Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial.

BACKGROUND: Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo. METHODS: We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053. FINDINGS: Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group. INTERPRETATION: The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. FUNDING: Bayer PLC and BTG PLC.

Laparoscopic right hepatectomy: a challenging, but feasible, safe and efficient procedure.

BACKGROUND: Few centers are undertaking major laparoscopic liver resections, because of the well-recognized technical difficulties and lack of training opportunities. METHODS: The authors describe their technique for laparoscopic right hepatectomy, highlighting relevant details for accomplishing a safe and efficient procedure. Patients were chronologically divided into 2 groups to evaluate the impact of increasing experience on the surgical outcomes. RESULTS: Group I included 17 patients and group II 18 patients. The conversion rate to open or hybrid techniques significantly decreased from 36% in group I to 6% in group II (P = .03). The hospital stay decreased from a median of 6 days in group I to a median of 4 days in group II (P = .05). Complications occurred in 4 patients (11%), of whom 3 were in group I. The mortality was zero. CONCLUSIONS: Laparoscopic right hepatectomy is a safe and efficient procedure when performed at specialized centers with extensive experience in hepatic surgery. Long-term training is necessary to acquire adequate expertise.

Surgical management of benign and indeterminate hepatic lesions in the era of laparoscopic liver surgery.

BACKGROUND/AIMS: The expansion of the laparoscopic approach for the management of benign liver lesions has raised concerns regarding the risk of widening surgical indications and compromising safety. Large single-centre series focusing on laparoscopic management of benign liver lesions are sporadic. METHODS: We reviewed a prospectively collected database of patients undergoing pure laparoscopic liver resection (LLR) for benign liver lesions. All cases were individually discussed at a multidisciplinary team meeting. RESULTS: Forty-six patients underwent 50 LLRs for benign disease. Indications for surgery were: symptomatic lesions, preoperative diagnosis of adenoma or cystadenoma, and lesions with an indeterminate diagnosis. The preoperative diagnosis was uncertain in 11 cases. Of these, histological diagnosis was hepatocellular carcinoma in one (9%) and benign lesion in 10 patients (91%). Thirteen patients (28%) required major hepatectomy. Three patients (7%) developed postoperative complications. Mortality was nil. The median postoperative hospital stay following major and minor hepatectomy was 4 and 3 days, respectively. CONCLUSION: The laparoscopic approach represents a safe option for the management of benign and indeterminate liver lesions, even when major hepatectomy is required. LLR should be only performed in specialized centres to ensure safety and strict adherence to orthodox surgical indication.

Single-centre comparative study of laparoscopic versus open right hepatectomy.

BACKGROUND: Expansion of laparoscopic major hepatectomy is still limited mainly due to the well-recognised technical difficulties compared to open surgery, and doubts regarding the oncological efficiency when major resections are required. METHODS: Patients undergoing open right hepatectomy (ORH) were matched with patients undergoing laparoscopic right hepatectomy (LRH) and compared for perioperative outcomes. RESULTS: Seventy patients were included: 36 patients underwent LRH and 34 ORH. Operative time was significantly longer for LRH (median, 300 min vs. 180 min for ORH; p < 0.0001). Intensive care unit (median, 2 days for LRH vs. 4 days for ORH; p < 0.0001) and postoperative length of stay (5 days for LRH vs. 9 days for ORH; p < 0.0001) were significantly shorter for LRH. Four laparoscopic cases were converted to open surgery. No significant difference in postoperative complications and mortality was observed between LRH and ORH. Among patients with colorectal carcinoma liver metastases, R0 resection was obtained in 20/21 (95%) cases after LRH, and in 20/25 (80%) after ORH (p = 0.198). Mid-term overall survival did not significantly differ between the laparoscopic and the open group. CONCLUSIONS: LRH can be a safe, effective, and oncologically efficient alternative to open resection in selected cases. Extensive experience in hepatic and laparoscopic surgery is required.