Advanced Bile Duct Cancers: A Focused Review on Current and Emerging Systemic Treatments

SIMPLE SUMMARY: Biliary tract cancer (BTC), comprising intrahepatic and extrahepatic cholangiocarcinoma as well as gallbladder carcinoma, continues to have poor outcomes for those with unresectable or metastatic disease. The mainstay of therapy has been cytotoxic chemotherapy. A paradigm shift is now occurring due to the widespread availability of next-generation sequencing identifying actionable genomic alterations in a patient subset and the observation that BTC may be sensitive to immune attack. The development of effective targeted therapies is helping to transforming care and combination chemoimmunotherapy appears to improve clinical outcomes. In this review, we discuss the current treatment landscape, available options, and future direction of the treatment of advanced BTC. ABSTRACT: Cancers arising in the biliary tract are rare, with varied incidence depending on geographical location. As clinical presentation is typically vague with non-specific symptoms, a large proportion of patients present with unresectable or metastatic disease at diagnosis. When unresectable, the mainstay of treatment is cytotoxic chemotherapy; however, despite this, 5-year overall survival remains incredibly poor. Diagnostic molecular pathology, using next-generation sequencing, has identified a high prevalence of targetable alterations in bile duct cancers, which is transforming care. Substantial genomic heterogeneity has been identified depending on both the anatomical location and etiology of disease, with certain alterations enriched for subtypes. In addition, immune checkpoint inhibitors with anti-PD-1/PD-L1 antibodies in combination with chemotherapy are now poised to become the standard first-line treatment option in this disease. Here, we describe the established role of cytotoxic chemotherapy, targeted precision treatments and immunotherapy in what is a rapidly evolving treatment paradigm for advanced biliary tract cancer.