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Cholangiocarcinoma (CCA) is a hepatic malignancy that has a rapidly increasing incidence. CCA is anatomically classified into intrahepatic (iCCA) and extrahepatic (eCCA), which is further divided into perihilar (pCCA) and distal (dCCA) subtypes, with higher incidence rates in Asia. Despite its rarity, CCA has a low 5-year survival rate and remains the leading cause of primary liver tumor-related death over the past 10–20 years. The systemic therapy section discusses gemcitabine-based regimens as primary treatments, along with oxaliplatin-based options. Second-line therapy is limited but may include short-term infusional fluorouracil (FU) plus leucovorin (LV) and oxaliplatin. The adjuvant therapy section discusses approaches to improve overall survival (OS) post-surgery. However, only a minority of CCA patients qualify for surgical resection. In comparison to adjuvant therapies, neoadjuvant therapy for unresectable cases shows promise. Gemcitabine and cisplatin indicate potential benefits for patients awaiting liver transplantation. The addition of immunotherapies to chemotherapy in combination is discussed. Nivolumab and innovative approaches like CAR-T cells, TRBAs, and oncolytic viruses are explored. We aim in this review to provide a comprehensive report on the systemic and locoregional therapies for CCA.

Background and aim Endoscopic biliary drainage serves as the primary palliative intervention for malignant hilar biliary obstruction (MHBO), especially unresectable perihilar cholangiocarcinoma (pCCA), with metal stents (MS) and plastic stents (PS) constituting the main therapeutic modalities. Despite widespread clinical adoption, persistent equipoise surrounds their comparative therapeutic efficacy, with current guidelines lacking consensus on optimal deployment strategies. Therefore, this study included the recent studies of endoscopic stent therapy for unresectable pCCA to explore further the drainage effect and postoperative complications of the two stents, and to provide clinical guidance for the selection of stent drainage. For unresectable pCCA, biliary drainage is the basis for subsequent systemic treatment and also one of the essential therapeutic methods for prolonging survival time. Endoscopic drainage has the advantages of less pain and better compliance with physiology compared with percutaneous transhepatic biliary drainage (PTBD). However, due to the difficulty of endoscopic treatment operation and the possibility of inducing biliary tract infection, especially for Bismuth-Corlette type III and above pCCA, endoscopic treatment is more challenging. Currently, there are still many controversial issues regarding the selection of stents and drainage strategies in endoscopic biliary drainage. This meta-analysis systematically evaluates contemporary evidence to establish evidence-based protocols for stent selection in MHBO, especially pCCA. Methods A comprehensive search of multiple databases (Pubmed, MEDLINE, Embase, Cochrane) and grey literature was conducted, covering articles from the inception of the databases until September 2024, without restrictions on publication year or language, provided they included at least an English abstract. Studies comparing MS and PS techniques through endoscopic retrograde cholangiopancreatography (ERCP) were included. Outcomes analyzed included technical and clinical success, complications, stent patency, and re-intervention rates. Meta-analysis was conducted using RevMan software, STATA 17.0, and R software on the data of interest extracted from the selected studies. Results A total of 10 cohort studies and two randomized controlled trials (RCT) were included, assessing 1 405 patients (714 patients in the MS group and 691 patients in the PS group). MS demonstrated comparable technical success rates [risk ratio (RR) = 1.00; 95% confidence interval (CI) 0.97–1.04, I 2  = 0%, p  = 0.82] and clinical success rates [RR = 0.99; 95%CI 0.93–1.06, I 2  = 1%, p  = 0.75] to PS. MS exhibited superior stent patency [hazard ratio (HR) = 2.11; 95% CI 1.31–3.39, I 2  = 0%, p  = 0.002] with 68% reduction in stent occlusion [odds ratio (OR) = 2.89; 95% CI 2.08–4.03, I 2  = 0%, p  < 0.00001] to PS. Complication profiles significantly favored MS to PS: 63% lower cholangitis incidence [OR = 3.61; 95% CI 2.46–5.30, I 2  = 32%, p  < 0.00001]; 87% reduction in stent migration [OR = 7.87; 95% CI 2.56–24.17, I 2  = 0%, p  < 0.0003]; 68% fewer reintervention [OR = 3.17, 95% CI 2.37–4.23, I 2  = 22%, p  < 0.00001]. No significant differences emerged in pancreatitis [OR = 0.96; 95%CI 0.57–1.61, I 2  = 1%, p  = 0.87], hemorrhage [OR = 1.29, 95%CI 0.41–4.04, I 2  = 0%, p  = 0.66], or survival [HR = 1.01; 95%CI 0.91–1.12, I 2  = 0%, p  = 0.894]. Conclusion This meta-analysis establishes MS as the preferential modality for endoscopic MHBO management, demonstrating 2.1-fold longer patency duration and 63–87% risk reduction in major complications compared to PS. These findings strongly support protocolized MS deployment in unresectable pCCA, particularly for reducing cholangitis burden and reintervention frequency.

This study aims to provide a deep insight into the incidence and clinical significance of postoperative anastomotic leakage (AL) and anastomotic stenosis (AS) of the hepaticojejunostomy (HJ) after curative-intent liver resection for perihilar cholangiocarcinoma (pCCA). Between 2011 and mid-2019, 114 patients with pCCA underwent surgery in curative intent at our institution and were analyzed regarding the postoperative incidence of AL and AS. Further, associations between AL and AS and clinical characteristics were assessed using multiple univariate logistic regression analyses. AL was diagnosed in 11.4% (13/114) of the patients resulting in postoperative mortality in the minority of patients (23.0%, 3/13). AS occurred in 11.0% (11/100) of the individuals eligible for follow-up with local tumor recurrence being the underlying pathology in 72.7% (8/11) of the cases. None of the investigated clinical factors including surgical difficulty of the HJ showed a meaningful association with AL or AS. AL and AS are frequent complications and can be treated by conservative, interventional or surgical therapy with a high success rate. Also, technical difficulty of the HJ appears not to be not associated with the occurrence of AL or AS. Moreover, AS is associated with tumor recurrence in the majority of cases.

Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient’s cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.