Guohong Han

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. METHODS In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. FINDINGS Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. INTERPRETATION Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. FUNDING Bayer.

Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with symptomatic portal hypertension in liver cirrhosis

BACKGROUND & AIMS Data on the management of portal vein thrombosis (PVT) in patients with decompensated cirrhosis are extremely limited, particularly in the cases of the transjugular intrahepatic portosystemic shunt (TIPS). We assessed the outcome of TIPS for PVT in patients with cirrhosis and symptomatic portal hypertension and determined the predictors of technical success and survival. METHODS In the retrospective study, 57 consecutive patients receiving TIPS were enrolled between December 2001 and September 2008. All were diagnosed with chronic PVT, and 30 had portal cavernoma. Indications for TIPS were variceal hemorrhage (n = 56) and refractory ascites (n = 1). RESULTS TIPS were successfully placed in 75% of patients (43/57). The independent predictors of technical success included portal cavernoma, and the degree of thrombosis within the main portal vein (MPV), the portal vein branches, and the superior mesenteric vein. Only one patient died of severe procedure-related complication. The cumulative 1-year shunt dysfunction and hepatic encephalopathy rates were 21% and 25%, respectively. The cumulative 1- and 5-year variceal re-bleeding rates differed significantly between the TIPS success and failure groups (10% and 28% versus 43% and 100%, respectively; p = 0.0004), while the cumulative 1- and 5-year survival rates were similar between the two groups (86% and 77% versus 78% and 62%, respectively; p = 0.34). The independent predictor of survival in PVT patients with decompensated cirrhosis was the degree of MPV occlusion (hazard ratio 0.189, 95% CI 0.042-0.848). CONCLUSIONS TIPS should be considered a safe and feasible alternative therapy for chronic PVT in selected patients with decompensated cirrhosis. Both technical success and survival were closely associated with the degree of MPV occlusion.

Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial

BACKGROUND & AIMS Transarterial chemoembolization with doxorubicin-eluting beads (DC Bead®; DEB-TACE) is effective in patients with Barcelona clinic liver cancer stage B hepatocellular carcinoma (HCC). The multikinase inhibitor sorafenib enhances overall survival (OS) and time-to-tumor progression (TTP) in patients with advanced HCC. This exploratory phase II trial tested the efficacy and safety of DEB-TACE plus sorafenib in patients with intermediate stage HCC. METHODS Patients with intermediate stage multinodular HCC without macrovascular invasion (MVI) or extrahepatic spread (EHS) were randomized 1:1 to DEB-TACE (150 mg doxorubicin) plus sorafenib 400 mg twice daily or placebo. The primary endpoint was TTP by blinded central review. Secondary endpoints included time to MVI/EHS, OS, overall response rate (ORR) using modified response evaluation criteria in solid tumors, disease control rate (DCR), time to unTACEable progression (TTUP), and safety. RESULTS Of 307 patients randomized, 154 received sorafenib and 153 received placebo. Median TTP for subjects receiving sorafenib plus DEB-TACE or placebo plus DEB-TACE was similar (169 vs. 166 days, respectively; hazard ratio (HR) 0.797, p=0.072). Median time to MVI/EHS (HR 0.621, p=0.076) and OS (HR 0.898, p=0.29) had not been reached. The ORRs for patients in the sorafenib and placebo groups with post-baseline scans were 55.9% and 41.3%, respectively, and the DCRs were 89.2% and 76.1%, respectively. TTUP was lower with sorafenib than with placebo (HR 1.586; 95% confidence intervals, 1.200-2.096; median 95 vs. 224 days). No unexpected adverse events related to sorafenib were observed. CONCLUSION Sorafenib plus DEB-TACE was technically feasible, but the combination did not improve TTP in a clinically meaningful manner compared with DEB-TACE alone.

