Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal cancers globally. While surgical resection and liver transplantation offer potential cures for early-stage HCC, the majority of patients are diagnosed at advanced stages where such interventions are not viable. Sorafenib, a multi-target kinase inhibitor, has been a cornerstone in the treatment of advanced HCC since its approval in 2007. Despite its significant clinical impact, less than half of the treated patients derive long-term benefits due to the emergence of resistance and associated side effects. This review focuses on the role of sorafenib, an FDA-approved multi-target kinase inhibitor, in treating advanced HCC, discusses the mechanisms underlying its therapeutic effects and associated resistance, and explores additional therapeutic strategies being investigated to improve patient outcomes.

Dipeptidyl peptidase 9 (DPP9) is an indispensable intracellular protease. Among its many molecular functions is suppression of the NLRP1 inflammasome. Inhibitors targeting all four proteases of the DPP4 family, including DPP9, can reduce tumour burden, including in mouse liver. To explore hepatocyte DPP9 in experimental hepatocellular carcinoma (HCC), we generated hepatocyte-specific DPP9-KO mice by crossing albumin-Cre mice with DPP9 floxed mice and treated sequentially with diethylnitrosamine, then with thioacetamide combined with an atherogenic high-fat diet until 28 weeks of age. DPP9-KO mice had less body, liver and subcutaneous adipose tissue mass, lower fasting plasma glucose and fewer small macroscopic liver nodules compared to DPP9-WT control mice. However, there were no differences in the total number of macroscopic liver nodules, or of microscopic tumour burden, inflammation, fibrosis or steatosis. Consistent with the known function of DPP9 to suppress NLRP1 activation, activated caspase-1 protein and inflammation markers Nfkbib, Cxcl10 and Ccl5 were elevated in DPP9-KO liver. The tumour suppressor protein p53 was increased and the autophagy proteins beclin1, LC3B and p62 were altered. In conclusion, hepatocyte-specific DPP9 gene deletion in experimental primary liver cancer improved energy metabolism and may reduce liver cancer initiation, via mechanisms that may include increased autophagy and tumour suppression.

In March 2024, the American Society of Clinical Oncology recommended the combination of tremelimumab plus durvalumab as a treatment for advanced hepatocellular carcinoma (HCC). Although safety data for first-line treatments are available, information on adverse events related to late-line treatments is limited. This study aimed to identify risk factors for adverse events in patients who received this combination.

We conducted a retrospective cohort study from March 2023 to January 2025 at Yokohama City University Hospital, involving 24 patients aged 18 years or older with unresectable HCC. All 24 patients experienced at least one adverse event during treatment. Of these, the incidence of treatment-related adverse events leading to treatment discontinuation after tremelimumab plus durvalumab therapy was 50.0% (12/24). In the discontinuation group, prior atezolizumab plus bevacizumab therapy (66.7% vs. 16.7%, p = 0.036) was more frequent than in the continuation group.

In patients with unresectable HCC who received tremelimumab plus durvalumab, the risk of treatment-related adverse events was associated with prior atezolizumab plus bevacizumab therapy. These factors may increase the likelihood of developing treatment-related adverse events.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.

Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.

Recently, a systemic therapy for advanced hepatocellular carcinoma (HCC) has been developed. The regimen for unresectable HCC varies and includes single or multi-tyrosine kinase inhibitors, monoclonal antibodies, immune checkpoint inhibitors, or their combinations. Treatment with these agents begins with sorafenib as the first-line drug for unresectable HCC. Subsequently, several systemic therapies, including lenvatinib, ramucirumab, cabozantinib, and regorafenib have been investigated and established. With advances in systemic therapy for unresectable HCC, the prognosis of patients with unresectable HCC has improved significantly than previously. Conversion surgery, consisting of systemic therapy and surgery, showed the possibility of improving the prognosis than systemic therapy alone. Although a combination of atezolizumab and bevacizumab is mostly used for initially unresectable HCC to conduct conversion surgery because of the high response rate and fewer adverse events compared to others, many trials are being conducted to assess their efficacy for initially unresectable HCC. However, the appropriate timing of surgery and interval between systemic therapy and surgery remain controversial. To address these issues, a multidisciplinary team can play a vital role in determining the strategies for treating unresectable HCC. This review describes previous and current trends in the treatment of HCC, with a particular focus on conversion surgery for initially unresectable HCC.

