Systemic Treatment Of Hepatocellular Carcinoma Research Articles

Hepatocellular Carcinoma: Current Drug Therapeutic Status, Advances and Challenges.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of liver neoplasms. It is the second leading cause of cancer-related deaths and the seventh most common cancer worldwide. Although there have been rapid developments in the treatment of HCC over the past decade, the incidence and mortality rates of HCC remain a challenge. With the widespread use of the hepatitis B vaccine and antiviral therapy, the etiology of HCC is shifting more toward metabolic-associated steatohepatitis (MASH). Early-stage HCC can be treated with potentially curative strategies such as surgical resection, liver transplantation, and radiofrequency ablation, improving long-term survival. However, most HCC patients, when diagnosed, are already in the intermediate or advanced stages. Molecular targeted therapy, followed by immune checkpoint inhibitor immunotherapy, has been a revolution in HCC systemic treatment. Systemic treatment of HCC especially for patients with compromised liver function is still a challenge due to a significant resistance to immune checkpoint blockade, tumor heterogeneity, lack of oncogenic addiction, and lack of effective predictive and therapeutic biomarkers.

Comparison of outcomes between preoperative and postoperative systemic treatment in patients with hepatocellular carcinoma: a SEER database-based study.

Significant advancements in systemic treatment for hepatocellular carcinoma have been made in recent years. However, the optimal timing of systemic treatment before or after surgery remains unknown. This study aims to evaluate the impact of sequencing systemic treatment and surgical intervention on the long-term prognosis of hepatocellular carcinoma patients. In our study, we analyzed data from patients diagnosed with primary liver cancer (2004-2015) extracted from the SEER database. Patients who underwent both systemic treatment and surgical intervention were selected, divided into preoperative and postoperative systemic therapy groups. The primary endpoint of the study is overall survival(OS), and the secondary endpoint is cancer-specific survival (CSS). Propensity score matching (PSM) reduced the influence of confounding factors, while Kaplan-Meier curves and a multivariable Cox proportional hazards model accounted for variables during survival analysis. A total of 1918 eligible HCC patients were included, with 1406 cases in the preoperative systemic treatment group and 512 cases in the postoperative systemic treatment group. Survival analysis showed that both the preoperative group demonstrated longer median overall survival (OS) and median cancer-specific survival (CSS) before and after PSM. After conducting multivariate COX regression analysis with stepwise adjustment of input variables, the postoperative systemic treatment group continued to exhibit a higher risk of all-cause mortality (HR: 1.84, 95% CI: 1.55-2.1) and cancer-specific mortality (HR: 2.10, 95% CI: 1.73-2.54). Subgroup analysis indicated consistent results for overall survival (OS) across different subgroups. Hepatocellular carcinoma patients from the SEER database who received preoperative systemic therapy had superior OS and CSS compared to those who received postoperative systemic therapy.

Single-cell RNA-Seq Elucidates the Crosstalk Between Cancer Stem Cells and the Tumor Microenvironment in Hepatocellular Carcinoma.

Background: The challenge of systemic treatment for hepatocellular carcinoma (HCC) stems from the development of drug resistance, primarily driven by the interplay between cancer stem cells (CSCs) and the tumor microenvironment (TME). However, there is a notable dearth of comprehensive research investigating the crosstalk between CSCs and stromal cells or immune cells within the TME of HCC. Methods: We procured single-cell RNA sequencing (scRNA-Seq) data from 16 patients diagnosed with HCC. Employing meticulous data quality control and cell annotation procedures, we delineated distinct CSCs subtypes and performed multi-omics analyses encompassing metabolic activity, cell communication, and cell trajectory. These analyses shed light on the potential molecular mechanisms governing the interaction between CSCs and the TME, while also identifying CSCs' developmental genes. By combining these developmental genes, we employed machine learning algorithms and RT-qPCR to construct and validate a prognostic risk model for HCC. Results: We successfully identified CSCs subtypes residing within malignant cells. Through meticulous enrichment analysis and assessment of metabolic activity, we discovered anomalous metabolic patterns within the CSCs microenvironment, including hypoxia and glucose deprivation. Moreover, CSCs exhibited aberrant activity in signaling pathways associated with lipid metabolism. Furthermore, our investigations into cell communication unveiled that CSCs possess the capacity to modulate stromal cells and immune cells through the secretion of MIF or MDK, consequently exerting regulatory control over the TME. Finally, through cell trajectory analysis, we found developmental genes of CSCs. Leveraging these genes, we successfully developed and validated a prognostic risk model (APCS, ADH4, FTH1, and HSPB1) with machine learning and RT-qPCR. Conclusions: By means of single-cell multi-omics analysis, this study offers valuable insights into the potential molecular mechanisms governing the interaction between CSCs and the TME, elucidating the pivotal role CSCs play within the TME. Additionally, we have successfully established a comprehensive clinical prognostic model through bulk RNA-Seq data.

