Emerging treatment options for cholangiocarcinoma

ABSTRACT

Introduction: Cholangiocarcinomas are rare malignancies arising from the epithelium of the biliary tree and are classified as either intrahepatic (iCCA) or extrahepatic (eCCA) subtypes based on their anatomic location. The overall prognosis for cholangiocarcinoma is poor, and potentially curative surgical options are limited to those few patients with early, localized disease. The majority of patients are diagnosed with unresectable or metastatic disease, for which treatment options have historically been limited to traditional systemic chemotherapy, with a median survival of only 12 months.

Areas covered: Although historically grouped together, the iCCA and eCCA subtypes have distinct anatomic, genetic, and molecular features, which have important prognostic and therapeutic implications. Technological advances using whole genome analysis and next-generation sequencing have recently afforded a better molecular understanding of these subtypes, and in turn helped identify novel, potentially targetable mutations. Among the most promising therapies under investigation are agents targeting fibroblast growth factor receptor (FGFR) gene fusions and mutations in isocitrate dehydrogenase (IDH)-1/2.

Expert opinion: Numerous targeted drugs and immunotherapies are currently in early phase trials and hold promise that major advances in the treatment of cholangiocarcinoma are on the horizon. In the near future, a personalized treatment approach, targeting individual tumor mutations such as FGFR and IDH1/2 and harnessing the native immune system with immunotherapy, will be required to optimize the outcomes of patients with this aggressive malignancy.

KEYWORDS:

• Cholangiocarcinoma
• bile duct cancer
• biliary tract cancer
• chemotherapy
• FGFR
• hepatic arterial infusion
• IDH
• immunotherapy

ARTICLE HIGHLIGHTS

• Treatment of locally advanced or metastatic cholangiocarcinoma has historically been limited to traditional gemcitabine/platinum-based chemotherapy, with meager response rates and poor survival outcomes.

• Intrahepatic and extrahepatic cholangiocarcinoma have distinct epidemiologic, biological, and molecular features that influence their prognosis and treatment options.

• Improved molecular understanding through whole genome analysis has identified multiple actionable mutations, leading to the development of targeted agents.

• Two of the most promising novel targeted therapies include IDH inhibitors and small molecule inhibitors of FGFR gene fusions.

• Checkpoint inhibitors and immunotherapy are being actively investigated in multiple early phase clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.