RAF kinases, particularly the BRAF isoform, play a crucial role in the MAPK/ERK signaling pathway, regulating key cellular processes such as proliferation, differentiation, and survival. Dysregulation of this pathway often caused by mutations in the BRAF gene or alterations in upstream regulators like Ras and receptor tyrosine kinases contributes significantly to cancer development. Mutations, such as BRAF-V600E, are present in a variety of malignancies, with the highest prevalence in melanoma. Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. These inhibitors have also shown clinical benefits in cancers such as thyroid and colorectal carcinoma, although to a lesser extent. Despite these successes, therapeutic resistance remains a major hurdle. Resistance mechanisms, including RAF dimerization, feedback reactivation of the MAPK pathway, and paradoxical activation of ERK signaling, often lead to diminished efficacy over time, resulting in disease progression or even secondary malignancies. In response, current research is focusing on novel therapeutic strategies, including combination therapies that target multiple components of the pathway simultaneously, such as MEK inhibitors used in tandem with RAF inhibitors. Additionally, next-generation RAF inhibitors are being developed to address resistance and enhance therapeutic specificity. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.

For patients with advanced or unresectable hepatocellular carcinoma (HCC), safe and effective therapies are urgently needed to improve their long-term prognosis. Although the guidelines recommend first-line treatments such as sorafenib, lenvatinib, and atezolizumab in combination with bevacizumab (T+A) and second-line treatments such as regorafenib, the efficacy comparison between drugs is lacking, that is, a treatment is not recommended as the optimal or alternative choice for a specific patient population. Therefore, we will conduct a high-quality network meta-analysis based on Phase III randomized controlled trials (RCTs) to systematically evaluate and compare overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and serious adverse events (SAE) of different treatment protocols in the context of first-line and second-line therapies, which are critical for clinical decision making and prognostic improvement in advanced HCC patients.

The studies of interest were Phase III RCTs evaluating the efficacy or safety of first- or second-line therapies in patients with unresectable or advanced HCC. Literature published in English from the four databases of PubMed, Embase, Cochrane Library, and Web of Science was comprehensively searched from the inception to May 23, 2022. Outcomes of interest included OS, PFS, ORR, and SAE. A league table was developed to show the results of the comparison between different treatments. A histogram of cumulative probability was drawn to discuss the ranking probability of treatments based on different outcomes. The effectiveness and safety of various treatments were comprehensively considered and the two-dimensional diagram was plotted to guide clinical practice. The Gemtc package in R Studio was used for network meta-analysis in a Bayesian framework.

The results showed that HAIC-FO was superior to T+A regimen, regardless of OS, PFS or ORR. TACE combined with lenvatinib performed better than T+A in PFS, and ORR. In addition to the T+A regimen, Sintilimab combined with IBI305 and camrelizumab combined with apatinib were also associated with longer OS, PFS, and ORR, and their SAE incidence was not higher than that of T+A, especially for camrelizumab combined with apatinib, its safety was better than that of T+A regimen. There were no new treatments or combinations that were more effective than regorafenib. It was important to note that for PFS, the efficacy of apatinib and cabozantinib was not statistically different from that of regorafenib, so these two treatments could be used as alternative treatment options in cases where regorafenib was not tolerated or treatment failed.

We conducted a network meta-analysis to evaluate the efficacy and safety of multiple treatment modalities by integrating the results of direct and indirect comparisons. This study included high-quality multicenter Phase III RCTs, collated and summarized all treatments involved in advanced or unresectable HCC in first-line and second-line settings, and compared with T+A and regorafenib, respectively, and ranked based on efficacy and safety to support clinical decision making.

Targeted therapies are the mainstay of systemic therapies for patients with advanced, unresectable, or metastatic hepatocellular carcinoma. Several therapeutic targets, such as c-Met, TGF-β, and FGFR, have been evaluated in the past, though results from these clinical studies failed to show clinical benefit. However, these remain important targets for the future with novel targeted agents and strategies. The Wnt/β-catenin signaling pathway, c-Myc oncogene, GPC3, PPT1 are exciting novel targets, among others, currently undergoing evaluation. Through this review, we aim to provide an overview of previously evaluated and potentially novel therapeutic targets and explore their continued relevance in ongoing and future studies for HCC.