The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence.

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.

Sequential systemic treatments for hepatocellular carcinoma: real-life clinical practice data in the time of multiple agents

Sequential systemic treatments for hepatocellular carcinoma: real-life clinical practice data in the time of multiple agents

First-line systemic treatment for hepatocellular carcinoma: A systematic review and network meta-analysis

The rapid development of novel therapeutic options for advanced hepatocellular carcinoma (aHCC) has generated some uncertainty about the rational choice of the systemic upfront treatment. So far, a variety of therapeutic strategies have been investigated, including the combination of immunecheckpoint inhibitors and anti-VEGF. To identify the treatment that should be preferred as front-line approach, we compared the efficacy and toxicity of a variety of therapeutic strategies. With this aim, we performed a systematic review and a meta-analysis of randomized clinical trials. OS, PFS, ORR and tolerability outcomes were considered, and for each outcome the treatment ranking was evaluated by the surface under the cumulative rankings (SUCRAs). Combination of Camrelizumab + Rivoceranib scored the best in OS, followed by Sintilimab + Bevacizumab, whereas Lenvatinib + Pembrolizumab showed higher probability to be the best treatment in PFS and Sintilimab + Bevacizumab performed best in ORR. Finally, Durvalumab is the most tolerated treatment.

Diagnosing Hepatocellular Carcinoma Using Sonazoid Contrast-Enhanced Ultrasonography: 2023 Guidelines from the Korean Society of Radiology and the Korean Society of Abdominal Radiology

Sonazoid, a second-generation ultrasound contrast agent, was introduced for the diagnosis of hepatic nodules. To clarify the issues with Sonazoid contrast-enhanced ultrasonography for the diagnosis of hepatocellular carcinoma (HCC), the Korean Society of Radiology and Korean Society of Abdominal Radiology collaborated on the guidelines. The guidelines are de novo, evidence-based, and selected using an electronic voting system for consensus. These include imaging protocols, diagnostic criteria for HCC, diagnostic value for lesions that are inconclusive on other imaging results, differentiation from non-HCC malignancies, surveillance of HCC, and treatment response after locoregional and systemic treatment for HCC.

Novel systemic treatment for hepatocellular carcinoma: a step-by-step review of current indications

Novel systemic treatment for hepatocellular carcinoma: a step-by-step review of current indications

A review of 2022 Chinese clinical guidelines on the management of hepatocellular carcinoma: updates and insights.

