Systemic therapy for biliary cancers

Abstract

Biliary tract cancers represent an uncommon, heterogenous malignant group of tumors that include gallbladder cancers (GBC) and cholangiocarcinomas that are frequently detected in the locally advanced or metastatic setting. The randomized phase III ABC-02 trial established the combination regimen of cisplatin plus gemcitabine as standard of care therapy. Nevertheless, despite prior and subsequent attempts utilizing a variety of treatment strategies clinical outcomes for these cancers remains disappointing, necessitating the innate call for improvements in treatment approaches. In this article, we provide an overview of prior first line studies of single, doublet and triplet systemic chemotherapy regimens as well as attempts to incorporate agents that target the EGFR and VEGF pathways in combination with a cytotoxic backbone and the current role of chemotherapy in the second line setting. Additionally, molecular profiling has the capability to identify genetic alterations to help guide rational treatment approaches; we highlight the molecular diverse profile within biliary cancer and the prior, current and emergent role of targeted therapy in biliary cancers as well as the ongoing investigational assessment of immunotherapy. Overall, combination therapy is superior to single agent therapy in the first line setting. For second line therapy, enrollment on to clinical trials is paramount as no standard of care currently exists and no specific regimen has shown a significant better outcome. Limitations of chemotherapy have been exposed and future trials must have a logical design with incorporation of biomarkers that can aid prognosis or predict benefit to therapy. Advances in genomic sequencing can allow identification of potential actionable targets that can be exploited therapeutically which is already underway with the targeting of FGFR2 fusions and IDH1/2 mutations in intrahepatic cholangiocarcinoma (IHCC). With these approaches there is potential to gain improvements in outcomes for patients affected by these adverse group of cancers.

Keywords: Biliary cancer; chemotherapy; immunotherapy; molecular profiling.