Despite advances in the treatment of hepatocellular carcinoma (HCC) over the last few decades, treatment opportunities for patients with HCC remain limited. HCC is the most common form of liver cancer, accounting for approximately 90% of all cases worldwide. Moreover, apart from the current pharmacological interventions, hepatic resection and liver transplantation are the mainstay curative approaches for patients with HCC. This systematic review included phase I, II, III, and IV clinical trials (CTs) and randomized controlled trials (RCTs) on current treatments for patients with HCC in Asian populations (2013-2023). A total of 427 articles were screened, and 184 non-duplicate publications were identified. After screening the titles and abstracts, 96 publications were excluded, and another 28 were excluded after full-text screening. The remaining 60 eligible RCTs/CTs were finally included. A total of 60 clinical trials fulfilled our inclusion criteria with 36 drugs used as monotherapy or combination therapy for HCC. Most studies used sorafenib alone or in combination with any of the treatment regimens. Lenvatinib or atezolizumab with bevacizumab was used for HCC after initial sorafenib treatment. Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations.

The selection of appropriate second-line therapy for liver cancer after first-line treatment failure poses a significant clinical challenge due to the lack of direct comparative studies and standard treatment protocols. A network meta-analysis (NMA) provides a robust method to systematically evaluate the clinical outcomes and adverse effects of various second-line treatments for hepatocellular carcinoma (HCC).

We systematically searched PubMed, Embase, Web of Science and the Cochrane Library to identify phase III/IV randomized controlled trials (RCTs) published up to March 11, 2024. The outcomes extracted were median overall survival (OS), median progression-free survival (PFS), time to disease progression (TTP), disease control rate (DCR), objective response rate (ORR), and adverse reactions. This study was registered in the Prospective Register of Systematic Reviews (CRD42023427843) to ensure transparency, novelty, and reliability.

We included 16 RCTs involving 7,005 patients and 10 second-line treatments. For advanced HCC patients, regorafenib (HR = 0.62, 95%CI: 0.53-0.73) and cabozantinib (HR = 0.74, 95%CI: 0.63-0.85) provided the best OS benefits compared to placebo. Cabozantinib (HR = 0.42, 95%CI: 0.32-0.55) and regorafenib (HR = 0.46, 95% CI: 0.31-0.68) also offered the most significant PFS benefits. For TTP, apatinib (HR = 0.43, 95% CI: 0.33-0.57), ramucirumab (HR = 0.44, 95% CI: 0.34-0.57), and regorafenib (HR = 0.44, 95% CI: 0.38-0.51) showed significant benefits over placebo. Regarding ORR, ramucirumab (OR = 9.90, 95% CI: 3.40-42.98) and S-1 (OR = 8.68, 95% CI: 1.4-154.68) showed the most significant increases over placebo. Apatinib (OR = 3.88, 95% CI: 2.48-6.10) and cabozantinib (OR = 3.53, 95% CI: 2.54-4.90) provided the best DCR benefits compared to placebo. Tivantinib showed the most significant advantages in terms of three different safety outcome measures.

Our findings suggest that, in terms of overall efficacy and safety, regorafenib and cabozantinib are the optimal second-line treatment options for patients with advanced HCC.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC.

Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future.

Hepatocellular carcinoma (HCC) remains a significant global health burden with a high mortality rate. Over the past 40 years, significant progress has been achieved in the prevention and management of HCC.

Hepatitis B vaccination programs, the development of direct acting antiviral drugs for Hepatitis C, and effective surveillance strategies provide a profound basis for the prevention of HCC. Advanced surgery and liver transplantation along with local ablation techniques potentially offer cure for the disease. Also, just recently, the introduction of immunotherapy opened a new chapter in systemic treatment. Finally, the introduction of the BCLC classification system for HCC, clearly defining patient groups and assigning reasonable treatment options, has standardized treatment and become the basis of almost all clinical trials for HCC. With this review, we provide a comprehensive overview of the evolving landscape of HCC management and also touch on current challenges.

A comprehensive and multidisciplinary approach is crucial for effective HCC management. Continued research and clinical trials are imperative to further enhance treatment options and will ultimately reduce the global burden of this devastating disease.

Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.

Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of its management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the second part of guidelines, focused on the multidisciplinary tumor board of experts and non-surgical treatments of HCC.

