• Hepatocellular carcinoma
• Meta-analysis
• Overall survival
• Progression-free survival
• Sorafenib
• Transarterial chemoembolization

• hepatocellular carcinoma
• molecular targeted agents
• network meta-analysis
• systematic review
• transarterial chemoembolization

Liver cancer is the second most common cause of cancer-related death, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Transarterial chemoembolization (TACE) in combination with different tyrosine kinase inhibitors (TKIs) has recently been widely used for unresectable HCC (uHCC). However, studies investigating different combinations of agents have shown inconsistent results. Thus, we conducted a network meta-analysis to assess and compare the response of different agents in an uHCC setting. According to our results, TACE plus lenvatinib provides optimal treatment for uHCC, with the highest ranking based on OS, PFS, and DCR rates and the second-best ranking based on ORR rates.

Transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) is the mainstay treatment for unresectable hepatocellular carcinoma (uHCC). However, studies investigating different combinations of agents have shown inconsistent results. Here, we used network meta-analysis (NMA) to compare different agents across 41 studies (36 cohort studies and five RCTs) in 11,540 patients. Multiple RCTs and cohort studies were searched to evaluate TACE combined with different TKIs. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and tumor response. NMA used a random-effects consistency model to pool evidence from direct and indirect comparisons. Hazard ratio (HR) and relative risks (RR) with 95% confidence intervals (CI) were analyzed. Further, heterogeneity and publication bias analyses were performed and agents were ranked. TACE plus lenvatinib provided the maximal OS (Rank probability: 0.7559), PFS (Rank probability: 0.8595), CR (Rank probability: 0.4179), and DCR (Rank probability: 0.3857). TACE plus anlotinib demonstrated the highest PR (p = 0.62649) and ORR (p = 0.51158). SD was more often associated with TACE plus sorafenib (Rank probability: 0.601685). TACE plus lenvatinib provides optimal treatment for uHCC based on the highest ranking of OS, PFS, and DCR rates. However, given the lack of statistically significant OS benefit, shared decision making should include other TKIs as acceptable alternatives.

• Angiogenesis
• Barcelona clinic liver cancer stage
• Biomarker
• Complete response
• Liver cancer
• Overall survival
• Polypeptide N-acetylgalactosaminyltransferase 14
• Progression-free survival
• Single-nucleotide polymorphism
• Targeted drug

• hepatocellular carcinoma
• overall survival
• progression-free survival
• surrogate endpoints
• time to progression
• transarterial chemoembolization

• Natural killer cells
• combination therapies
• hepatocellular carcinoma
• sorafenib

• R01 CA209886 NCI NIH HHS
• R01 CA241532 NCI NIH HHS
• U38 PR000012 OCPHP CDC HHS

To compare the efficacy of three types of palliative therapy for advanced hepatocellular carcinoma (HCC), including transarterial chemoembolisation (TACE) monotherapy, sorafenib alone and their combination.

The databases of PubMed, Embase and Cochrane Library were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) was used to investigate the binary variables, and the standardised mean difference (SMD) with its 95% CI was employed to evaluate the continuous variables. All statistical tests were performed by using Stata/SE, version 12.0.

Thirty-one clinical studies, containing 5125 unique cases of patients with advanced HCC, were included. There were significant improvements in overall survival (OS) (pooled SMD = 2.54; 95% CI 1.74–3.34) and time to progression (TTP) (pooled SMD = 2.49; 95% CI 0.87–4.12) of the patients after receiving the combination therapy of TACE and sorafenib, compared to TACE monotherapy, and the OS in the combined treatment cohort was also longer than that in the sorafenib-alone cohort (pooled SMD = 2.92; 95% CI 1.72–4.13). The combination therapy group in comparison to the TACE group benefited a significantly increased overall response rate (ORR) (pooled OR = 2.61; 95% CI 1.43–4.77), 1-year (pooled OR = 2.96; 95% CI 1.71–5.14) and 2-year (pooled OR = 1.64; 95% CI 1.18–2.28) survival rates and reduced disease progression rate (DPR) (pooled OR = 0.47; 95% CI 0.33–0.68); in parallel, the ORR in the group was also significantly higher than that in the sorafenib-alone group (pooled OR = 3.62; 95% CI 1.28–10.22), although without a difference in the DPR (pooled OR = 0.28; 95% CI 0.05–1.48). In addition, we discovered that the 1-year (pooled OR = 1.39; 95% CI 0.84–2.29) and 2-year (pooled OR = 1.70; 95% CI 0.69–4.18) survival rates in the TACE monotherapy cohort were not significantly different to those in the sorafenib-alone cohort.

