Astaxanthin Augmented the Anti-Hepatocellular Carcinoma Efficacy of Sorafenib Through the Inhibition of the JAK2/STAT3 Signaling Pathway and Mitigation of Hypoxia within the Tumor Microenvironment.

SCOPE: The optimization of anti-cancer drug effectiveness through dietary modifications has garnered significant attention among researchers in recent times. Astaxanthin (AST) has been identified as a safe and biologically active dietary supplement. METHODS AND RESULTS: The tumor-bearing mice are treated with sorafenib, along with supplementation of 60 mg kg-1 AST during the treatment. The coadministration of AST and a subclinical dosage of 10 mg kg-1 sorafenib demonstrates a tumor inhibition rate of 76.5%, which is notably superior to the 45% inhibition rate observed with the clinical dosage of 30 mg kg-1 sorafenib (p < 0.05). The administration of AST leads to a tumor inhibition increase of around 25% when combined with the clinical dose of 30 mg kg-1 sorafenib (p <0.05). AST enhances the inhibitory effect of sorafenib on tumor angiogenesis through the JAK2/STAT3 signaling pathway. Furthermore, AST exhibits a reduction in hypoxia within the tumor microenvironment. CONCLUSION: The results suggest that AST supplement enhances the inhibitory effects of sorafenib on hepatocellular carcinoma. This study presents a new dietary management program for oncology patients.

Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer.

Thyroid cancer is the most common endocrine malignancy, affecting nearly 600,000 new patients worldwide. Treatment with the BRAF inhibitor sorafenib partially prolongs progression-free survival in thyroid cancer patients, but fails to improve overall survival. This study examines enhancing sorafenib efficacy by combination therapy with the novel HSP90 inhibitor onalespib. In vitro efficacy of sorafenib and onalespib monotherapy as well as in combination was assessed in papillary (PTC) and anaplastic (ATC) thyroid cancer cells using cell viability and colony formation assays. Migration potential was studied in wound healing assays. The in vivo efficacy of sorafenib and onalespib therapy was evaluated in mice bearing BHT-101 xenografts. Sorafenib in combination with onalespib significantly inhibited PTC and ATC cell proliferation, decreased metabolic activity and cancer cell migration. In addition, the drug combination approach significantly inhibited tumor growth in the xenograft model and prolonged the median survival. Our results suggest that combination therapy with sorafenib and onalespib could be used as a new therapeutic approach in the treatment of thyroid cancer, significantly improving the results obtained with sorafenib as monotherapy. This approach has the potential to reduce treatment adaptation while at the same time providing therapeutic anti-cancer benefits such as reducing tumor growth and metastatic potential.

Therapeutic inhibition of ATR in differentiated thyroid cancer.

Ataxia telangiectasia and Rad3-related protein (ATR) is a critical component of the DNA damage response and a potential target in the treatment of cancers. An ATR inhibitor, BAY 1895344, was evaluated for its use in differentiated thyroid cancer (DTC) therapy. BAY 1895344 inhibited cell viability in four DTC cell lines (TPC1, K1, FTC-133, and FTC-238) in a dose-dependent manner. BAY 1895344 treatment arrested DTC cells in the G2/M phase, increased caspase-3 activity, and caused apoptosis. BAY 1895344 in combination with either sorafenib or lenvatinib showed mainly synergistic effects in four DTC cell lines. The combination of BAY 1895344 with dabrafenib plus trametinib revealed synergistic effects in K1 cells that harbor BRAFV600E. BAY 1895344 monotherapy retarded the growth of K1 and FTC-133 tumors in xenograft models. The combinations of BAY 1895344 plus lenvatinib and BAY 1895344 with dabrafenib plus trametinib were more effective than any single therapy in a K1 xenograft model. No appreciable toxicity appeared in animals treated with either a single therapy or a combination treatment. Our findings provide the rationale for the development of clinical trials of BAY 1895344 in the treatment of DTC.

Changing treatment landscape associated with improved survival in advanced hepatocellular carcinoma: a nationwide, population-based study.