Advanced primary liver cancer patients with malignant ascites have a poor prognosis and lack effective treatment plans. This phase Ib study aims to explore the safety and clinical efficacy of intraperitoneal anti-programmed cell death protein 1 (PD-1) antibody in these patients.

Patients received sintilimab 100 mg intraperitoneally plus best supportive care on days 1, 8, and 15 in three cycles of 4 weeks. The course was repeated every 28 days until intolerable toxicity had developed or disease progression. The primary endpoint was safety, while the secondary endpoints were objective response rate (ORR), ascites control rate (ACR), and overall survival (OS).

From February 2021 through November 2022, a total of 21 patients (14 hepatocellular carcinoma and 7 cholangiocarcinoma) were enrolled to receive intraperitoneal sintilimab. Twelve patients had adverse events (AEs). The most common grade 3 AEs were fatigue, rash, and abdominal pain. No grade ≥4 AEs occurred in any patients. ORR was only evaluated in 13 patients, including partial response in 4, stable disease in 7, and progressive disease in 2. A reduction in the median maximum diameter of the tumor after treatment was observed; however, there was no statistical significance among patients. The objective remission rate of ascites was 43.75%, and the median OS for all 21 patients was 17.6 weeks.

This exploratory study represents the first trial to demonstrate the safety and clinical efficacy of intraperitoneal anti-PD-1 antibody administration. No unexpected safety concerns were identified. A large, multicenter, prospective study is needed to confirm the promising clinical efficacy.

The recognition that hepatocellular carcinoma (HCC) is a rising problem globally dates back decades; however, the development of effective medical treatment for the disease has only led to robust improvements in patient outcomes in the recent past. As knowledge evolves and regimens are proven to be more active, the importance of multidisciplinary management in patients with all stages of HCC will become more important to optimize patient outcomes. Key to optimizing patient outcomes is an understanding of the evolution and current role of these therapies in the HCC landscape.

We aim to assess the role of radiological response to atezolizumab-bevacizumab in patients with HCC to predict overall survival.

We retrospectively included patients with HCC treated by atezolizumab-bevacizumab in 2 tertiary centers. A retrospective blinded analysis was performed by 2 radiologists to assess Response Evaluation Criteria in Solid Tumor (RECIST 1.1) and modified RECIST (mRECIST) criteria at 12 weeks. Imaging response and treatment decisions in the multidisciplinary tumor board at 12 weeks were registered. Among 125 patients, 9.6% and 20.8% had a response, 39.2% and 35.2% had stable disease, and 51.2% and 44% had progression, according to RECIST 1.1 and mRECIST, respectively, with a substantial interobserver agreement (k coefficient=0.79). Metastasis was independently associated with a higher risk of progression. Patients classified as responders did not reach median survival, which was 16.2 and 15.9 months for patients classified as stable and 9.1 and 9.0 months for patients classified as progressors, in RECIST 1.1 and mRECIST criteria, respectively. We observed a wide variability in the identification of progression in the multidisciplinary tumor board in clinical practice compared with the blind evaluation by radiologists mainly due to discrepancy in the evaluation of the increase in size of intrahepatic lesions. The appearance of new extrahepatic lesions or vascular invasion lesions was associated with a worse overall survival ( p =0.032).

RECIST 1.1 and mRECIST criteria predict overall survival with more responders identified by mRECIST and the appearance of new extrahepatic lesion or vascular invasion was associated with a poor prognosis. A noticeable discrepancy was observed between patients classified as progressors at reviewing and the decision reached during the multidisciplinary tumor board.

Despite being commonly recommended, the impact of anticancer drugs (ACDs) on patient-important outcomes beyond survival for advanced hepatobiliary cancers (HBCs) may not have been sufficiently assessed. We aim to identify and map the evidence regarding ACDs versus best supportive care (BSC) for advanced HBCs, considering patient-centered outcomes.

In this mapping review, we included systematic reviews, randomized controlled trials, quasi-experimental, and observational studies comparing ACDs (chemotherapy, immunotherapy, biological/targeted therapy) versus BSC for advanced HBCs. We searched MEDLINE (PubMed), EMBASE (Ovid), Cochrane Library, Epistemonikos, PROSPERO and clinicaltrials.gov for eligible studies. Two reviewers performed the screening and data extraction processes. We developed evidence maps for each type of cancer.