The combination therapy is more effective than monotherapy in improving the prognostic outcomes of patients with advanced HCC. Therefore, we recommend it as the preferred treatment intervention for those patients.

• Hepatocellular carcinoma
• Meta-analysis
• Sorafenib
• TACE

• Sorafenib
• hepatocellular carcinoma (HCC)
• meta-analysis
• transarterial chemoembolization (TACE)

To present the early results of pirarubicin-eluting microsphere transarterial chemoembolization (PE-TACE) for patients with unresectable hepatocellular carcinoma (HCC).

We retrospectively analyzed 55 consecutive patients with HCC who received PE-TACE between April 1, 2015 and August 30, 2016. The complication rate, tumor response rate, progression-free survival (PFS), and overall survival (OS) were analyzed.

Adverse events were generally mild and included abdominal pain and fever, although a major complication was reported in 1 patient (1.8%). During a median follow-up of 10.0 months (range, 3.0–24.0 months), 14 patients (25.5%) achieved a complete tumor response, 25 (45.5%) had a partial response, 9 (16.4%) showed stable disease, and 7 (12.7%) had disease progression. The 1-month overall response rate was 70.9%, and the local tumor response rate was 89.0%. The 1-month tumor response rate was 100% for Barcelona Clinic Liver Cancer (BCLC) stage A or B disease and 62.8% for BCLC stage C disease. The median PFS was 6.1 months (95% confidence interval [95%CI], 3.4–8.8 months; range, 1.0–24.0 months). The median OS was 11.0 months (95%CI, 7.1–14.9 months; range, 2.0–24.0 months). Kaplan-Meier analysis (log-rank test) found significant differences in OS between patients grouped by tumor number (P = 0.006), tumor size (P = 0.035), and Eastern Cooperative Oncology Group (ECOG) score (P = 0.005). The tumor number (1 vs. ≥2) was the only factor independently associated with OS (hazard ratio [HR], 2.867; 95%CI, 1.330–6.181; P = 0.007).

PE-TACE for unresectable HCC may be safe, with favorable tumor response rates and survival time, especially in patients with a single large tumor. Longer follow-up using a larger series is necessary to confirm these preliminary results.

Psychological intervention has been proved a complementary approach to drug analgesia. Another study suggested that health knowledge is associated with psychological symptoms in patients with liver cancer. This study is conducted to assess whether improving the health education (HE) alleviates the postembolization pain during transarterial chemoembolization (TACE).

One hundred and fifteen patients, who required TACE for hepatocellular carcinoma (HCC) and suffered postembolization pain, were randomized into control group (n=63) and HE group (n=52). The health knowledge was scaled with the health knowledge questionnaire (HKQ). The postembolization pain was scored using a 0–10 numeric rating scale (NRS-10) after arterial embolization in both groups.

There were no statistical differences between male and female in all HKQ scores (P>0.05). The HKQ scores of young people (≤45 years old) were significantly higher than those of elders (>45 years old; P<0.05). After teaching HE, the HKQ scores were significantly increased in patients of the HE group (P<0.01). The postembolization pain score in the HE group was significantly lower than that in the control group (P<0.05). The HKQ scores of question 1, 3, and total were negatively correlated with the pain score in this sample (P<0.05).

Improving the HE among HCC patients before TACE is beneficial for the pain relief during interventional procedure.

• health education
• liver neoplasms
• non-pharmacological
• pain
• radiology

Transarterial chemoembolization (TACE) is the recommended treatment for hepatocellular carcinoma (HCC) patients at Barcelona Clinic Liver Cancer (BCLC) B-stage, whereas sorafenib is an orally administered small molecule target drug for BCLC C-stage. This updated systemic review and meta-analysis focuses on identifying the efficacy of the combination of TACE with sorafenib, which remains controversial despite years of exploration.

