Validation of the six-and-twelve criteria among patients with hepatocellular carcinoma and performance score 1 receiving transarterial chemoembolization.

BACKGROUND: Transarterial chemoembolization (TACE) is recommended for patients with intermediate hepatocellular carcinoma (HCC) according to treatment guidelines. However, a large number of patients with advanced HCC also receive TACE in clinical practice, especially for those with liver-confined HCC and Eastern Cooperative Oncology Group score (ECOG) 1. In view of previous studies, such patients have different prognoses from advanced HCC patients with macrovascular invasion or extrahepatic spread; therefore, patients with ECOG 1 alone might be classified into the intermediate stage and benefit from TACE treatment, but a study particularly focusing on such patients and exploring the effectiveness of TACE therapy is lacking. AIM: To investigate treatment outcomes of TACE in HCC patients with ECOG 1 alone and propose a specific prognostic model. METHODS: Patients from 24 Chinese tertiary hospitals were selected in this nationwide multicenter observational study from January 2010 to May 2016. Overall survival (OS) was estimated using Kaplan-Meier curves and compared by the log-rank test. Multivariate Cox regression was used to develop the potential prognostic models. The discriminatory ability of the models was compared and validated in various patient subgroups. The individual survival prediction for six-and-twelve (6&12) criteria, defined as the algebraic sum of tumor size (cm) and tumor number, was illustrated by contour plot of 3-year survival probability and nomogram. RESULTS: A total of 792 eligible patients were included. During follow-up, median OS reached 18.9 mo [95% confidence interval (CI): 16.9-21.0]. Three independent multivariate analyses demonstrated that tumor size, tumor number, α-fetoprotein level, albumin-bilirubin grade and total bilirubin were prognostic factors of OS (P < 0.05). The previously proposed 6&12 criteria was comparable or even better than currently proposed with the highest predictive ability. In addition, the 6&12 criteria was correlated with OS in various subgroups of patients. The patients were stratified into three strata with score ≤ 6, > 6 but ≤ 12, and > 12 with different median OS of 39.8 mo (95%CI: 23.9-55.7), 21.1 mo (95%CI: 18.4-23.8) and 9.8 mo (95%CI: 8.3-11.3), respectively (P < 0.001). CONCLUSION: TACE is effective for advanced HCC patients with ECOG 1 alone, and the 6&12 criteria may help with clinical decision-making.

Validation and evaluation of clinical prediction systems for first and repeated transarterial chemoembolization in unresectable hepatocellular carcinoma: A Chinese multicenter retrospective study.

BACKGROUND: The treatment outcome of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) varies greatly due to the clinical heterogeneity of the patients. Therefore, several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE (re-TACE). AIM: To investigate the correlations between prognostic systems and radiological response, compare the predictive abilities, and integrate them in sequence for outcome prediction. METHODS: This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016. The Hepatoma Arterial-embolization Prognostic (HAP) score system and its modified versions (mHAP, mHAP2 and mHAP3), as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival (OS) prediction for first TACE. The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART (assessment for re-treatment with TACE) and ABCR (alpha-fetoprotein, Barcelona Clinic Liver Cancer, Child-Pugh and Response) systems for post re-TACE survival (PRTS). RESULTS: All the prognostic systems were correlated with radiological response achieved by first TACE, and the six-and-twelve criteria exhibited the highest correlation (Spearman R = 0.39, P = 0.026) and consistency (Kappa = 0.14, P = 0.019), with optimal performance by area under the receiver operating characteristic curve of 0.71 [95% confidence interval (CI): 0.68-0.74]. With regard to the prediction of OS, the mHAP3 system identified patients with a favorable outcome with the highest concordance (C)-index of 0.60 (95%CI: 0.57-0.62) and the best area under the receiver operating characteristic curve at any time point during follow-up; whereas, PRTS was well-predicted by the ABCR system with a C-index of 0.61 (95%CI: 0.59-0.63), rather than ART. Finally, combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo, compared with non-candidates with a median PRTS of 20.0 mo (log-rank test P < 0.001). CONCLUSION: Radiological response to TACE is closely associated with tumor burden, but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.

Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition).

