• Chemotherapy
• Cytoreductive surgery
• HIPEC
• Hepatocellular carcinoma
• Systemic therapy

• advanced hepatocellular carcinoma
• hepatic arterial infusion chemotherapy
• propensity score matching
• transarterial chemoembolization

• work was supported by the National Natural Science Foundation of China
• Key Projects of CSCO-Bayer Cancer Research Fund
• Beijing Hospital authority of Hospitals’ Ascent Plan

• Autophagy
• Epithelial-mesenchymal transition
• Exosomes
• Ferroptosis
• Liver cancer stem cells
• Non-coding RNAs

• Diagnosis
• Guidelines
• Hepatocellular carcinoma
• Management

• Diagnosis
• Guidelines
• Hepatocellular carcinoma
• Management

• Male
• Humans
• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/therapy
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/therapy
• Hepatitis B, Chronic/complications
• Hepatitis B
• Republic of Korea

• National Cancer Center

• Diagnosis
• Guidelines
• Hepatocellular carcinoma
• Management

• Humans
• Male
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/pathology
• Hepatitis B, Chronic/complications
• Liver Neoplasms/diagnosis
• Liver Neoplasms/therapy
• Liver Neoplasms/pathology
• Prevalence
• Republic of Korea/epidemiology

• 2112570-2 National Cancer Center

Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.

• biomarkers
• cancer biology
• cancer-associated fibroblasts
• gene expression
• personalized medicine
• tumor microenvironment
• tumor stroma

Several biomarkers of gemcitabine effectiveness have been studied in cancers, but less so in hepatocellular carcinoma (HCC), which is identified as the fifth most common cancer worldwide. Investigation of human equilibrative nucleoside transporter‐1 (HENT‐1) and deoxycytidine kinase (DCK), genes involved in gemcitabine uptake and metabolism, can be beneficial in the selection of potential cancer patients who could be responding to the treatment.

To study HENT‐1 and DCK gene expression in HCC patients with different protocols of treatment.

Using real‐time PCR, we analyzed expression levels of HENT‐1 and DCK genes from peripheral blood samples of 109 patients (20 controls & 89 HCC patients) between March 2015 and March 2017. All the 89 HCC patients received the antioxidants selenium (Se) and vitamin E (Vit.E) either alone (45 patients) or in combination with gemcitabine (24 patients) or radiofrequency ablation (RFA) (20 patients).

There was a significant increase in HENT‐1 expression levels in HCC patients treated with Se and Vit.E alone as compared to controls (P ˂ .0001), while there was no significant difference between HCC patients treated with gemcitabine or RFA as compared to controls. In contrast, expression of DCK was significantly increased in all groups of HCC patients as compared to controls (P ˂ .0001).

HENT‐1 and DCK mRNA expressions are important markers of HCC and for GEM effect and GEM sensitivity in patients with HCC. This could be beneficial in the selection of HCC patients sensitive to gemcitabine to avoid subjecting resistant patients to unnecessary chemotherapy.

• deoxycytidine kinase
• gemcitabine
• hepatocellular carcinoma
• human equilibrative nucleoside transporter-1

• Carcinoma, hepatocellular
• Diagnosis
• Guidelines
• Management

• Aged
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Female
• Hepatitis B, Chronic/epidemiology
• Humans
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Prevalence
• Republic of Korea/epidemiology

• National Cancer Center

• Carcinoma
• Diagnosis
• Guidelines
• Management
• hepatocellular

• Carcinoma, Hepatocellular/virology
• Disease Management
• Gastroenterology/standards
• Hepacivirus
• Hepatitis B virus
• Hepatitis B, Chronic/complications
• Hepatitis C, Chronic/complications
• Humans
• Liver Neoplasms/virology
• Republic of Korea

• Cytotoxic chemotherapy
• Hepatocellular carcinoma
• Sorafenib
• Survival rate

Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial.

This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m²/day) for 20 days by intravenous infusion in 1 month as one cycle.

Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m²/day, and 350 mg/m²/day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%.

Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC.

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it’s still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

• Hepatocellular carcinoma
• Systemic therapy
• Chemotherapy
• Molecular targeted therapy
• Cytotoxic therapy
• Immunotherapy
• Perspectives

• Alphafetoprotein
• Hepatocellular carcinoma
• MEK
• Nivolumab
• Sorafenib

• Chemotherapy
• Hepatocellular carcinoma
• Molecular targeted therapy
• Progress
• Systemic therapy

• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Carcinoma, Hepatocellular/drug therapy
• Deoxycytidine/administration & dosage
• Deoxycytidine/analogs & derivatives
• Fluorouracil/administration & dosage
• Humans
• Immunotherapy
• Leucovorin/administration & dosage
• Liver Neoplasms/drug therapy
• Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
• Molecular Targeted Therapy
• Organoplatinum Compounds/administration & dosage
• Transforming Growth Factor beta/antagonists & inhibitors

• AJCC staging
• SEER
• chemoembolization
• drug-eluting-bead transarterial chemoembolization
• hepatocellular carcinoma
• locoregional therapy

Hepatocellular carcinoma (HCC) is the most common liver-derived malignancy with a high fatality rate. Risk factors for the development of HCC have been identified and are clearly described. However, due to the lack of tumor-specific symptoms, HCC are diagnosed at progressed tumor stages in most patients, and thus curative therapeutic options are limited. The focus of this review is on surgical therapeutic options which can be offered to patients with HCC with special regard to recent findings, not exclusively focused on surgical therapy, but also to other treatment modalities. Further, potential promising future perspectives for the treatment of HCC are discussed.

• Hepatocellular carcinoma
• Surgical therapy
• Interventional therapy
• Multimodal treatment
• Extended indications

• Drug development
• Hepatocellular carcinoma
• Molecular biomarkers
• Molecular targeted agents
• Signalling pathway
• Sorafenib
• Systemic treatment