BACKGROUND AND AIMS: The treatment of hepatocellular carcinoma (HCC) is undergoing a historic transformation with the approval of several new systemic therapies in the last few years. This study aimed to examine the impact of this changing landscape on survival and costs in a Western nationwide, real-world cohort. METHODS: A nationwide representative claims database (InGef) was screened for HCC cases between 2015 and 2020. Survival in an era with only sorafenib (period A, January 2015 to July 2018) and after approval of lenvatinib and other systemic treatments (period B, August 2018 to December 2020) was analysed. Health care costs were assessed. RESULTS: We identified 2876 individuals with HCC in the study period. The proportion of patients receiving systemic therapy increased significantly over time, from 11.8% in 2015 to 15.1% in 2020 (p < 0.0001). The median overall survival in period B was 6.5 months (95% confidence interval [CI]: 4.9-8.9) and in period A was 5.3 months (95% CI: 4.5-6.3; p = 0.046). In period B, the median overall survival with lenvatinib was 9.7 months (95% CI: 6.3-18.4) versus 4.8 months with sorafenib (95% CI: 4.0-7.1, p = 0.008). Costs for prescription drugs per patient increased from €6150 in 2015 to €9049 in 2020 (p < 0.0001), and costs for outpatient care per patient increased from €1646 to €2149 (p = 0.0240). CONCLUSION: The approval of new systemic therapies resulted in a survival benefit in patients with HCC. The magnitude of the effect is modest and associated with a moderate increase in health costs.

Advances in the molecular mechanism and targeted therapy of radioactive-iodine refractory differentiated thyroid cancer.

Most patients with differentiated thyroid cancer have a good prognosis after radioactive iodine-131 treatment, but there are still a small number of patients who are not sensitive to radioiodine treatment and may subsequently show disease progression. Therefore, radioactive-iodine refractory differentiated thyroid cancer treated with radioiodine usually shows reduced radioiodine uptake. Thus, when sodium iodine symporter expression, basolateral membrane localization and recycling degradation are abnormal, radioactive-iodine refractory differentiated thyroid cancer may occur. In recent years, with the deepening of research into the pathogenesis of this disease, an increasing number of molecules have become or are expected to become therapeutic targets. The application of corresponding inhibitors or combined treatment regimens for different molecular targets may be effective for patients with advanced radioactive-iodine refractory differentiated thyroid cancer. Currently, some targeted drugs that can improve the progression-free survival of patients with radioactive-iodine refractory differentiated thyroid cancer, such as sorafenib and lenvatinib, have been approved by the FDA for the treatment of radioactive-iodine refractory differentiated thyroid cancer. However, due to the adverse reactions and drug resistance caused by some targeted drugs, their application is limited. In response to targeted drug resistance and high rates of adverse reactions, research into new treatment combinations is being carried out; in addition to kinase inhibitor therapy, gene therapy and rutin-assisted iodine-131 therapy for radioactive-iodine refractory thyroid cancer have also made some progress. Thus, this article mainly focuses on sodium iodide symporter changes leading to the main molecular mechanisms in radioactive-iodine refractory differentiated thyroid cancer, some targeted drug resistance mechanisms and promising new treatments.

A Single Nucleotide Polymorphism rs1010816 Predicts Sorafenib Therapeutic Outcomes in Advanced Hepatocellular Carcinoma.

Sorafenib is currently a targeted agent widely used in the treatment of advanced hepatocellular carcinoma (aHCC). However, to date there is still a lack of a reliable marker capable of predicting sorafenib therapeutic responses. Here, we conducted a genome-wide association study (GWAS) to identify candidate single-nucleotide polymorphism outcome predictors in aHCC patients. A total of 74 real-world sorafenib-treated aHCC patients were enrolled for GWAS and outcome analysis. GWAS showed that rs1010816 (p = 2.2 × 10-7) was associated with sorafenib therapeutic response in aHCC patients. Kaplan-Meier analysis indicated that the "TT" genotype was significantly associated with a favorable therapeutic response but not significantly associated with overall survival (OS). Univariate followed by multivariate Cox proportional hazard analysis showed that ascites, main portal vein thrombosis, lower platelet count, lower total sorafenib doses, higher PALBI score in model A and higher ALBI grade in model B were significantly associated with a shorter OS. Subgroup analysis showed that only in alcoholic aHCC patients treated by sorafenib, rs1010816 "TT" genotype was significantly associated with longer OS (p = 0.021). Sorafenib had a favorable therapeutic outcome in alcoholic aHCC patients carrying rs1010816 "TT" genotype.

Comparison of nivolumab and sorafenib for first systemic therapy in patients with hepatocellular carcinoma and Child-Pugh B cirrhosis.