Significant improvements in the management of hepatocellular carcinoma (HCC) during the past three years have urged the timely update of clinical guidelines in China. In brief, aMAP score is newly recommended as an effective risk stratification tool to predict HCC occurrence especially for non-cirrhotic patients. Biomarker-based surveillance including 7 micro-RNA panel and GALAD score are advocated to assist early diagnosis. China liver cancer (CNLC) staging system proposed in the 2017 guideline continues to be the standard model for staging with modifications in the treatment allocations. Conversion therapies using multi-modal, high intensity strategies are advocated to facilitate subsequent resection for patients with technically unresectable CNLC stage Ia, Ib, IIa HCC, or technically resectable IIb, IIIa HCC. Super-selective transcatheter arterial chemoembolization (TACE) with the assistance of Cone-Beam CT if necessary is recommended to guarantee the efficacy of TACE. Hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin (FOLFOX) regimen alone or in combination with systemic therapy is recommended for TACE-refractory patients or for patients with locally advanced HCC. The systemic treatments for HCC have evolved considerably since atezolizumab plus bevacizumab, and suntilimab plus bevacizumab analogue showing superior survival benefit to sorafenib, and donafenib with comparable efficacy with sorafenib are added to the first-line treatments. In addition to regorafenib, apatinib, camrelizumab and tislelizumab are added as the second-line systemic therapies for patients who progressed on sorafenib. Updates in the 2022 Barcelona Clinic Liver Cancer (BCLC) guidelines and Japanese Society of Hepatology (JSH) consensus statement are also introduced and compared with the 2022 Chinese guidelines.

Tyrosine kinase inhibitors as potential sensitizers of adoptive T cell therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. However, either targeted therapy or immunotherapy alone is inefficient and has limited survival benefits on part of HCC patients. Investigations have proved that tyrosine kinase inhibitors (TKIs) have regulatory effects on the tumor microenvironment and immune response, which are potential sensitizers for immunotherapy. Herein, a combination therapy using TKIs and immunotherapy has been explored and demonstrated to improve the effectiveness of treatment. As an effective immunotherapy, adoptive T cell therapy in solid tumors is required to improve tumor infiltration and killing activity which can be possibly achieved by combination with TKIs.

Efficacy and safety of frontline systemic therapy for advanced HCC: A network meta-analysis of landmark phase III trials

Direct comparisons across first-line regimens for advanced hepatocellular carcinoma are not available. We performed a network metanalysis of phase III of trials to compare first-line systemic treatments for hepatocellular carcinoma in terms of overall survival (OS), progression-free survival (PFS), objective response rate, disease control rate, and incidence of adverse events (AEs). After performing a literature review from January 2008 to September 2022, we screened 6,329 studies and reviewed 3,009 studies, leading to identification of 15 phase III trials for analysis. We extracted odds ratios for objective response rate and disease control rate, relative risks for AEs, and hazard ratios (HRs) with 95% CIs for OS and PFS, and used a frequentist network metanalysis, with fixed-effect multivariable meta-regression models to estimate the indirect pooled HRs, odds ratios, relative risks, and corresponding 95% CIs, considering sorafenib as reference. Of 10,820 included patients, 10,444 received active treatment and 376 placebo. Sintilimab+ IBI350, camrelizumab+ rivoceranib, and atezolizumab+ bevacizumab provided the greatest reduction in the risk of death compared with sorafenib, with HRs of 0.57 (95% CI 0.43-0.75), 0.62 (95% CI 0.49-0.79), and 0.66 (95% CI 0.52-0.84), respectively. Considering PFS, camrelizumab+ rivoceranib and pembrolizumab+ lenvatinib were associated with the greatest reduction in the risk of PFS events compared with sorafenib, with HRs of 0.52 (95% CI 0.41-0.65) and 0.52 (95% CI 0.35-0.77), respectively. Immune checkpoint inhibitor (ICI) monotherapies carried the lowest risk for all-grade and grade ≥3 AEs. The combinations of ICI+ anti-vascular endothelial growth factor, and double ICIs lead to the greatest OS benefit compared with sorafenib, whereas ICI+ kinase inhibitor regimens are associated with greater PFS benefit at the cost of higher toxicity rates. In the last few years, many different therapies have been studied for patients with primary liver cancer that cannot be treated with surgery. In these cases, anticancer drugs (alone or in combination) are given with the intent to keep the cancer at bay and, ultimately, to prolong survival. Among all the therapies that have been investigated, the combination of immunotherapy (drugs that boost the immune system against the cancer) and anti-angiogenic agents (drugs that act on tumoural vessels) has appeared the best to improve survival. Similarly, the combination of two types of immunotherapies that activate the immune system at different levels has also shown positive results. PROSPERO CRD42022366330.