We included 87 studies (60 for advanced liver cancer and 27 for gallbladder or bile duct cancers). Most of the evidence favored ACDs for survival outcomes, and BSC for toxicity. We identified several evidence gaps for non-survival outcomes, including quality of life or quality of end-of-life care.

Patient-important outcomes beyond survival in advanced HBCs are insufficiently assessed by the available evidence. Future studies need to address these gaps to better inform decision-making processes.

Globally, primary liver cancer is the third leading cause of cancer-related deaths, with approximately 830 000 deaths worldwide in 2020, accounting for 8.3% of total deaths from all cancer types (1). This disease disproportionately affects those in countries with low or medium Human Development Index scores in Eastern Asia, South-Eastern Asia, and Northern and Western Africa (2). Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, often develops in the background of chronic liver disease, caused by hepatitis B or C virus, non-alcoholic steatohepatitis (NASH), or other diseases that cause cirrhosis. Prognosis can vary dramatically based on number, size, and location of tumors. Hepatic synthetic dysfunction and performance status (PS) also impact survival. The Barcelona Clinic Liver Cancer (BCLC) staging system best accounts for these variations, providing a reliable prognostic stratification. Therapeutic considerations of this complex disease necessitate a multidisciplinary approach and can range from curative-intent surgical resection, liver transplantation or image-guided ablation to more complex liver-directed therapies like transarterial chemoembolization (TACE) and systemic therapy. Recent advances in the understanding of the tumor biology and microenvironment have brought new advances and approvals for systemic therapeutic agents, often utilizing immunotherapy or VEGF-targeted agents to modulate the immune response. This review will discuss the current landscape in the treatments available for early, intermediate, and advanced stage HCC.

Hepatocellular carcinoma (HCC) represents a significant global burden, with management complicated by its heterogeneity, varying presentation, and relative resistance to therapy. Recent advances in the understanding of the genetic, molecular, and immunological underpinnings of HCC have allowed a detailed classification of these tumors, with resultant implications for diagnosis, prognostication, and selection of appropriate treatments. Through the correlation of genomic features with histopathology and clinical outcomes, we are moving toward a comprehensive and unifying framework to guide our diagnostic and therapeutic approach to HCC.

Hepatocellular carcinoma (HCC) is one of the most common solid tumor malignancies in the world and represents roughly 90% of all primary malignancies of the liver. The most common risk factors for HCC include hepatitis B virus, hepatitis C virus, alcohol, and increasingly, fatty liver. Most HCC is diagnosed at advanced stages, excluding the possibility of curative resection, which leaves systemic therapy as the only treatment option. However, given the extreme mutational diversity and heterogenous nature of HCC, efforts to develop new targeted systemic therapies were largely unsuccessful until recently. HCC pathogenesis is thought to be a multistage process driven by a wide array of nonmutually exclusive driver mutations accompanied by many passenger mutations, with the average tumor possessing approximately 40 genomic aberrations. Over the past two decades, several efforts to categorize HCC prognostically and therapeutically according to different molecular subclassifications with the intent to guide treatment and identify drug targets have emerged, though, no single consensus has been reached. Recent breakthroughs in drug development have greatly expanded treatment options, but the ideal of uniting each patient's unique HCC with a targeted systemic therapy remains elusive.

Hepatocellular carcinoma (HCC) is the fourth most common malignancy worldwide and exhibits a universal burden as the incidence of the disease continues to rise. In addition to curative-intent therapies such as liver resection and transplantation, locoregional and systemic therapy options also exist. However, existing treatments carry a dismal prognosis, often plagued with high recurrence and mortality. For this reason, understanding the tumor microenvironment and mutational pathophysiology has become the center of investigation for disease control. The use of precision medicine and genetic analysis can supplement current treatment modalities to promote individualized management of HCC. In the search for personalized medicine, tools such as next-generation sequencing have been used to identify unique tumor mutations and improve targeted therapies. Furthermore, investigations are underway for specific HCC biomarkers to augment the diagnosis of malignancy, the prediction of whether the tumor environment is amenable to available therapies, the surveillance of treatment response, the monitoring for disease recurrence, and even the identification of novel therapeutic opportunities. Understanding the mutational landscape and biomarkers of the disease is imperative for tailored management of the malignancy. In this review, we summarize the molecular targets of HCC and discuss the current role of precision medicine in the treatment of HCC.