BACKGROUND: Hepatocellular carcinoma (HCC) (about 85-90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people. SUMMARY: This guideline presents official recommendations of the National Health and Family Planning Commission of the People's Republic of China on the surveillance, diagnosis, staging, and treatment of HCC occurring in China. The guideline was written by more than 50 experts in the field of HCC in China (including liver surgeons, medical oncologists, hepatologists, interventional radiologists, and diagnostic radiologists) on the basis of recent evidence and expert opinions, balance of benefits and harms, cost-benefit strategies, and other clinical considerations. KEY MESSAGES: The guideline presents the Chinese staging system, and recommendations regarding patients with HCC in China to ensure optimum patient outcomes.

Irradiation stents vs. conventional metal stents for unresectable malignant biliary obstruction: A multicenter trial.

BACKGROUND & AIMS: Placement of an irradiation stent has been demonstrated to offer longer patency and survival than an uncovered self-expandable metallic stent (SEMS) in patients with unresectable malignant biliary obstruction (MBO). We aim to further assess the efficacy of an irradiation stent compared to an uncovered SEMS in those patients. METHODS: We performed a randomized, open-label trial of participants with unresectable MBO at 20 centers in China. A total of 328 participants were allocated in parallel to the irradiation stent group (ISG) or the uncovered SEMS group (USG). Endpoints included stent patency (primary), technical success, relief of jaundice, overall survival, and complications. RESULTS: The first quartile stent patency time (when 25% of the patients experienced stent restenosis) was 212 days for the ISG and 104 days for the USG. Irradiation stents were significantly associated with a decrease in the rate of stent restenosis (9% vs. 15% at 90 days; 16% vs. 27% at 180 days; 21% vs. 33% at 360 days; p = 0.010). Patients in the ISG obtained longer survival time (median 202 days vs. 140 days; p = 0.020). No significant results were observed in technical success rate (93% vs. 95%; p = 0.499), relief of jaundice (85% vs. 80%; p = 0.308), and the incidence of grade 3 and 4 complications (8.5% vs. 7.9%; p = 0.841). CONCLUSIONS: Insertion of irradiation stents instead of uncovered SEMS could improve patency and overall survival in patients with unresectable MBO. LAY SUMMARY: For patients with unresectable malignant biliary obstruction (MBO), placement of a self-expandable metallic stent (SEMS) is a recommended palliative modality to relieve pruritus, cholangitis, pain, and jaundice. However, restenosis is a main pitfall after stent placement. Data from this first multicenter randomized controlled trial showed that insertion of an irradiation stent provided longer patency and better survival than a conventional metal stent. ClinicalTrials.gov ID: NCT02001779.

MET inhibitors for treatment of advanced hepatocellular carcinoma: A review.

The current standard treatment option for advanced hepatocellular carcinoma (HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first- or second-line therapy of choice in phase III randomized controlled trials. Recently, the subgroup analysis of a phase II randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients with MET-positive advanced HCC after the failure or intolerance of a prior systemic therapy. These findings enlighten the role of MET inhibitors in the treatment of advanced HCC. In this paper, we review all ongoing and completed clinical trials regarding this topic. As for the first-line therapy of advanced HCC, INC280 and foretinib are being evaluated in 2 phase II single-arm trials; and MSC2156119J and golvatinib plus sorafenib are being compared with sorafenib alone in 2 phase II randomized controlled trials. As for the second-line therapy of advanced HCC, tivantinib and cabozantinib are being compared with placebo in 2 phase III randomized controlled trials.

Transarterial chemoembolization combined with sorafenib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

Sorafenib in combination with Transarterial chemoembolization (TACE) is increasingly used in patients with unresectable hepatocellular carcinoma (HCC), but the current evidence is still controversial. The aim of this systematic review was to evaluate the effectiveness and safety of TACE plus sorafenib versus TACE alone for unresectable HCC. We searched PubMed, EMBASE and the Cochrane Library for clinical trials comparing TACE plus sorafenib with TACE alone for unresectable HCC. The study outcomes included overall survival (OS), time to progression (TTP), objective response and adverse events (AEs). Six studies including 1,181 patients were included. Meta-analysis of all studies suggested that the combination therapy group had significant longer OS than TACE group [hazard ratio (HR) = 0.64, 95 % confidence interval (CI) = 0.43-0.97], but the pooled HR of randomized controlled trials (RCTs) failed to achieve statistical significance. For TTP, meta-analysis in both RCTs subgroup and retrospective studies subgroup suggested that combination therapy was superior to TACE group. The combination therapy was also associated with better response to treatment (risk ratio = 1.45, 95 % CI = 1.04-2.02) when both RCTs and retrospective studies were pooled. However, the sorafenib associated AEs were more frequent in the combination therapy group. In conclusion, the combination of TACE and sorafenib is likely to improve OS, TTP and response to treatment when compared with TACE monotherapy. The combination group is also associated with more sorafenib-related AEs.

