BackgroundNext-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA.MethodsThis multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks.ResultsTwenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04–9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%).ConclusionDerazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).

The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing worldwide. Although several advances have been made in the past decades to better understand this complex malignancy and to develop new treatment strategies, the prognosis of iCCA remains dismal. Liver resection (LR) is the mainstay of treatment but only a minority of patients are amenable to surgery. In most cases, patients with iCCA will require a major hepatectomy for complete resection of the tumour. This may be contraindicated or increase the surgical burden in patients with chronic liver disease and small remnant liver volume. Lymphadenectomy with a minimal harvest of 6 lymph nodes is considered adequate, as microscopic nodal metastases have been shown in more than 40% of patients. Current 5-year overall survival following LR is in the range of 25%-40%. For locally advanced disease not amenable to upfront LR, neoadjuvant locoregional therapies may be used with the aim of converting these patients to resectability or even to transplantation in well-selected cases. Recent studies have shown that liver transplantation (LT) might be a treatment option for patients with unresectable very-early iCCA (i.e. < − 2 cm), with survival outcomes comparable to those of hepatocellular carcinoma. In patients with unresectable, advanced tumours, confined to the liver who achieve sustained response to neoadjuvant treatment, LT may be considered an option within prospective protocols. The role of adjuvant therapies in iCCA is still under debate. Herein, we review the recent advances in the surgical treatment of iCCA and examine its correlation with locoregional therapies, adjuvant and neo-adjuvant strategies.

Background. Liver transplantation cures hepatocellular carcinoma (HCC) if within conventional selection criteria. Expanded criteria are elusive. Loco-regional treatments pursue tumor downstaging from outside Milan criteria to within criteria. No trial investigated HCC-downstaging strategy to expand transplant eligibility. Methods. This multi-center trial aimed at comparing successfully downstaged HCC followed by transplantation vs. non-transplant therapies. Eligible patients had good liver function (Child-Pugh A-B7), HCC beyond Milan, 5-year estimated post-transplant survival ≥50%, no macrovascular or extrahepatic spread. Only partial-complete responses according to modified-RECIST were randomized 1:1 after 3 months observation period, during which sorafenib was allowed. Co-endpoints were survival and timeto-tumor event. We used Kaplan-Meier method, log-rank test, Cox regression for intention-to-treat analysis. Survival benefit was the difference between groups mean survival time. Organ allocation policy changed over time and limited patients' accrual to 4 years. After 4 additional years conditional power calculation estimated the probability that the final results would be statistically significant in the remaining study, given the data observed. ClinicalTrials.gov NCT01387503. Findings. 74 patients were enrolled between March 2011 to March 2015: 29 dropped-out pre-randomization. Downstaging median duration was 6 months (1-17). Success-rate was 73%. Progression during observation was 17%. 45 patients were randomized: 23 transplanted vs. 22 controls. Median followup was 71 months (IQR 60-85). 5-year overall survival was 77.5% (95%CI 61.9-97.1%) in transplants vs. 31.2% (95%CI: 16.6-58.5%) in controls (Cox hazard ratio [HR] 0.22, 95%CI: 0.08-0.61; p=0.004). 5-year tumor eventfree survival was 76.8 (95%CI: 60.8-96.9%) vs. 18.3% (95%CI: 7.1-47.0%) in controls (HR: 0.14, 95%CI: 0.05-0.38; p<0001). 5-year survival-benefit favored transplantation by 14.5 months (95%CI: 3.6-25.3; p=0.009). The trial retained a conditional power of 98.6%. Interpretation. After effective and sustained downstaging of eligible HCCs beyond Milan criteria, liver transplantation is superior to nontransplant therapies. Post-downstaging tumor response should contribute to HCC transplant criteria expansion. Funding. Italian Ministry of Health

Objective: The aim of this study was to assess safety and efficacy of pancreatic duct occlusion (PDO) with neoprene-based glue in selected patients undergoing pancreatoduodenectomy (PD) at high risk of postoperative pancreatic fistula (POPF). Background Data: PD is the reference standard approach for tumors of the pancreaticoduodenal region. POPF is the most relevant complication after PD. PDO has been proposed as an alternative to anastomosis to manage the pancreatic stump. Methods: A single-center, prospective, nonrandomized trial enrolled 100 consecutive PD for cancer. Patients at high risk for POPF according to Fistula Risk Score (FRS) >15% (≥6 points) were treated with PDO using neoprene glue (study cohort); patients with FRS ≤15% (≤5 points) received pancreaticojejunal anastomosis (PJA: control cohort). Primary endpoint was complication rate grade ≥3 according to Dindo–Clavien Classification (DCC). Other postoperative outcomes were monitored (ClinicalTrials.gov NCT03738787). Results: Fifty-one patients underwent PDO and 49 PJA. DCC ≥3, postoperative mortality, and POPF grade B-C were 25.5% versus 24.5% (P = 0.91), 5.9% versus 2% (P = 0.62), and 11.8% versus 16.3% (P = 0.51) in the study versus control cohort, respectively. At 1 and 3 years, new-onset diabetes was diagnosed in 13.7% and 36.7% of the study cohort versu 4.2% and 12.2% in controls (P = 0.007). Conclusions: PDO with neoprene-based glue is a safe technique that equalizes early outcome of selected patients at high risk of POPF to those at low risk undergoing PJA. Neoprene-based PDO, however, triples the risk of diabetes at 1 and 3 years.