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Cholangiocarcinoma — evolving concepts and therapeutic strategies

Key Points

  • Each anatomical subtype of cholangiocarcinoma, intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA), has a distinct epidemiology, biology, and prognosis, thus necessitating different management approaches

  • Fluorescence in situ hybridization (FISH) has improved the diagnostic performance of conventional cytology for the detection of pCCA and dCCA; several emerging diagnostic modalities, including liquid biopsy techniques, might further improve cholangiocarcinoma diagnosis

  • Neoadjuvant chemoradiotherapy followed by liver transplantation offers the best outcomes for a subset of patients with pCCA; liver transplantation might also be an option for patients with very early stage iCCA

  • Emerging evidence indicates that high-dose, conformal external-beam radiation therapy is a potential treatment option for patients with localized, unresectable iCCA

  • An enhanced understanding of the potential driver genetic aberrations in cholangiocarcinomas has heralded several novel drugs for advanced-stage disease, including FGFR inhibitors and IDH inhibitors; targeted therapy and immunotherapy combinations also hold promise

Abstract

Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.

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Figure 1: Illustrative examples of the radiographic modalities used in the visualization of the different anatomical subtypes of cholangiocarcinoma.
Figure 2: Current clinical management algorithms for adult patients with cholangiocarcinoma.
Figure 3: Proton radiotherapy of intrahepatic cholangiocarcinoma (iCCA).
Figure 4: Evolving molecular stratification of cholangiocarcinoma (CCA) and therapeutic implications.
Figure 5: Biological rationale for the ongoing clinical trials of immunotherapies for cholangiocarcinoma.

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Acknowledgements

The authors thank Ms Courtney Hoover for her excellent secretarial support. The work of the authors is supported by the US NIH (grants DK59427 to G.J.G., 1R03CA212877-01 to R.K.K., and DK84567 to the Mayo Center for Cell Signalling in Gastroenterology), and by the Mayo Foundation. S.R. has also received support from the Cholangiocarcinoma Foundation and from the Mayo Center for Cell Signalling in Gastroenterology (Pilot & Feasibility Award P30DK084567).

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Correspondence to Gregory J. Gores.

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R.K.K has received research support from Agios, Eli Lilly, Merck, and Novartis, via her institution, for conduct of clinical trials in cholangiocarcinoma. S.R., S.A.K., C.L.H., and G.J.G. declare no competing interests.

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Rizvi, S., Khan, S., Hallemeier, C. et al. Cholangiocarcinoma — evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 15, 95–111 (2018). https://doi.org/10.1038/nrclinonc.2017.157

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