PubMed, EMBASE, Scopus and the Cochrane Library were systematically reviewed to search for studies published from January 1990 to May 2017. Studies focusing on the efficacy of combination therapy for unresectable HCC were eligible. The hazard ratio (HR) with 95% confidence intervals (95% CIs) for time to progression (TTP), overall survival (OS), disease control rate (DCR) and aetiology were collected. The data were then analysed through fixed/random effects meta-analysis models with STATA 13.0. The incidence and severity of treatment-related adverse events (AEs) were also evaluated.

Twenty-seven studies were included. Thirteen non-comparative studies reported median OS (ranging from 18.5 to 20.4 months), median TTP (ranging from 7 to 13.9 months) and DCR (ranging from 18.4 to 95%). Fourteen comparative studies provided median OS (ranging from 7.0 to 29.7 months) and median TTP (ranging from 2.6 to 10.2 months). Five comparative studies provided DCR (ranging from 32 to 97.2%). Forest plots showed that combination therapy significantly improved TTP (HR = 0.66, 95% CI 0.50–0.81, P = 0.002) rather than OS (HR = 0.63, 95% CI 0.55–0.71, P = 0.058), compared to TACE alone. DCR increased significantly in the combination therapy group (OR = 2.93, 95% CI 1.59–5.41, P = 0.005). Additional forest plots were drawn and no significant differences were observed with regard to survival outcome among various aetiologies. Forest plots for separate analysis of regions showed the HR for TTP was 0.62 (95% CI 0.45–0.79, P = 0.002) in the Asian countries group, and 0.82 (95% CI 0.59–1.05, P = 0.504)) in western countries. The HR for OS was 0.61 (95% CI 0.48–0.75, P = 0.050) in the Asian countries group and was 0.88 (95% CI 0.56–1.20, P = 0.845) in western countries. These data may indicate positive TTP outcome in Asian patients but not in European patients while no positive findings regarding OS were observed in either region. The most common AEs included fatigue, hand-foot skin reaction, diarrhoea and hypertension.

Combination therapy may benefit unresectable HCC patients in terms of prolonged TTP and DCR. More well-designed studies are needed to investigate its superiority for OS.

The online version of this article (10.1186/s12876-018-0849-0) contains supplementary material, which is available to authorized users.

• Hepatocellular carcinoma
• Meta-analysis
• Sorafenib
• Systemic review
• Transarterial chemoembolization

To compare the efficacy and safety profiles of sorafenib and apatinib in patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC).

This was a single-center, retrospective study where we collected the clinical data of 72 patients, diagnosed with intermediate or advanced HCC from January 2014 to December 2016. Depending on the treatment received, 38 patients were categorized into group S (sorafenib group) and 34 into group A (apatinib group). The patients in group A received the initial recommended dose of 750 mg once daily (QD), which was reduced to 250 mg QD in the case of any class 3 or 4 adverse event (AE). Sorafenib was administered orally 400 mg twice daily (BID), and dose was modified to 400 mg or 200 mg QD in the case of grade 3 or 4 AEs. The median overall survival (OS), progression-free survival (PFS), and AEs reported in the two groups were analyzed and compared.

Among the 38 patients treated with sorafenib, one patient had complete response (CR), 5 patients had partial response (PR), and 10 patients had stable disease (SD), and among the 34 patients treated with apatinib, 6 patients had PR and 7 patients had SD with no cases of CR. PFS in group S was significantly longer compared with that in group A (7.39 vs 4.79 months, respectively, P=0.031). Similar observations were made for median OS (10.4 months in group S vs 7.18 months in group A, P=0.011). However, there was no significant difference in the objective response rates (ORRs) among the study population (15.7 vs 17.6%, P=0.829). Common AEs in group S included hand and foot syndrome (HFS) and diarrhea, whereas common AEs in group A included hypertension, proteinuria, and increased transaminase.

Our study showed promising clinical outcome with apatinib, but the sorafenib group exhibited better clinical efficacy with no significant difference in safety profile.

