Second-line Treatment Strategies in Biliary Tract Cancers

Abstract

Biliary tract cancers (BTCs) are a highly heterogenous group of tumours arising from the bile ducts (cholangiocarcinoma [CCA]) and gallbladder. Of note, tumours of the ampulla of Vater typically fall under this definition but tend to be excluded from second-line treatment studies. Cholangiocarcinomas are further classified into intrahepatic (iCCA, including hilar) and extrahepatic (eCCA). Together, they account for approximately 15% of primary liver cancers and 3% of all gastrointestinal malignancies. However, iCCA and eCCA are separate entities that differ in incidence, clinical presentation, natural evolution, and molecular profile. Specifically, iCCA is less commonly associated with biliary obstructive symptoms and thus tends to be diagnosed incidentally and at a more advanced stage than eCCA. The diagnostic challenges partly stem from the localization of these tumours, deep in the hepatic and biliary systems, where it is often difficult to obtain a tissue biopsy or an adequate aspiration cytology. iCCA can be misclassified as carcinoma of unknown primary (CUP) as histologically it can be impossible to distinguish from metastatic adenocarcinoma of an extrahepatic primary tumour, and the primary tumour can be small and not well identified on imaging. 

The unique features of these tumours may in part explain their poor prognosis. Overall, the 5-year survival rate of CCA is estimated to be less than 25% for all stages combined, reflecting a very modest treatment effect. Chemoimmunotherapy combinations are now globally accepted as the standard first-line treatment, but uncertainties remain regarding second and later lines of treatment. This review will summarize the available treatments beyond the first line with a focus on the emerging field of molecular precision medicine.