Real-world systemic sequential therapy with regorafenib for recurrent hepatocellular carcinoma: analysis of 93 cases from a single center

BackgroundRegorafenib is an oral multikinase inhibitor and became the first second-line systemic treatment for hepatocellular carcinoma (HCC) following the phase III RESORCE trial. This single-center study retrospectively analyzed the clinical data and follow-up results of patients with recurrent HCC treated with regorafenib and discussed the prognostic factors to provide guidance for clinical treatment.MethodsNinety-three recurrent HCC patients were enrolled in the research and follow up from December 2017 to December 2020. Clinical and pathological data were collected. SPSS software v26.0 was used (Chicago, IL, USA) for statistical analysis. A two-sided P < 0.05 was considered statistically significant.ResultsThe patients included 81 males and 12 females with a median age of 57 years. Eighty-seven patients had hepatitis B virus (HBV) infection. The objective response rate (ORR) was 14.0%, and the disease control rate (DCR) was 62.4%. The median overall survival (mOS) and median time to progression (mTTP) were 15.9 and 5.0 months. Multivariate analysis showed that Child–Pugh classification, the Eastern Cooperative Oncology Group performance status (ECOG PS), the neutrophil-to-lymphocyte ratio (NLR), combined treatment, and the time from first diagnosis of HCC to second-line treatment were independent factors affecting the prognosis of recurrent HCC patients.ConclusionsThis real-world study demonstrated similar findings to those of the RESORCE trial. Regorafenib could effectively improve the prognosis of patients after first-line treatment failure. Combination therapy under multidisciplinary treatment (MDT) team guidance could be effective in impeding tumor progression and improving the prognosis of recurrent HCC patients.

Alkaline phosphatase combined with γ-glutamyl transferase is an independent predictor of prognosis of hepatocellular carcinoma patients receiving programmed death-1 inhibitors.

Immunotherapy plays an increasingly critical role in the systemic treatment of HCC. This current study aimed to establish a novel prognostic predictor of Programmed death 1 (PD-1) inhibitor therapy in hepatocellular carcinoma (HCC) independent of Child-Pugh grade. Our study screened patients with HCC who received PD-1 inhibitors at Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from January 2018 to December 2020. ALG grade was determined by the patient's serum ALP and GGT levels before the initiation of PD-1 inhibitors. The endpoints of our study were overall survival (OS) and progression free survival (PFS). Follow-up ended at May 31, 2022. Eighty- five patients (77 with Child-Pugh grade A, 8 with Child-Pugh grade B at baseline) were enrolled according to the inclusion criteria. Patients with Child-Pugh grade A achieved longer PFS and OS than those with Child-Pugh grade B. Patients with ALG grade 3 at baseline showed worse tumor response and poorer survival, and ALG grade could stratify patients with Child-Pugh grade A into subgroups with significantly different prognosis. ALG grade, combining ALP and GGT, is a novel and readily available prognostic marker and the predictive effect of ALG grade on patient prognosis is independent of Child-Pugh grade.

Systemic treatment for hepatocellular carcinoma beyond milan criteria on the waitlist: is it time for a neoadjuvant therapy?

Systemic treatment for hepatocellular carcinoma beyond milan criteria on the waitlist: is it time for a neoadjuvant therapy?

Diagnosing Hepatocellular Carcinoma Using Sonazoid Contrast-Enhanced Ultrasonography: 2023 Guidelines From the Korean Society of Radiology and the Korean Society of Abdominal Radiology.

Sonazoid, a second-generation ultrasound contrast agent, was introduced for the diagnosis of hepatic nodules. To clarify the issues with Sonazoid contrast-enhanced ultrasonography for the diagnosis of hepatocellular carcinoma (HCC), the Korean Society of Radiology and Korean Society of Abdominal Radiology collaborated on the guidelines. The guidelines are de novo, evidence-based, and selected using an electronic voting system for consensus. These include imaging protocols, diagnostic criteria for HCC, diagnostic value for lesions that are inconclusive on other imaging results, differentiation from non-HCC malignancies, surveillance of HCC, and treatment response after locoregional and systemic treatment for HCC.