The role of hepatic resection in the treatment of hepatocellular cancer

Current guidelines recommend surgical resection as the primary treatment for a single hepatocellular cancer (HCC) with Childs A cirrhosis, normal serum bilirubin, and no clinically significant portal hypertension. We determined how frequently guidelines were followed and whether straying from them impacted survival. BRIDGE is a multiregional cohort study including HCC patients diagnosed between January 1, 2005 and June 30, 2011. A total of 8,656 patients from 20 sites were classified into four groups: (A) 718 ideal resection candidates who were resected; (B) 144 ideal resection candidates who were not resected; (C) 1,624 nonideal resection candidates who were resected; and (D) 6,170 nonideal resection candidates who were not resected. Median follow‐up was 27 months. Log‐rank and Coxs regression analyses were conducted to determine differences between groups and variables associated with survival. Multivariate analysis of all ideal candidates for resection (A+B) revealed a higher risk of mortality with treatments other than resection. For all resected patients (A+C), portal hypertension and bilirubin >1 mg/dL were not associated with mortality. For all patients who were not ideal candidates for resection (C+D), resection was associated with better survival, compared to embolization and “other” treatments, but was inferior to ablation and transplantation. Conclusions: The majority of patients undergoing resection would not be considered ideal candidates based on current guidelines. Not resecting ideal candidates was associated with higher mortality. The study suggests that selection criteria for resection may be modestly expanded without compromising outcomes, and that some nonideal candidates may still potentially benefit from resection over other treatment modalities. (Hepatology 2015;62:440–451

Patency and clinical outcomes of transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stents versus bare stents: A meta-analysis

Background and Aim:  Transjugular intrahepatic portosystemic shunt (TIPS) with polytetrafluoroethylene‐(PTFE)‐covered stent has been increasingly used for patients with complications of portal hypertension. It is still debated whether the new endoprostheses will improve some clinical outcomes (except for shunt patency) compared to the bare stents. The aims of our meta‐analysis were to explore the patency and clinical outcomes of TIPS with PTFE‐covered stent‐grafts versus bare stents.

Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial

Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate‐stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double‐blind, placebo‐controlled, phase III study, 870 patients with TACE‐eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once‐daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow‐up was approximately 16 months. Intention‐to‐treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0‐30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66‐1.23]; log‐rank P = 0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45‐0.90]), TTP (0.61 [0.48‐0.77]), and rate of TACE (0.72 [0.61‐0.86]), but not TTDP (0.94 [0.72‐1.22]) versus placebo. Most frequent grade 3‐4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%). Conclusions: In this study, brivanib as adjuvant therapy to TACE did not improve OS. (Hepatology 2014;60:1697–1707)

Predictors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in cirrhotic patients: A systematic review

Background and Aim:  Hepatic encephalopathy (HE) is a very common complication in patients after transjugular intrahepatic portosystemic shunt (TIPS). The purpose of this study is to determine the most robust predictors of post‐TIPS HE by performing a systematic review of studies that identified the risk factors for patients with post‐TIPS HE.

Percutaneous Recanalization for Budd-Chiari Syndrome: An 11-year Retrospective Study on Patency and Survival in 177 Chinese Patients from a Single Center

