are dermatological effects, diarrhea, fatigue, and hypertension. Immune-mediated adverse effects are associated with checkpoint inhibitors. Targeted agents and checkpoint inhibitors are the standard of therapy for patients who need systemic therapy for advanced HCC.

Profile of Cabozantinib for the Treatment of Hepatocellular Carcinoma: Patient Selection and Special Considerations.

Management of advanced hepatocellular carcinoma is challenging. With an increasing number of options for the first and second-line treatment, understanding and developing optimal systemic treatment strategies are crucial. In second line, two tyrosine kinase inhibitors (TKI) and one monoclonal antibody have been approved after sorafenib by both the European Medicines Agency and the Food and Drug Administration based on the results of phase 3 trials: cabozantinib, regorafenib and ramucirumab. Cabozantinib has demonstrated an improved overall survival and progression-free survival in the phase 3 CELESTIAL study in second and third line, in patients in good general condition (performance status 0–1) and with a normal liver function Child-Pugh class A. Analysis of subgroups has shown that even elderly patients over 65 years, or patients with high baseline alpha-fetoprotein ≥400 ng/mL benefit from cabozantinib. The choice in second-line between the three drugs should be based on factors such as previous tolerance of sorafenib, safety profile of drugs and quality of life. In this review, we will analyze clinical data available on cabozantinib, clarifying the choice between the different possible treatments. However, the upcoming of a new standard in first line with the combination atezolizumab and bevacizumab will change the game and will warrant further investigations to define the accurate subsequent sequence of TKIs. Cabozantinib is also actually tested in first-line in combination with atezolizumab, results of the phase 3 COSMIC trial are eagerly awaited.

Nonsurgical management of advanced hepatocellular carcinoma: a clinical practice guideline.

Practice guidelines based on a systematic review of the literature regarding the nonsurgical management of hepatocellular carcinoma (hcc) in North America are lacking. Resection and transplantation are the foundations for cure of hcc; however, most patients are diagnosed at an advanced stage, precluding those curative treatments. A number of local or regional therapies are used and are followed by systemic therapy for advanced or progressive disease. Other treatments are available, but their efficacy, compared with those standards, is not well known. First, systematic review questions were developed. Literature searches of the medline, embase, and Cochrane library databases (January 2000 to July 2018 or January 2005 to July 2018 depending on the question) were conducted; in addition, abstracts from the 2018 annual meeting of the American Society of Clinical Oncology were reviewed. A practice guideline was drafted that was then scrutinized by internal and external reviewers. Seventy-seven studies were included in the guideline: no guidelines, two systematic reviews, and seventy-five primary studies published in full (including one pooled analysis). Five recommendations were developed. There is no evidence for or against the use of local or regional interventions other than transarterial chemoembolization for the treatment of intermediate- or advanced-stage hcc. Furthermore, there is no evidence to support the addition of sorafenib to any local or regional therapy. Sorafenib or lenvatinib are recommended for first-line systemic treatment of intermediate-stage hcc. Regorafenib or cabozantinib provide survival benefits when given as second-line treatment. Antiviral treatment is recommended in individuals with advanced hcc who are positive for the hepatitis B surface antigen.

Quantitative phosphoproteomic analysis identifies the potential therapeutic target EphA2 for overcoming sorafenib resistance in hepatocellular carcinoma cells

Limited therapeutic options are available for advanced-stage hepatocellular carcinoma owing to its poor diagnosis. Drug resistance to sorafenib, the only available targeted agent, is commonly reported. The comprehensive elucidation of the mechanisms underlying sorafenib resistance may thus aid in the development of more efficacious therapeutic agents. To clarify the signaling changes contributing to resistance, we applied quantitative phosphoproteomics to analyze the differential phosphorylation changes between parental and sorafenib-resistant HuH-7 cells. Consequently, an average of ~1500 differential phosphoproteins were identified and quantified, among which 533 were significantly upregulated in resistant cells. Further bioinformatic integration via functional categorization annotation, pathway enrichment and interaction linkage analysis led to the discovery of alterations in pathways associated with cell adhesion and motility, cell survival and cell growth and the identification of a novel target, EphA2, in resistant HuH-7R cells. In vitro functional analysis indicated that the suppression of EphA2 function impairs cell proliferation and motility and, most importantly, overcomes sorafenib resistance. The attenuation of sorafenib resistance may be achieved prior to its development through the modulation of EphA2 and the subsequent inhibition of Akt activity. Binding analyses and in silico modeling revealed a ligand mimic lead compound, prazosin, that could abate the ligand-independent oncogenic activity of EphA2. Finally, data obtained from in vivo animal models verified that the simultaneous inhibition of EphA2 with sorafenib treatment can effectively overcome sorafenib resistance and extend the projected survival of resistant tumor-bearing mice. Thus our findings regarding the targeting of EphA2 may provide an effective approach for overcoming sorafenib resistance and may contribute to the management of advanced hepatocellular carcinoma.

Inhibition of EZH2 Attenuates Sorafenib Resistance by Targeting NOTCH1 Activation-Dependent Liver Cancer Stem Cells via NOTCH1-Related MicroRNAs in Hepatocellular Carcinoma

Acquired resistance and intrinsic to sorafenib therapy represents a major hurdle in improving the management of advanced hepatocellular carcinoma (HCC), which has been recently shown to be associated with the emergence of liver cancer stem cells (CSCs). However, it remains largely unknown whether and how histone posttranslational modifications, especially H3K27me3, are causally linked to the maintenance of self-renewal ability in sorafenib-resistant HCC. Here, we found that NOTCH1 signaling was activated in sorafenib-resistant HCC cells and NOTCH1 activation conferred hepatoma cells sorafenib resistance through enhanced self-renewal and tumorigenecity. Besides, the overexpression of EZH2 was required for the emergence of cancer stem cells following prolonged sorafenib treatment. As such, modulating EZH2 expression or activity suppressed activation of NOTCH1 pathway by elevating the expression of NOTCH1-related microRNAs, hsa-miR-21-5p and has-miR-26a-1-5p, via H3K27me3, and consequently weakened self-renewal ability and tumorigenecity and restored the anti-tumor effects of sorafenib. Overall, our results highlight the role of EZH2/NICD1 axis, and also suggest that EZH2 and NOTCH1 pathway are rational targets for therapeutic intervention in sorafenib-resistant HCC.