Selection of treatment modalities for Budd-Chiari Syndrome in China: a preliminary survey of published literature.

AIM: To evaluate the frequency of use of various treatment modalities for Budd-Chiari syndrome (BCS) in China by conducting a preliminary survey of relevant literature. METHODS: All papers regarding the treatment of BCS in Chinese patients were identified by searching PubMed, Chinese Scientific and Technological Journal, and China National Knowledge Infrastructure databases. Data regarding the number of BCS patients treated with different treatment modalities over time were collected. The proportions of BCS patients undergoing various treatment modalities were calculated. RESULTS: Overall, 300 of 3005 papers initially retrieved were included. These papers included 23352 BCS patients treated with different treatment modalities. The treatment modalities include surgery (n = 8625), interventional treatment (n = 13940), surgery combined with interventional treatment (n = 363), medical therapy (n = 277), other treatments (n = 91), and no treatment (n = 56). After 2005, the number of BCS patients treated with surgery was drastically decreased, but the number of BCS patients who underwent interventional treatment was almost maintained. Shunt surgery was the most common type of surgery (n = 3610). Liver transplantation was rarely employed (n = 2). Balloon angioplasty with or without stenting was the most common type of interventional treatment (n = 13747). Transjugular intrahepatic portosystemic shunt was rarely employed (n = 81). CONCLUSION: Selection of treatment modalities for BCS might be different between China and Western countries. Further work should be necessary to establish a unanimous therapeutic strategy for BCS in China.

TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis.

AIM: To compare the liver transplantation-free (LTF) survival rates between patients who underwent transjugular intrahepatic portosystemic shunts (TIPS) and those who underwent paracentesis by an updated meta-analysis that pools the effects of both number of deaths and time to death. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from the inception to October 2012. LTF survival, liver transplantation, liver disease-related death, non-liver disease-related death, recurrent ascites, hepatic encephalopathy (HE) and severe HE, and hepatorenal syndrome were assessed as outcomes. LTF survival was estimated using a HR with a 95%CI. Other outcomes were estimated using OR with 95%CIs. Sensitivity analyses were performed to assess the effects of potential outliers in the studies according to the risk of bias and the study characteristics. RESULTS: Six randomized controlled trials with 390 patients were included. In comparison to paracentesis, TIPS significantly improved LTF survival (HR = 0.61, 95%CI: 0.46-0.82, P < 0.001). TIPS also significantly decreased liver disease-related death (OR = 0.62, 95%CI: 0.39-0.98, P = 0.04), recurrent ascites (OR = 0.15, 95%CI: 0.09-0.24, P < 0.001) and hepatorenal syndrome (OR = 0.32, 95%CI: 0.12-0.86, P = 0.02). However, TIPS increased the risk of HE (OR = 2.95, 95%CI: 1.87-4.66, P = 0.02) and severe HE (OR = 2.18, 95%CI: 1.27-3.76, P = 0.005). CONCLUSION: TIPS significantly improved the LTF survival of cirrhotic patients with refractory ascites and decreased the risk of recurrent ascites and hepatorenal syndrome with the cost of increased risk of HE compared with paracentesis. Further studies are warranted to validate the survival benefit of TIPS in clinical practice settings.

Prognostic factors in non-malignant and non-cirrhotic patients with portal cavernoma: an 8-year retrospective single-center study.