BACKGROUND: Patients with decompensated cirrhosis are excluded or underrepresented in clinical trials of systemic therapies for hepatocellular carcinoma (HCC) and comparisons of available therapies are lacking. We aimed to compare overall survival for patients with HCC and Child-Pugh B cirrhosis treated with nivolumab or sorafenib as first systemic treatment. METHODS: We performed a retrospective cohort study in patients with HCC and Child-Pugh B cirrhosis treated at Veterans Affairs medical centers to compare overall survival, adverse events, and reason for discontinuation of therapy between patients treated with nivolumab or sorafenib as first systemic treatment. All statistical tests were 2-sided. RESULTS: Of those meeting inclusion criteria, 431 patients were treated with sorafenib and 79 with nivolumab. Median OS was 4.0 months (95% CI 3.5-4.8) in the sorafenib cohort and 5.0 months (95% CI 3.3-6.8) in the nivolumab cohort. In the multivariable Cox proportional hazards model, nivolumab was associated with a significantly reduced hazard of death compared to sorafenib (HR 0.69; 95% CI 0.52-0.91; p = 0.008). In a secondary analysis using propensity score methods, results did not reach statistical significance (HR 0.77; 95% CI 0.55-1.06; p = 0.11). Treatment was discontinued due to toxicity in 12% of patients receiving nivolumab compared to 36% receiving sorafenib (p = 0.001). CONCLUSION: In patients with HCC and Child-Pugh B cirrhosis, nivolumab treatment may be associated with improved overall survival and improved tolerability compared to sorafenib and should be considered for the first systemic treatment in this population.

Natural Products for Liver Cancer Treatment: From Traditional Medicine to Modern Drug Discovery.

Primary liver cancer was the seventh most diagnosed cancer and the second leading cause of cancer death with about 906,000 cases and 830,000 deaths, respectively, in 2020. Conventional treatment for liver cancer, such as transarterial chemoembolization (TACE) or sorafenib, has limitations in that there is the recurrence of cancer, drug inefficacy, and adverse effects. Traditional medicine and natural products of several regions including Korea, China, Europe, North America, India, and the Middle East have attracted a lot of attention since they have been reported to have anticancer effects with low adverse effects. In this review, several in vivo studies on the effects of natural compounds on liver cancer and clinical trials approving their therapeutic benefits were selected and discussed. As a result of the analysis of these studies, the effects of natural compounds were classified into a few mechanisms: apoptosis, anti-metastasis, and antiangiogenesis. In addition, medications including natural products in clinical trials were observed to exhibit improvements in various liver cancer symptoms and patients' survival rates. This study presents findings suggestive of the anticancer potential of natural products and their properties in relieving related symptoms.

Therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Immune checkpoint inhibitor therapy is the backbone of numerous combination regimens for improving the therapeutic response of patients with hepatocellular carcinoma (HCC). We aimed to investigate the therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable HCC. METHODS: Patients with unresectable HCC who received sorafenib and followed at Taipei Tzu Chi Hospital from January 2016 to May 2022 were selected for this study, and those treated with nivolumab plus sorafenib and those with sorafenib alone were propensity score matched. The primary outcome was overall survival (OS) presented as a hazard ratio calculated using Cox proportional hazards regression models. RESULTS: In the analysis, 36 patients receiving nivolumab plus sorafenib and 36 receiving sorafenib alone were propensity score matched. The median OS for those receiving nivolumab plus sorafenib and sorafenib alone were 3.6 years and 1.2 years, respectively (p = 0.031). The hazard ratio of OS for nivolumab plus sorafenib compared to sorafenib alone was 0.36 (95 %CI, 0.19-0.70; p = 0.003). Furthermore, patients receiving nivolumab plus sorafenib with a baseline α-fetoprotein(AFP) < 10 ng/mL and early reduction in AFP had a 100 % objective response rate and disease control rate. CONCLUSION: In patients with unresectable HCC, nivolumab plus sorafenib resulted in better OS outcomes than sorafenib.

Potential Therapeutic Agents against Paclitaxel-And Sorafenib-Resistant Papillary Thyroid Carcinoma.

