Cholangiocarcinoma - evolving concepts and therapeutic strategies

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.

Conflict of interest statement

Competing interests statement

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.

Figures

Figure 1. Illustrative examples of the radiographic modalities used in the visualization of the different anatomical subtypes of cholangiocarcinoma

a | Axial CT image of a large, left lobe heterogeneous mass with peripheral bile-duct dilatation (black arrow) consistent with an intrahepatic cholangiocarcinoma (iCCA). The pattern of vascular enhancement on CT imaging, with initial rim enhancement followed by centripetal enhancement, helps distinguish iCCA from hepatocellular carcinoma, but does not enable assessment of resectability. b | Axial T2-weighted MRI scan of a circumferential, soft-tissue, perihilar mass (white arrow) consistent with a perihilar cholangiocarcinoma (pCCA). c | Coronal magnetic resonance cholangiopancreatography image of pCCA separating the right and left hepatic ducts (white arrows). d | Endoscopic retrograde cholangiopancreatography image of a malignant-appearing (‘dominant’) distal stricture (white arrow) consistent with a distal cholangiocarcinoma.

Figure 2. Current clinical management algorithms for adult patients with cholangiocarcinoma

a | For patients with intrahepatic cholangiocarcinoma (iCCA). b | For those with perihilar cholangiocarcinoma (pCCA). c | For patients with distal cholangiocarcinoma (dCCA). Patients with unresectable pCCA/dCCA who are not candidates for liver transplantation and have a poor performance status generally have short survival durations; thus, the use of plastic stents is usually sufficient and probably more cost-effective than the use of metallic stents.

Figure 3. Proton radiotherapy of intrahepatic cholangiocarcinoma (iCCA)

Proton-beam radiotherapy plan for a patient with localized, unresectable iCCA, with a total radiation dose of 6,750 cGy delivered in 15 fractions over 3 weeks. The orange line depicts the tumour. The white, cyan, magenta, and yellow lines represent the 6,750, 5,000, 3,000, and 1,000 cGy isodose lines, respectively. Radiation is delivered in two beams from the right lateral (R) and posterior (P) directions (as indicated by the 1,000 cGy isodose lines). Proton beams have no ‘exit dose’ deposition, which for this patient, enabled complete sparing of the left lobe of the liver, stomach, and bowel from radiation exposure.

Figure 4. Evolving molecular stratification of cholangiocarcinoma (CCA) and therapeutic implications

Emerging and conventional analytical techniques, such as RNA and/or DNA sequencing, fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC), can be used for the detection of molecular aberrations in CCA tissue obtained via biopsy or surgery. The listed molecular alterations represent potential therapeutic targets in CCA. ATM, ataxia-telangiectasia mutated; BH3, BCL-2 homology domain 3; CDK4/6, cyclin-dependent kinases 4 and 6; DNMT, DNA methyltransferase; EZH2, enhancer of zeste homolog 2; FGFR, fibroblast growth factor receptor; HDAC, histone deacetylase; IDH, isocitrate dehydrogenase; Mcl-1, induced myeloid leukaemia cell differentiation protein Mcl-1; PARP, poly [ADP-ribose] polymerase; PD-L1, programmed cell death 1 ligand 1; PKA, protein kinase A.

Figure 5. Biological rationale for the ongoing clinical trials of immunotherapies for cholangiocarcinoma

The mechanisms of action or targets of the immunotherapy combinations currently being tested in the ongoing trials listed in TABLE 1 are represented schematically. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) transmits inhibitory signals that limit T-cell priming by antigen-presenting cells (APCs), such as dendritic cells, in lymphoid organs, which can restrict responses to tumour antigens; thus, blockade of this inhibitory immune-checkpoint protein using the monoclonal antibodies ipilimumab or tremelimumab can enhance the activation of T cells with the capacity to recognize tumour cells. Similarly, programmed cell death 1 ligand 1 (PD-L1) is an inhibitory immune-checkpoint protein commonly expressed by tumour cells and immune cells in the tumour microenvironment (TME). Antibodies targeting PD-L1, such as durvalumab, or its receptor programmed cell death protein 1 (PD-1), such as pembrolizumab or nivolumab, can inhibit immunosuppressive signalling in T cells capable of recognizing tumour cells, potentiating anticancer immune responses. In combination with immune-checkpoint inhibition, intravenous adoptive transfer of tumour-infiltrating lymphocytes (TILs) isolated from the TME and expanded ex vivo might enhance anticancer immunity. Alternatively, targeting the vascular endothelial growth factor receptor 2 (VEGFR2) with the monoclonal antibody ramucirumab might enhance T-cell recruitment into the TME, as a result of normalization of the dysfunctional tumour vasculature, and can also have direct, beneficial immunological effects, for example, on tumour-associated macrophages. Immune-checkpoint inhibitors are also being combined with helper cytokines that might potentiate anticancer immunity, such as granulocyte- macrophage colony-stimulating factor (GM-CSF) and pegylated IFNα-2b (Peg-IFNα-2b), as well as small-molecular inhibitors of targets relevant to cholangiocarcinoma, such as fibroblast growth factor receptors (FGFR1–3) and heat-shock protein 90 (HSP90). ACT, adoptive cell therapy; MHC I, major histocompatibility complex class I; RFA, radiofrequency ablation; SBRT, stereotactic body radiation therapy; TACE, transarterial chemoembolization; TCR, T-cell receptor; Treg cell, regulatory T cell.