Cholangiocarcinoma: Biology, Clinical Management, and Pharmacological Perspectives

Abstract

Cholangiocarcinoma (CCA), or tumor of the biliary tree, is a rare and heterogeneous group of malignancies associated with a very poor prognosis. Depending on their localization along the biliary tree, CCAs are classified as intrahepatic, perihilar, and distal, and these subtypes are now considered different entities that differ in tumor biology, the staging system, management, and prognosis. When diagnosed, an evaluation by a multidisciplinary team is essential; the team must decide on the best therapeutic option. Surgical resection of tumors with negative margins is the best option for all subtypes of CCA, although this is only achieved in less than 50% of cases. Five-year survival rates have increased in the recent past owing to improvements in imaging techniques, which permits resectability to be predicted more accurately, and in surgery. Chemotherapy and radiotherapy are relatively ineffective in treating nonoperable tumors and the resistance of CCA to these therapies is a major problem. Although the combination of gemcitabine plus platinum derivatives is the pharmacological treatment most widely used, to date there is no standard chemotherapy, and new combinations with targeted drugs are currently being tested in ongoing clinical trials. This review summarizes the biology, clinical management, and pharmacological perspectives of these complex tumors.

Figure 1

Main signalling pathways (PI3K/AKT and RAS/MAPK) activated in cholangiocarcinogenesis by activation of tyrosine kinase receptors, such as EGFR, ERBB2, VEGFR, and others, and molecular mechanism of action of targeted therapies. In tumoral cells, the activation of signalling pathways induces the transcription of genes involved in proliferation, survival, and cell growth, while in endothelial cells the activation of these pathways stimulates angiogenesis.