Cholangiocarcinoma landscape in Europe: diagnostic, prognostic and therapeutic insights from the ENSCCA Registry
Laura Izquierdo-Sanchez 1 , Angela Lamarca 2 , Adelaida La Casta 3 , Stefan Buettner 4 , Kirsten Utpatel 5 , Heinz-Josef Klümpen 6 , Jorge Adeva 7 , Arndt Vogel 8 , Ana Lleo 9 , Luca Fabris 10 , Mariano Ponz-Sarvise 11 , Raffaele Brustia 12 , Vincenzo Cardinale 13 , Chiara Braconi 14 , Gianpaolo Vidili 15 , Nigel B Jamieson 16 , Rocio Ir Macias 17 , Jan Philipp Jonas 18 , Marco Marzioni 19 , Wacław Hołówko 20 , Trine Folseraas 21 , Juozas Kupčinskas 22 , Zeno Sparchez 23 , Marcin Krawczyk 24 , Łukasz Krupa 25 , Viorel Scripcariu 26 , Gian Luca Grazi 27 , Ana Landa-Magdalena 3 , Jan Nm Ijzermans 4 , Katja Evert 5 , Joris I Erdmann 28 , Flora López-López 7 , Anna Saborowski 8 , Alexander Scheiter 5 , Alvaro Santos-Laso 3 , Guido Carpino 29 , Jesper B Andersen 30 , Jose Jg Marin 17 , Domenico Alvaro 31 , Luis Bujanda 1 , Alejandro Forner 32 , Juan W Valle 2 , Bas Groot Koerkamp 4 , Jesus M Banales 33
Background and aims: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, with increasing incidence and related mortality. This study investigates the clinical course of CCA and subtypes (intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA)) in a pan-European cohort.
Methods: The ENSCCA Registry is a multicenter observational study. Patients with histologically-proven CCA diagnosis between 2010-2019 were included. Demographic, histomorphological, biochemical, and clinical studies were performed.
Results: Overall, 2,234 patients were enrolled (male:female=1.29). iCCA (n=1,243) was associated with overweight/obesity (58.5%) and chronic liver diseases involving cirrhosis (12.6%) and/or viral hepatitis (10.4%); pCCA (n=592) with primary sclerosing cholangitis (8.8%); and dCCA (n=399) with choledocholithiasis (10.3%). At diagnosis, 42.2% of patients had local disease, 29.4% locally-advanced disease (LAD), and 28.4% metastatic disease (MD).
Serum CEA and CA19-9 showed low diagnostic sensitivity (69.1% and 40.9% below cutoff, respectively), but their concomitant elevation was associated with increased risk of presenting with LAD [OR=2.16;95%CI:1.43-3.27] or MD [OR=5.88;95%CI:3.69-9.25]. Patients undergoing resection (50.3%) showed the best outcome, particularly with negative-resection margin (R0) [median overall survival (mOS)=45.1 months]; however, margin involvement (R1) [HR=1.92;95%CI:1.53-2.41;mOS=24.7 months] and lymph node invasion [HR=2.13;95%CI:1.55-2.94;mOS=23.3 months] compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%). Patients receiving best supportive care (20.6%) had mOS of 4.0 months, with iCCAs showing worst outcome compared to p/dCCAs. ECOG performance status [HR=1.52;95%CI:1.01-2.31], MD [HR=4.03;95%CI:1.82-8.92] and CA19-9 [HR=2.79;95%CI:1.46-5.33] were independently prognostic for OS.
Conclusion: CCA is still diagnosed at advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis is dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality.
Lay summary: This is, to date, the largest and more complete international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of CCA is investigated, comparing the three subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) [i.e., intrahepatic (2C12), perihilar (2C18), or distal (2C15) affected bile ducts] (coming into effect in 2022).
General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, among others, are presented and compared, outlining the current European scenario on the clinical state of CCA.
CITATION J Hepatol. 2022 May;76(5):1109-1121.
doi: 10.1016/j.jhep.2021.12.010. Epub 2022 Feb 12.