• HCC
• apatinib
• observational
• overall survival
• progression-free survival
• sorafenib

• hepatocellular carcinoma
• overall survival
• portal vein invasion
• sorafenib
• transarterial chemoembolization

• TACE in combination with sorafenib
• cost-effectiveness
• hepatocellular carcinoma
• transcatheter arterial chemoembolization

A small proportion of hepatocellular carcinoma (HCC) patients are suitable for surgical resections and various minimally invasive procedures have been introduced as alternatives to surgical resections. However, the relative efficacy of minimally invasive procedures remains to be studied in the current literature. Several popular minimally invasive procedures (monotherapy or combined therapies) were selected for comparison and their relative long-term efficacy were determined by using the statistics of hazard ratio (HR) which evaluates the survival status of HCC patients in one, two, three and four years, respectively. Evidence were obtained from the current literature and synthesized by using the approach of conventional pairwise meta-analysis and network meta-analysis (NMA). Moreover, selected minimally invasive procedures were ranked according to their surface under the cumulative ranking curve (SUCRA) which was produced by NMA in conjunction with the Markov Chain Monte Carlo (MCMC) sampling method. HCC patients treated by combined minimally invasive procedures, particularly transcatheter arterial chemoembolization (TACE) + high intensity focused ultrasound (HIFU), TACE + radiofrequency ablation (RFA), TACE + radiotherapy (RT) and TACE + Sorafenib (SOR) exhibited a significant decrease in the HR compared to those with standard TACE (HR < 1). The combined minimally invasive procedure of TACE + HIFU appears to be the most preferable therapy. PEI seems to be less favorable than other minimally invasive procedures. Combined minimally invasive procedures may be more preferable than standard minimally invasive procedures. Percutaneous ethanol injection (PEI) may not provide adequate efficacy compared to other minimally invasive procedures for unresectable HCC patients.

• long-term efficacy
• network meta-analysis
• transarterial chemoembolization
• unresectable hepatocellular carcinoma

• Adverse events
• Hepatocellular carcinoma
• Portal vein tumor thrombus
• Sorafenib
• Transarterial chemoembolization

We performed a meta-analysis of transcatheter hepatic arterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC), which included 4 double-blind, randomized controlled trials (RCTs) that investigated the effects of TACE combined with sorafenib (experimental groups) on time to disease progression (TTP), overall survival (OS), and various sorafenib-related adverse events, compared to those in the placebo (control) groups. A total of 877 HCC cases from 14 countries, including China and the USA, were included in our meta-analysis. The TTP increased significantly in the experimental groups (hazard ration [HR]: 0.82; 95% CI: 0.69–0.97; p = 0.02), but OS did not improve significantly (HR: 0.97; 95% CI: 0.72–1.29; p = 0.82), compared with the control groups. The risks of hand and foot skin reactions (HFSR), rash, fatigue, and diarrhea were significantly greater in the experimental groups (p < 0.05 for all), compared to those in the control groups, whereas the risk of nausea was statistically similar (p > 0.05). Among these, the risk of HFSR was highest (risk ratio [RR]: 5.93; 95% CI: 2.00–17.53; p = 0.001), and a subgroup analysis of studies that lacked significant heterogeneity in the HFSR data showed a higher risk of HFSR (RR: 10.96; 95% CI: 5.54–21.69; p < 0.05). In conclusion, although TACE plus sorafenib increases TTP, it does not improve OS. Therefore, the risk of the adverse events of TACE plus sorafenib should be considered as a potential therapeutic limitation.

• disease progression
• hepatocellular carcinoma
• overall survival
• randomized controlled trial
• transcatheter hepatic arterial chemoembolization

• combination treatment
• hepatocellular carcinoma
• molecular targeted agents
• targeted therapy

• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Chemoradiotherapy/methods
• Combined Modality Therapy/methods
• Combined Modality Therapy/trends
• Humans
• Immunotherapy/methods
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Molecular Targeted Therapy/methods
• Molecular Targeted Therapy/trends
• Neoplasm Staging
• Signal Transduction/drug effects

• Combined modality therapy
• Liver neoplasms
• Meta-analysis
• Sorafenib
• Systematic review
• Therapeutic chemoembolization

• complete response
• hepatocellular carcinoma
• radiofrequency ablation
• sorafenib
• transarterial chemoembolization

• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Catheter Ablation
• Chemoembolization, Therapeutic
• Combined Modality Therapy
• Disease Progression
• Disease-Free Survival
• Female
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Niacinamide/adverse effects
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Phenylurea Compounds/adverse effects
• Phenylurea Compounds/therapeutic use
• Quality of Life
• Retrospective Studies
• Sorafenib
• Treatment Outcome