Thyroid carcinoma, a disease in which malignant cells form in the thyroid tissue, is the most common endocrine carcinoma, with papillary thyroid carcinoma (PTC) accounting for nearly 80% of total thyroid carcinoma cases. However, the management of metastatic or recurrent therapy-refractory PTC is challenging and requires complex carcinoma therapy. In this study, we proposed a new clinical approach for the treatment of therapy-refractory PTC. We identified sarco/endoplasmic reticulum calcium ATPase (SERCA) as an essential factor for the survival of PTC cells refractory to the treatment with paclitaxel or sorafenib. We validated its use as a potential target for developing drugs against resistant PTC, by using patient-derived paclitaxel- or sorafenib-resistant PTC cells. We further discovered novel SERCA inhibitors, candidates 7 and 13, using the evolutionary chemical binding similarity method. These novel SERCA inhibitors determined a substantial reduction of tumors in a patient-derived xenograft tumor model developed using paclitaxel- or sorafenib-resistant PTC cells. These results could provide a basis for clinically meaningful progress in the treatment of refractory PTC by identifying a novel therapeutic strategy: using a combination therapy between sorafenib or paclitaxel and specific SERCA inhibitors for effectively and selectively targeting extremely malignant cells such as antineoplastic-resistant and carcinoma stem-like cells.

Expanding Sorafenib Treatment for Hepatocellular Carcinoma Beyond Barcelona Clinic Liver Cancer Stage C Patients: A National Study.

BACKGROUND/AIM: The reimbursement criteria of sorafenib for advanced hepatocellular carcinoma (HCC) were expanded in 2016 by Taiwan's National Health Insurance (NHI) to include patients without macrovascular invasion or extrahepatic spread. This study explored sorafenib treatment outcomes before and after this expansion. PATIENTS AND METHODS: The NHI database was searched for patients who initiated sorafenib treatment between January 1, 2013, and December 31, 2017. Clinical variables were retrieved from the Taiwan Cancer Registry database. Overall survival (OS) and time to treatment discontinuation (TTD) were calculated as the times from the first sorafenib prescription date until death and the final prescription date, respectively. RESULTS: A total of 13,862 patients were included. The median age was 64 years, 78.1% of patients were male. Approximately a quarter of patients (25.1%) received sorafenib after the criteria expansion and exhibited significantly longer OS (median 7.9 vs. 6.6 months, p<0.001) and TTD (median 3.0 vs. 2.6 months, p=0.003) compared with patients who started before. These results were verified in patients with available data regarding clinical prognostic factors (n=9,378, 67.7% of the entire study population). In the multivariate analysis, sorafenib prescription after criteria expansion remained an independent predictor of longer OS [hazard ratio (HR)=0.87, p<0.001] and TTD (HR=0.93, p=0.004). In the subgroup analysis, these trends were consistently observed across different patient subgroups. CONCLUSION: Patients with HCC who received sorafenib treatment after the reimbursement criteria expansion exhibited longer OS and TTD.

Multikinase Inhibitors for the Treatment of Asymptomatic Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Global Noninterventional Study (RIFTOS MKI).

Background: Sorafenib and lenvatinib are multikinase inhibitors (MKIs) approved for patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC). There is no consensus on when to initiate MKI treatment. The objective of this study was to evaluate time to symptomatic progression (TTSP) in patients with RAI-R DTC for whom the decision to treat with an MKI was made at study entry. Methods: International, prospective, open-label, noninterventional cohort study (NCT02303444). Eligible patients had asymptomatic progressive RAI-R DTC, with ≥1 lesion ≥1 cm in diameter and life expectancy ≥6 months. The decision to treat with an MKI was at the treating physician's discretion. Primary endpoint was TTSP from study entry. Two cohorts were evaluated: patients for whom a decision to initiate an MKI was made at study entry (Cohort 1) and patients for whom there was a decision not to initiate an MKI at study entry (Cohort 2). Cohorts were compared descriptively. Results: The full analysis set (FAS) comprised 647 patients. The median duration of observation was 35.5 months (range <1-59.4). Of 344 MKI-treated patients, 209 received sorafenib, 191 received lenvatinib, and 19 received another MKI at some point. Median TTSP was 55.4 months (interquartile range [IQR] 18.6-not estimable [NE]) overall, 55.4 months (IQR 15.2-NE) in Cohort 1 (n = 169), and 51.4 months (IQR 20.0-NE) in Cohort 2 (n = 478). TTSP ≥36 months was achieved in 64.5% of patients overall, 59.5% of patients in Cohort 1, and 66.4% of patients in Cohort 2. Median overall survival from classification as RAI-R was 167 months and median progression-free survival from start of MKI therapy was 19.2 months and from start of sorafenib therapy 16.7 months. Among sorafenib-treated patients, 70% had dose modifications, 35% had a dose reduction, 89% experienced ≥1 treatment-emergent adverse event (TEAE), and 82% experienced ≥1 drug-related TEAE. Conclusions: This real-world study provides valuable insight into outcomes in patients with asymptomatic, progressive RAI-R DTC under observation or receiving MKI treatment. TTSP in the FAS provides insight into the current prognosis for patients with RAI-R DTC in the era of MKIs. Registration: NCT02303444.