AIM: To evaluate the outcome of non-malignant and non-cirrhotic patients with portal cavernoma and to determine the predictors for survival. METHODS: Between July 2002 and June 2010, we retrospectively enrolled all consecutive patients admitted to our department with a diagnosis of portal cavernoma without abdominal malignancy or liver cirrhosis. The primary endpoint of this observational study was death and cause of death. Independent predictors of survival were identified using the Cox regression model. RESULTS: A total of 64 patients were enrolled in the study. During a mean follow-up period of 18 ± 2.41 mo, 7 patients died. Causes of death were pulmonary embolism (n = 1), acute leukemia (n = 1), massive esophageal variceal hemorrhage (n = 1), progressive liver failure (n = 2), severe systemic infection secondary to multiple liver abscesses (n = 1) and accident (n = 1). The cumulative 6-, 12- and 36-mo survival rates were 94.9%, 86% and 86%, respectively. Multivariate Cox regression analysis demonstrated that the presence of ascites (HR = 10.729, 95%CI: 1.209-95.183, P = 0.033) and elevated white blood cell count (HR = 1.072, 95%CI: 1.014-1.133, P = 0.015) were independent prognostic factors of non-malignant and non-cirrhotic patients with portal cavernoma. The cumulative 6-, 12- and 36-mo survival rates were significantly different between patients with and without ascites (90%, 61.5% and 61.5% vs 97.3%, 97.3% and 97.3%, respectively, P = 0.0008). CONCLUSION: The presence of ascites and elevated white blood cell count were significantly associated with poor prognosis in non-malignant and non-cirrhotic patients with portal cavernoma.

Sorafenib in combination with transarterial chemoembolization improves the survival of patients with unresectable hepatocellular carcinoma: a propensity score matching study.

OBJECTIVE: This prospective non-randomized controlled trial aimed to compare the efficacy of sorafenib in combination with transarterial chemoembolization (TACE) vs TACE alone for the treatment of patients with unresectable intermediate or advanced hepatocellular carcinoma. METHODS: A total of 304 patients were enrolled, in which 82 received concurrent sorafenib (400 mg orally twice daily, initiated within 14 days after TACE), and these patients were matched with 164 patients who received TACE alone at a 1:2 ratio using propensity score matching to minimize selection bias. The response to treatment, time-to-progression (TTP), overall survival (OS) as well as adverse events were compared between the two groups. RESULTS: During a median follow-up period of 21.4 weeks (range 0.5-103 weeks), the addition of sorafenib prolonged TTP (6.3 vs 4.3 months; hazard ratio [HR] 0.60, 95% CI 0.422-0.853, P = 0.004) and median survival (7.5 vs 5.1 months; HR 0.61, 95% CI 0.423-0.884, P = 0.009) compared with TACE alone. Significant prognostic factors for OS by multivariate analysis included the use of sorafenib, Barcelona Clinic Liver Cancer stage, metastasis/vascular invasion and Child-Pugh score. CONCLUSIONS: The combined use of sorafenib and TACE was generally well tolerated and significantly improved OS and TTP compared with TACE alone in patients with intermediate or advanced HCC. Further studies are warranted to confirm the safety and efficacy of this combination therapy.

Prospective randomized clinical trial of two drug delivery pathway in the treatment of inoperable advanced pancreatic carcinoma.

OBJECTIVES: Evaluate the effect of an implanted percutaneous left subclavian artery port-catheter drug delivery system for regional chemotherapy of inoperable pancreatic carcinoma. METHODS: One hundred and forty patients with inoperable pancreatic carcinoma were enrolled and randomized into two groups to receive the FAM regimen on a 6-day cycle at 1-month intervals: 70 patients in the regional interventional chemotherapy group in which treatment was infused directly into the common hepatic artery, and 70 patients who received the same chemotherapy regimen via the peripheral vein. RESULT: In the interventional chemotherapy group, there were 5 cases of complete remission (CR) and 49 cases of partial remission (PR), giving a response rate (CR+PR) of 77.1%; pain control was effective in 95.7% cases; survival time was 3-34 months (median 13.5). There was no case of CR in the systemic chemotherapy group, and 25 cases of PR, giving a response rate of 35.7%; pain control was effective in 35.7%, and survival time was 1-13 months (median 6.2). The differences between the two groups in response rate and survival were statistically significant (P < 0.005). Nausea and vomiting occurred in 48.6% of the interventional chemotherapy group and 41.3% of the systemic chemotherapy group (NS). There were three cases of serious myelosuppression in the systemic chemotherapy group and one case died. There was a significant difference between the two groups in white blood cell count after the chemotherapy, indicating that the myelosuppressive effect was serious in the systemic chemotherapy group. CONCLUSION: Interventional arterial infusion chemotherapy could significantly improve quality of life and prolong the survival of patients with inoperable pancreatic carcinoma.