Intermediate stage, or stage B according to Barcelona Clinic Liver Cancer classification, of hepatocellular carcinoma (HCC) comprises a heterogeneous population with different tumor burden and liver function. This heterogeneity is confirmed by the large variability of treatment choice and disease-relate survival. The aim of this review was to highlight the existing evidences regarding this specific topic. In a multidisciplinary evaluation, patients with large (> 5 cm) solitary HCC should be firstly considered for liver resection (LR). When LR is unfeasible, locoregional treatments are evaluable therapeutic options, being transarterial chemoembolization (TACE), the most used procedure. Percutaneous ablation can be an evaluable treatment for large HCC. However, the efficacy of all ablative procedures decrease as tumor size increases over 3 cm. In clinical practice, a combination treatment strategy [TACE or transarterial radioembolization (TARE)-plus percutaneous ablation] is “a priori” preferred in a relevant percentage of these patients. On the other hands, sorafenib is the treatment of choice in patients who are unsuitable to surgery and/or with a contraindication to locoregional treatments. In multifocal HCC, TACE is the first-line treatment. The role of TARE is still undefined. Surgery may have also a role in the treatment of multifocal HCC in selected cases (patients with up to three nodules, multifocal HCC involving 2-3 adjacent liver segments). In some patients with bilobar disease the combination of LR and ablative treatment may be a valuable option. The choice of the best treatment in the patient with intermediate stage HCC should be “patient-tailored” and made by a multidisciplinary team.

• Hepatocellular carcinoma
• Percutaneous ablation
• Hepatectomy
• Chemoembolization
• Liver transplantation
• Combination therapy

• Advanced hepatocellular carcinoma
• Advanced hepatocellular carcinoma second line therapies
• Barcelona clinic liver cancer
• Diffusion weighted imaging
• Hepatocellular carcinoma follow-up
• Modified Response Evaluation Criteria in Solid Tumors
• Perfusion weighted imaging
• Response Evaluation Criteria in Solid Tumors
• Response evaluation
• Sorafenib

• Hepatocellular carcinoma
• Liver transplantation
• Radiofrequency ablation
• Sorafenib
• Transarterial chemoembolization

• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/radiotherapy
• Carcinoma, Hepatocellular/surgery
• Carcinoma, Hepatocellular/therapy
• Catheter Ablation
• Chemoembolization, Therapeutic
• Combined Modality Therapy
• Humans
• Hyperthermia, Induced
• Liver Cirrhosis/complications
• Liver Neoplasms/complications
• Liver Neoplasms/pathology
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/surgery
• Liver Neoplasms/therapy
• Liver Transplantation
• Microwaves
• Neoplasm Staging
• Prognosis

• HCC
• TACE
• combination therapy
• intermediate stage
• sorafenib

• Aged
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic/adverse effects
• Chemoembolization, Therapeutic/methods
• Combined Modality Therapy
• Diarrhea/etiology
• Female
• Gastrointestinal Hemorrhage/etiology
• Hepatic Encephalopathy/etiology
• Humans
• Hypertension/etiology
• Kaplan-Meier Estimate
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Multivariate Analysis
• Neoplasm Staging
• Niacinamide/adverse effects
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Outcome Assessment, Health Care/statistics & numerical data
• Phenylurea Compounds/adverse effects
• Phenylurea Compounds/therapeutic use
• Propensity Score
• Proportional Hazards Models
• Retrospective Studies
• Skin Diseases/etiology
• Sorafenib

• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/surgery
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Combined Modality Therapy
• Disease Progression
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/surgery
• Liver Neoplasms/therapy
• Niacinamide/adverse effects
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Phenylurea Compounds/adverse effects
• Phenylurea Compounds/therapeutic use
• Sorafenib
• Survival Analysis
• Time Factors

¹²⁵I seeds have good physical and radiobiological characteristics. Interstitial brachytherapy has advantages of minimal invasive, precise stereotactic treatment and high local control rate and plays an important role in the treatment of hepatocellular carcinoma (HCC). Brachytherapy with ¹²⁵I seeds has been used in unresectable HCC, HCC with portal vein tumor thrombus, intrahepatic cholangiocarcinoma, hepatic metastases, and some other tumors, providing encouraging survival rates. Radiation-related complications are rare in highly selected patients. In a word, ¹²⁵I brachytherapy is a safe and effective treatment for newly diagnosed or recurrent unresectable intrahepatic malignancies and can provide better survival rates and decent quality of life.

• ¹²⁵I seeds
• Brachytherapy
• Hepatocellular carcinoma