The Efficacy of Combined Therapy of Regorafenib with Detoxicating and Stasis Softening Chinese Herbal Spleen Tonics in Mid-/Late-Stage Hepatocellular Carcinoma.

Objective: To explore the efficacy of combined therapy of Regorafenib with detoxicating and stasis softening Chinese herbal spleen tonics (DSS-splenic tonics) in mid-/late-stage hepatocellular carcinoma. Methods: Retrospective observational data of 120 patients were obtained, 60 of which received combined therapy of DSS-splenic tonics and regorafenib. Adverse event, overall survival (OS), and time-to-progress (TTP) were analyzed. Synergistic effect of DSS-spleen tonics was found and validated in human hepatocellular carcinoma HCCLM3 cell line and xenograft mouse models. Results: Combination of regorafenib and DSS-splenic tonics also slightly extended the TTP and OS compared with treatment of regorafenib alone, suggesting DSS-splenic tonics has synergistic effect with regorafenib. Both Regorafenib and DSS-spleen tonics exerted inhibitory effect on cell viability and invasion capability of HCCLM3 cells, and combining both could enhance the antitumor effect. At molecular level, we found that VEGF, HIF-1α, MVD, and VEGF2 were all suppressed by regorafenib and DSS-splenic tonics. These results suggest that DSS-spleen tonics function synergistically with regorafenib in HCC by enhancing the regulation of regorafenib on VEGF, MMP-2, HIF-1α, and MVD, and may diminish angiogenesis during HCC progression. Conclusion: DSS-spleen tonics could exert synergistic antitumor effect with regorafenib via targeting VEGF.

Extracellular Vesicles May Predict Response to Radioembolization and Sorafenib Treatment in Advanced Hepatocellular Carcinoma: An Exploratory Analysis from the SORAMIC Trial.

PURPOSE: SORAMIC is a randomized controlled trial in patients with advanced hepatocellular carcinoma (HCC) undergoing sorafenib ± selective internal radiation therapy (SIRT). We investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction. EXPERIMENTAL DESIGN: The analysis population comprised 25 patients receiving SIRT+sorafenib and 20 patients receiving sorafenib alone. Patients were classified as responders or nonresponders based on changes in AFP and imaging or overall survival. Proteomic analysis was performed on plasma EVs by LC/MS, followed by bioinformatics analysis. Clinical relevance of candidate EV proteins was validated by survival and receiver-operating characteristic analysis with bootstrap internal sampling validation. Origin of circulating EV was explored by IHC staining of liver and tumor tissues and transcriptomics of blood cells. RESULTS: Proteomic analysis identified 56 and 27 EV proteins that were differentially expressed in plasma EVs between responders and nonresponders receiving SIRT+sorafenib and sorafenib alone, respectively. High EV-GPX3/ACTR3 and low EV-ARHGAP1 were identified as candidate biomarkers at baseline from the 13 responders to SIRT+sorafenib with statistically significant AUC = 1 for all and bootstrap P values 2.23 × 10-5, 2.22 × 10-5, and 2.23 × 10-5, respectively. These patients showed reduced abundance of EV-VPS13A and EV-KALRN 6 to 9 weeks after combined treatment with significant AUC and bootstrap P values. In reverse, low GPX3 and high ARHGAP1 demonstrated better response to sorafenib monotherapy with AUC = 0.9697 and 0.9192 as well as bootstrap P values 8.34 × 10-5 and 7.98 × 10-4, respectively. HCC tumor was the likely origin of circulating EVs. CONCLUSIONS: In this exploratory study, EV-based proteomics predicted response to SIRT+sorafenib and sorafenib-only treatment in patients with advanced HCC of metabolic origin.

The Cost-Effectiveness of Selective Internal Radiation Therapies Compared With Sorafenib for Treating Advanced Unresectable Hepatocellular Carcinoma in the United Kingdom.