Issue on combined locoregional and systemic treatment for hepatocellular carcinoma

Treatment for hepatocellular carcinoma (HCC) has been challenging as most patients present with late, advanced disease, where curative options are limited. For years, locoregional therapy (LRT) has been the first-line therapy for intermediate-stage HCC and sorafenib for advanced HCC. However, these treatments are often palliative since they are plagued by tumor recurrence or progression. Therefore, there is growing interest in combined therapy to utilize their respective strengths to produce synergistic effects. This review outlines past and current research on the efficacy and safety of combined LRT and systemic therapy.

Is There a Place for Somatostatin Analogues for the Systemic Treatment of Hepatocellular Carcinoma in the Immunotherapy Era?

Patients with advanced hepatocellular carcinoma (HCC) have a very limited survival rate even after the recent inclusion of kinase inhibitors or immune checkpoint inhibitors in the therapeutic armamentarium. A significant problem with the current proposed therapies is the considerable cost of treatment that may be a serious obstacle in low- and middle-income countries. Implementation of somatostatin analogues (SSAs) has the potential to overcome this obstacle, but due to some negative studies their extensive evaluation came to a halt. However, experimental evidence, both in vitro and in vivo, has revealed various mechanisms of the anti-tumor effects of these analogues, including inhibition of cancer cell proliferation and angiogenesis and induction of apoptosis. Favorable indirect effects such as inhibition of liver inflammation and fibrosis and influence on macrophage-mediated innate immunity have also been noted and are presented in this review. Furthermore, the clinical application of SSAs is both presented and compared with clinical trials of kinase and immune checkpoint inhibitors (ICIs). No direct trials have been performed to compare survival in the same cohort of patients, but the cost of treatment with SSAs is a fraction compared to the other modalities and with significantly less serious side effects. As in immunotherapy, patients with viral HCC (excluding alcoholics), as well as Barcelona stage B or C and Child A patients, are the best candidates, since they usually have a survival prospect of at least 6 months, necessary for optimum results. Reasons for treatment failures are also discussed and further research is proposed.

A Review of Current and Emerging Therapies for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma remains a leading cause of cancer-related deaths worldwide. Liver disease including cirrhosis and viral hepatitis remains among the leading causes of hepatocellular carcinoma and despite increased screening, many patients are diagnosed in the advanced stages precluding them from locoregional therapy. Therapeutic agents for advanced hepatocellular carcinoma were limited to Sorafenib for several years; however, with the emergence of molecular targeted therapies including tyrosine kinase inhibitors and vascular endothelial growth factor inhibitors, in addition to immunotherapies, the way hepatocellular carcinoma is treated has changed significantly. In this review, we summarize the key clinical trials that lead to the approval of these agents for systemic treatment of hepatocellular carcinoma and discuss the preferred sequence of treatment options as well as prospective studies for management of hepatocellular carcinoma.

Protocol of notable-HCC: a phase Ib study of neoadjuvant tislelizumab with stereotactic body radiotherapy in patients with resectable hepatocellular carcinoma

IntroductionLiver resection is the mainstay of curative-intent treatment for hepatocellular carcinoma (HCC), but the postoperative 5-year recurrence rate reaches 70%, and there are no adjuvant or neoadjuvant therapies recommended by...

Advances in novel systemic therapies for advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the most frequent type of primary liver tumor. Most HCC patients present with advanced disease at diagnosisand the recurrence rate after surgery remains high. Treatment options for advanced HCC are limited, with sorafenib representing the only systemic agent approved for treatment of advanced HCC in more than a decade. However, in recent years new molecular targeted therapies and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC. In particular, combinations of ICIs with antiangiogenic drugs, or with other ICIs, represent one of the most promising strategies. Herein we provide a comprehensive overview of the main therapeutic advances in the systemic treatment of HCC, focusing on the most relevant ongoing clinical trials.