PURPOSE To evaluate the long-term outcomes of percutaneous recanalization and determine the predictors of patency and survival in a large case series of Chinese patients with Budd-Chiari syndrome (BCS). MATERIALS AND METHODS This retrospective study was approved by the institutional ethics committee. Informed consent for the procedure was obtained from all patients. Between July 1999 and August 2010, 177 consecutive Chinese patients with primary BCS were treated with percutaneous recanalization and followed up until death or their last clinical evaluation. Recanalization therapeutic strategy and complications were recorded. Cumulative patency and survival rates were assessed with Kaplan-Meier curves. Independent predictors of patency and survival were calculated with the Cox regression model. RESULTS Percutaneous recanalization was technically successful in 168 of the 177 patients (95%). Fifty-one of the 168 patients (30%) were treated with percutaneous transluminal angioplasty (PTA) alone and 117 (70%) were treated with a combination of PTA and stent placement. Procedure-related complications occurred in seven of the 168 patients (4%). The cumulative 1-, 5-, and 10-year primary patency rates were 95%, 77%, and 58%, respectively. Independent predictors of reocclusion included increased white blood cell count and use of PTA alone. The cumulative 1-, 5-, and 10-year secondary patency rates were 97%, 90%, and 86%, respectively. Twenty-two patients died during a median follow-up of 30 months (range, 0.25-137 months). The cumulative 1-, 5-, and 10-year survival rates were 96%, 83%, and 73%, respectively. Independent predictors of survival included variceal bleeding, increased alkaline phosphatase and blood urea nitrogen levels, and reocclusion. CONCLUSION Percutaneous recanalization could achieve excellent long-term patency and survival in most Chinese patients with BCS. PTA combined with stent placement should be recommended to decrease the frequency of reocclusion and its associated mortality.

Sorafenib combined with transarterial chemoembolization for the treatment of advanced hepatocellular carcinoma: a large-scale multicenter study of 222 patients

BACKGROUND Data on the efficacy and safety of sorafenib in combination with transarterial chemoembolization (TACE) in patients with advanced hepatocellular carcinoma (HCC) are lacking. PATIENTS AND METHODS In this multicenter retrospective study, 222 consecutive HCC patients receiving combination therapy were enrolled between June 2008 and July 2011. RESULTS Chronic hepatitis B was the predominant cause of HCC (86%). Eighty percent patients were at Barcelona Clinic Liver Cancer (BCLC) stage C, and 86% patients were in Child-Pugh (CP) A class. The overall median survival was 12 months (95% CI 10.1-13.9). The overall incidence of adverse events (AEs) was 87%. In 177 BCLC-C patients, performance status, the number of HCC nodules, Child-Pugh score and macrovascular invasion were significantly associated with overall survival (OS) and were included in the final risk scores (R), where R = 5 × (vascular invasion: 0 if no, 1 yes) + 6 × (CP: 0 if A, 1 if B) + 7 × (no. of lesions: 0 if 1-2, 1 ≥3) + 8 × ( Eastern Cooperative Oncology Group, ECOG: 0 if 0, 1 ≥1). CONCLUSIONS Sorafenib in combination with TACE should be considered a safe and effective therapy for advanced HCC. Further validation of the new subgroup of BCLC-C stage is warranted in an independent patient cohort.BACKGROUND Data on the efficacy and safety of sorafenib in combination with transarterial chemoembolization (TACE) in patients with advanced hepatocellular carcinoma (HCC) are lacking. PATIENTS AND METHODS In this multicenter retrospective study, 222 consecutive HCC patients receiving combination therapy were enrolled between June 2008 and July 2011. RESULTS Chronic hepatitis B was the predominant cause of HCC (86%). Eighty percent patients were at Barcelona Clinic Liver Cancer (BCLC) stage C, and 86% patients were in Child-Pugh (CP) A class. The overall median survival was 12 months (95% CI 10.1-13.9). The overall incidence of adverse events (AEs) was 87%. In 177 BCLC-C patients, performance status, the number of HCC nodules, Child-Pugh score and macrovascular invasion were significantly associated with overall survival (OS) and were included in the final risk scores (R), where R = 5 × (vascular invasion: 0 if no, 1 yes) + 6 × (CP: 0 if A, 1 if B) + 7 × (no. of lesions: 0 if 1-2, 1 ≥3) + 8 × ( Eastern Cooperative Oncology Group, ECOG: 0 if 0, 1 ≥1). CONCLUSIONS Sorafenib in combination with TACE should be considered a safe and effective therapy for advanced HCC. Further validation of the new subgroup of BCLC-C stage is warranted in an independent patient cohort.

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

BACKGROUND In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. METHODS This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266. FINDINGS Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. INTERPRETATION Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. FUNDING Eisai Inc.