OBJECTIVES: To assess the cost-effectiveness of selective internal radiation therapy (SIRT) compared with sorafenib for the treatment of patients with advanced hepatocellular carcinoma in the United Kingdom, including a selected subgroup of patients who have been identified as benefiting from treatment with SIRT. METHODS: A de novo economic model was developed comparing SIRT with sorafenib using data from two large randomized controlled trials. The model structure comprised a decision tree representing the outcome of the work-up procedure, transitioning into a 3-state partitioned survival model to project long-term survival outcomes. Cost-effectiveness in a post hoc defined subgroup with low tumor burden and good liver function was explored. RESULTS: At list price, SIRT was predicted to be less costly but less effective than sorafenib with an estimated saving of £156 089 per quality-adjusted life-year forgone, with cost savings of £4589 and 0.029 fewer quality-adjusted life-years than sorafenib. Accounting for existing confidential discounts for sorafenib, two SIRTs were cost-effective at a £30 000 willingness-to-pay threshold compared with sorafenib when a discount for the technologies was introduced. In the subgroup with low tumor burden and good liver function, SIRT may be associated with greater survival benefits and cost savings. CONCLUSIONS: Accounting for confidential discounts, on average, SIRT technologies represent value for money in the whole advanced hepatocellular carcinoma population, being less effective but less costly than sorafenib. Results from a subgroup with low tumor burden and good liver function suggest that the cost-effectiveness of SIRTs may be maximized in this group, but further research is required to demonstrate the validity of effectiveness benefits.

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer.

Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways' inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways' inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC.

Early predictive value of circulating biomarkers for sorafenib in advanced hepatocellular carcinoma.

INTRODUCTION: Sorafenib is currently the first-line therapeutic regimen for patients with advanced hepatocellular carcinoma (HCC). However, many patients did not experience any benefit and suffered extreme adverse events and heavy economic burden. Thus, the early identification of patients who are most likely to benefit from sorafenib is needed. AREAS COVERED: This review focused on the clinical application of circulating biomarkers (including conventional biomarkers, immune biomarkers, genetic biomarkers, and some novel biomarkers) in advanced HCC patients treated with sorafenib. An online search on PubMed, Web of Science, Embase, and Cochrane Library was conducted from the inception to 15 August 2021. Studies investigating the predictive or prognostic value of these biomarkers were included. EXPERT OPINION: The distinction of patients who may benefit from sorafenib treatment is of utmost importance. The predictive roles of circulating biomarkers could solve this problem. Many biomarkers can be obtained by liquid biopsy, which is a less or noninvasive approach. The short half-life of sorafenib could reflect the dynamic changes of tumor progression and monitor the treatment response. Circulating biomarkers obtained from liquid biopsy resulted as a promising assessment method in HCC, allowing for better treatment decisions in the near future. ABBREVIATIONS: Alpha-fetoprotein (AFP); American Association for the Study of Liver Diseases (AASLD); Angiopoietin (Ang); Barcelona Clinic Liver Cancer stage (BCLC); Circulating endothelial progenitor (CEP); Circulating free DNA (cfDNA); Complete response (CR); Des-γ-carboxy prothrombin (DCP); Endothelium-derived nitric oxide synthase (eNOS); Hepatocellular carcinoma (HCC); Hepatocyte growth factor (HGF); Hepatoma arterial-embolization prognosis score (HAP); High mobility group box 1 (HMgb1); Interferon-gamma (IFN-γ); Long non-coding RNA (lncRNAs); Micro RNAs (miRNAs); Monocyte-to-lymphocyte ratio (MLR); National Comprehensive Cancer Network (NCCN); Neutrophil-lymphocyte ratio (NLR); Newcastle-Ottawa Scale (NOS); Nitric oxide (NO); Overall survival (OS); Partial response (PR); Platelet-lymphocyte ratio (PLR); Prediction of survival in advanced sorafenib-treated HCC (PROSASH); Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA); Prognostic nutritional index (PNI); Progression-free survival (PFS); Progressive disease (PD); Randomized controlled trials (RCTs); Response Evaluation Criteria in Solid Tumors (RECIST); Single nucleotide polymorphisms (SNPs); Sorafenib advanced HCC prognosis score (SAP); Stable disease (SD); Time to progression (TTP); Transcatheter arterial chemoembolization (TACE); Vascular endothelial growth factor (VEGF).