Hispanic individuals comprise the second-largest subpopulation after non-Hispanic White (NHW) individuals in the United States (US). We compared the relative contribution of Hispanic individuals to the ten most common causes of cancer-related deaths and studied enrollment of Hispanic patients in multinational phase III advanced liver cancer trials with the aim to investigate whether racial subpopulations are adequately represented in liver cancer trials.

Relative cancer incidence rates in Hispanic individuals, NHW individuals, non-Hispanic black (NHB) individuals, and Asian individuals were obtained from both the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results Program and the Center for Disease Control and Prevention (CDC), United States Cancer Statistics (USCS) database. Searching PubMed, Embase, and Web of Science, we identified phase III clinical trials studying advanced liver cancer in the last ten years and collected enrollment for each race and ethnicity. Incidence rates of liver cancer and enrollment rates in phase III trials were compared by race and ethnicity.

The cancer type with the relatively highest contribution of Hispanic individuals was liver cancer. From 2015 to 2019, 15.1% of liver cancer cases occurred in Hispanic individuals compared to 12.5% in Asian individuals, 11% in NHB individuals, and 7.5% in NHW individuals. In the last ten years, Hispanic individuals made up 1.6% of patients and NHB individuals 1.3% of patients included in phase III multinational liver cancer trials, compared to 31% NHW individuals and 47% Asian individuals.

Hispanic individuals are disproportionately underrepresented in multinational phase III clinical trials for liver cancer despite having the highest relative incidence rates among the four major racial or ethnic groups in the US.

The intestinal flora plays an important role in the occurrence and development of liver cancer, affecting the efficacy and side effects of conventional antitumor therapy. Recently, immunotherapy for liver cancer has been a palliative treatment for patients with advanced liver cancer lacking surgical indications. Representative drugs include immune checkpoint inhibitors, regulators, tumor vaccines, and cellular immunotherapies. The effects of immunotherapy on liver cancer vary because of the heterogeneity of the tumors. Intestinal flora can affect the efficacy and side effects of immunotherapy for liver cancer by regulating host immunity. Therefore, applying probiotics, prebiotics, antibiotics, and fecal transplantation to interfere with the intestinal flora is expected to become an important means of assisting immunotherapy for liver cancer. This article reviews publications that discuss the relationship between intestinal flora and immunotherapy for liver cancer and further clarifies the potential relationship between intestinal flora and immunotherapy for liver cancer.

Several breakthroughs in hepatocellular carcinoma (HCC) therapy across tumor stages provide hope to improve its dismal prognosis. Although surgical and local ablative therapies have few significant changes in technique, an improved understanding of tumor biology has facilitated increase numbers of patients who are now eligible to undergo curative-intent procedures. Most notably, acceptable post-transplant outcomes can be achieved in well selected patients whose tumors are downstaged into Milan Criteria. Adjuvant therapy in patients at high risk of recurrence also significantly improves recurrence-free survival after resection or ablation. For patients with liver-localized disease who are not eligible for curative-intent procedures, transarterial chemoembolization (TACE) was historically the treatment modality of choice, regardless of tumor burden; however, there is now increased recognition of patients who are "TACE unsuitable" and may be better treated with systemic therapy. The greatest evolution in HCC treatment options has occurred with systemic therapy, where several new agents are now available in the first- and second-line setting, including immune checkpoint inhibitor combinations. Objective responses are observed in approximately 30% of patients and median survival is approaching 2 years. The availability of immune checkpoint inhibitors has renewed interest in combination therapies for earlier tumor stages, with several phase III trials ongoing. Considering increasing complexities of HCC care, requiring decisions between therapies delivered by different providers, multidisciplinary care is critical and is associated with improved clinical outcomes. In this review, we detail major breakthroughs in HCC therapy, how these breakthroughs can be applied in clinical practice, and remaining areas in need of further research.

Hepatocellular carcinoma (HCC) is the most common type of cancer and causes a significant number of cancer-related deaths worldwide. The molecular mechanisms underlying the development of HCC are complex, and the heterogeneity of HCC has led to a lack of effective prognostic indicators and drug targets for clinical treatment of HCC. Previous studies have indicated that the unfolded protein response (UPR), a fundamental pathway for maintaining endoplasmic reticulum homeostasis, is involved in the formation of malignant characteristics such as tumor cell invasiveness and treatment resistance. The aims of our study are to identify new prognostic indicators and provide drug treatment targets for HCC in clinical treatment based on UPR-related genes (URGs).

