Cholangiocarcinoma (CCA) constitutes a diverse group of malignancies emerging in the biliary tree. CCAs are divided into three subtypes depending on their anatomical site of origin: intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) CCA 1,2 (Fig. 1). Of note, considered as an independent entity, mixed HCC-CCA tumours are a rare type of liver malignancy sharing features of both iCCA and HCC and presenting an aggressive disease course and poor prognosis 3,4. iCCAs arise above the second-order bile ducts, whereas the point of anatomical distinction between pCCA and dCCA is the insertion of the cystic duct. pCCA and dCCA can also be collectively referred to as 'extrahepatic' (eCCA) 5. In the USA, pCCA is the single largest group, accounting for approximately 50-60% of all CCAs, followed by dCCA (20-30%) and iCCA (10-20%) 1,6,7. CCA is the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC), comprising approximately 15% of all primary liver tumours and 3% of gastrointestinal cancers 1,6,7. CCAs are usually asymptomatic in early stages and, therefore, often diagnosed when the disease is already in advanced stages, which highly compromises therapeutic options, resulting in a dismal prognosis 1,8. CCA is a rare cancer, but its incidence (0.3-6 per 100,000 inhabitants per year) 1 and mortality (1-6 per 100,000 inhabitants per year, globally 9 , not taking into account specific regions with incidence >6 per 100,000 habitants such as South Korea, China and Thailand) have been increasing in the past few decades worldwide, representing a global health problem. Despite advances in

Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients presents with resectable disease; however, relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been suggested. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g. radioembolization or external beam radiation); pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next generation sequencing analyses have identified actionable mutations (e.g. FGFR fusion rearrangements and IDH-1 and -2 mutations) with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC is rapidly evolving and the subject of this review.

Background Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer. MethodsThe ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m², L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m² [bolus], and fluorouracil 2400 mg/m² as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30.

The randomized NCRN phase III ABC-02 trial provided level-A evidence for first-line chemotherapy with cisplatin and gemcitabine combination in advanced biliary cancer (ABC). This systematic literature review aims to evaluate the level of evidence for the use of second-line chemotherapy for patients with ABC in terms of overall survival (OS), response, toxicity and quality of life. Eligible studies were identified using Medline, ASCO, ESMO and the World Gastrointestinal Congress databases. Searches were last updated on 15 December 2013. Eligible studies reported survival and/or response data for patients with ABC receiving second-line systemic chemotherapy. This systematic review was registered in the PROSPERO database (No. CRD42013004205). Five hundred and fifty-eight studies were identified from the searches in Medline (n = 342), ASCO (n = 160), ESMO (n = 27) and World Gastrointestinal Congress (n = 29). Twenty-five studies were eligible: 14 phase II clinical trials, 9 retrospective analyses and 2 case reports. In total, data from 761 patients were reported with median number of patients included in each study of 22 (range 9-96). The mean OS was 7.2 months [95% confidence interval (CI) 6.2-8.2] [phase II: 6.6 (95% CI 5.1-8.1); retrospective analysis: 7.7 (95% CI 6.5-8.9)]. The mean progression-free survival (PFS), response rate (RR) and disease control rate were 3.2 months (95% CI 2.7-3.7), 7.7% (95% CI 4.6-10.9) and 49.5% (95% CI 41.4-57.7), respectively. The best correlations were between OS and PFS for all studies (r = 0.54; P = 0.01) and between OS and PFS (r = 0.61; P = 0.04) and OS and RR (r = 0.62; P = 0.03) for phase II studies, respectively. Biliary tract cancer is known to be a chemo-responsive disease. There is insufficient evidence (level C) to recommend a second-line chemotherapy schedule in ABC, although the available data suggest that a cohort of patients may benefit. Further prospective and randomized studies are needed to clarify the relative value of second-line chemotherapy in this setting.

The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and-2 mutations which are each present in around 10-20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.

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Cholangiocarcinoma (CCA) is a heterogeneous group of tumours, derived from cells of the biliary tree, which represent the second most frequent primary liver tumour. According to the most recent classifications, CCA can be subdivided into intrahepatic (iCCA) and extrahepatic (eCCA) which include perihilar (pCCA) and distal (dCCA) CCA. CCA are usually identified at advanced stages, when the primary tumour grows enough to produce a large liver mass or when jaundice has developed because of biliary tree obstruction. The ongoing challenges in the identification of risk factors and definition of a specific population at higher risk of developing CCA are the main challenges for the development of screening programs. Therefore, late diagnosis remains an unresolved issue in CCA. Imaging plays an important role in the detection and characterization of CCA, helping with radiological diagnosis, guiding biopsy procedures and allowing staging of the tumour. This review focuses on clinical presentations and diagnosis and staging techniques of CCA.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent a rare diagnosis of the gastro-entero-pancreatic tract. Evidence from the current literature regarding their epidemiology, biology, and management is of variable quality and conflicting. Based on available data, the MiNEN has an aggressive biological behaviour, mostly driven by its (often high-grade) neuroendocrine component, and a dismal prognosis. In most cases, the non-neuroendocrine component is of adenocarcinoma histology. Due to limitations in diagnostic methods and poor awareness within the scientific community, the incidence of MiNENs may be underestimated. In the absence of data from clinical trials, MiNENs are commonly treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from the same sites of origin, based on the assumption of a biological similarity to their pure counterparts. However, little is known about the molecular aberrations of MiNENs, and their pathogenesis remains controversial; molecular/genetic studies conducted so far point towards a common monoclonal origin of the two components. In addition, mutations in tumour-associated genes, including TP53, BRAF, and KRAS, and microsatellite instability have emerged as potential drivers of MiNENs. This systematic review (91 full manuscripts or abstracts in English language) summarises the current reported literature on clinical, pathological, survival, and molecular/genetic data on MiNENs.