Gene expression profiles and clinical information were downloaded from the TCGA, ICGC and GEO databases. Consensus cluster analysis was performed to classify the molecular subtypes of URGs in HCC patients. Univariate Cox regression and machine learning LASSO algorithm were used to establish a risk prognosis model. Kaplan-Meier and ROC analyses were used to evaluate the clinical prognosis of URGs. TIMER and XCell algorithms were applied to analyze the relationships between URGs and immune cell infiltration. Real time-PCR was performed to analyze the effect of sorafenib on the expression levels of four URGs.

Most URGs were upregulated in HCC samples. According to the expression pattern of URGs, HCC patients were divided into two independent clusters. Cluster 1 had a higher expression level, worse prognosis, and higher expression of immunosuppressive factors than cluster 2. Patients in cluster 1 were more prone to immune escape during immunotherapy, and were more sensitive to chemotherapeutic drugs. Four key UPR genes (ATF4, GOSR2, PDIA6 and SRPRB) were established in the prognostic model and HCC patients with high risk score had a worse clinical prognosis. Additionally, patients with high expression of four URGs are more sensitive to sorafenib. Moreover, ATF4 was upregulated, while GOSR2, PDIA6 and SRPRB were downregulated in sorafenib-treated HCC cells.

The UPR-related prognostic signature containing four URGs exhibits high potential application value and performs well in the evaluation of effects of chemotherapy/immunotherapy and clinical prognosis.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the "primum movens" of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments.

Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8⁺ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

Hepatocellular carcinoma often develops in the context of chronic liver disease. It is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related mortality worldwide. Although the mainstay of therapy is surgical resection, most patients are not eligible because of liver dysfunction or tumor extent. Sorafenib was the first tyrosine kinase inhibitor that improved the overall survival of patients who failed to respond to local therapies or had advanced disease, and for many years, it was the only treatment approved for the first-line setting. However, in recent years, trials have demonstrated an improvement in survival with treatments based on immunotherapy and new targeting agents, thereby extending the treatment options. A phase III trial showed that a combination of immunotherapy and targeted therapy, including atezolizumab plus bevacizumab, improved survival in the first-line setting, and is now considered the new standard of care. Other agents and combinations are being tested, including the combination of nivolumab plus ipilimumab and tremelimumab plus durvalumab, and they reportedly have clinical benefits. The aim of this manuscript is to review the latest approved therapeutic options in first- and second-line settings for advanced HCC and discuss future perspectives.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.

The trade-off between systemic oncological treatments (SOTs) and UPSC in patients with primary advanced hepatobiliary cancers (HBCs) is not clear in terms of patient-centred outcomes beyond survival. This overview aims to assess the effectiveness of SOTs (chemotherapy, immunotherapy and targeted/biological therapies) versus UPSC in advanced HBCs.

We searched for systematic reviews (SRs) in PubMed, EMBASE, the Cochrane Library, Epistemonikos and PROSPERO. Two authors assessed eligibility independently and performed data extraction. We estimated the quality of SRs and the overlap of primary studies, performed de novo meta-analyses and assessed the certainty of evidence for each outcome.

We included 18 SRs, most of which were of low quality and highly overlapped. For advanced hepatocellular carcinoma, SOTs showed better overall survival (HR = 0.62, 95% CI 0.55-0.77, high certainty for first-line therapy; HR = 0.85, 95% CI 0.79-0.92, moderate certainty for second-line therapy) with higher toxicity (RR = 1.18, 95% CI 0.87-1.60, very low certainty for first-line therapy; RR = 1.58, 95% CI 1.28-1.96, low certainty for second-line therapy). Survival was also better for SOTs in advanced gallbladder cancer. No outcomes beyond survival and toxicity could be meta-analysed.

SOTs in advanced HBCs tend to improve survival at the expense of greater toxicity. Future research should inform other patient-important outcomes to guide clinical decision making.

Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy.

We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization.

Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC.

Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease.

NCT01761266.

This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.

Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.

Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives.