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Cholangiocarcinoma landscape in Europe: diagnostic, prognostic and therapeutic insights from the ENSCCA Registry

Izquierdo-Sanchez, L.
; 
Lamarca, Angela
; 
La Casta, A.
; 
Buettner, S.
; 
Utpatel, K.
; 
Klümpen, H. J.
; 
Adeva, J.
; 
Vogel, A.
; 
Lleo, A.
; 
Fabris, L.
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Abstract
Background & Aims Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. 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 were included if they had a histologically proven diagnosis of CCA between 2010-2019. 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 and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. 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, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 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%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. Conclusion CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains 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 international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 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), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.
Authors
Izquierdo-Sanchez, L.
Lamarca, Angela
La Casta, A.
Buettner, S.
Utpatel, K.
Klümpen, H. J.
Adeva, J.
Vogel, A.
Lleo, A.
Fabris, L.
Ponz-Sarvise, M.
Brustia, R.
Cardinale, V.
Braconi, C.
Vidili, G.
Jamieson, N. B.
Macias, R. I.
Jonas, J. P.
Marzioni, M.
Hołówko, W.
Folseraas, T.
Kupčinskas, J.
Sparchez, Z.
Krawczyk, M.
Krupa, Ł.
Scripcariu, V.
Grazi, G. L.
Landa-Magdalena, A.
Ijzermans, J. N.
Evert, K.
Erdmann, J. I.
López-López, F.
Saborowski, A.
Scheiter, A.
Santos-Laso, A.
Carpino, G.
Andersen, J. B.
Marin, J. J.
Alvaro, D.
Bujanda, L.
Forner, A.
Valle, Juan W
Koerkamp, B. G.
Banales, J. M.
Affiliation
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, 'Instituto de Salud Carlos III' (ISCIII), Madrid, Spain. Department of Medical Oncology, The Christie NHS Foundation Trust/Institute of Cancer Sciences, University of Manchester, Manchester, UK. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain. Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands. Institute of Pathology, University of Regensburg, Regensburg, Germany. Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, the Netherlands. Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Division of Internal Medicine and Hepatology, Humanitas Clinical Research Center IRCSS, Humanitas University, Rozzano, Milan, Italy. Department of Molecular Medicine (DMM), University of Padua School of Medicine, Padua, Italy; Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA. Clinica Universidad de Navarra and Program in Solid Tumors (CIMA), Universidad de Navarra, IDISNA, Pamplona, Spain. Department of Hepatobiliary and Liver Transplantation Surgery, AP-HP, Hôpital Pitié Salpêtrière, CRSA, Sorbonne Université, Paris, France. Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino 'Sapienza' University of Rome, Latina, Italy. Institute of Cancer Sciences, University of Glasgow, UK; The Royal Marsden NHS Trust, London & Surrey, UK. Department of Medical, Surgical and Experimental Sciences, Clinica Medica Unit, University of Sassari, Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy. Institute of Cancer Sciences, University of Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, 'Instituto de Salud Carlos III' (ISCIII), Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Biomedical Research Institute (IBSAL), Salamanca, Spain. University Hospital Zurich, Department of Visceral- and Transplant Surgery, Zurich, Switzerland; Clinic Favoriten, Department for Surgery, Wien, Austria. Università Politecnica delle Marche, Department of Gastroenterology, Ancona, Italy. Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland. Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway. Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania. 3rd Medical Department, Institute for Gastroenterology and Hepatology, University of Medicine and Pharmacy, Cluj Napoca, Romania. Department of Medicine II Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland. Department of Gastroenterology and Hepatology with General Medicine Unit, Teaching Hospital No. 1, Rzeszów, Poland. Department of Morpho-Functional Sciences I, Department of Surgery II, Grigore T. Popa University of Medicine and Pharmacy, Iaşi, Romania. Regina Elena National Cancer Institute, Rome, Italy. Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. Department of Movement, Human and Health Sciences, University of Rome 'Foro Italico', Rome, Italy. Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy. National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, 'Instituto de Salud Carlos III' (ISCIII), Madrid, Spain; Liver Unit. Barcelona Clinic Liver Cancer (BCLC) group. Hospital Clinic Barcelona. IDIBAPS. University of Barcelona, Spain. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, 'Instituto de Salud Carlos III' (ISCIII), Madrid, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona; Ikerbasque, Basque Foundation for Science, Bilbao, Spain. Electronic address: jesus.banales@biodonostia.org.
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2022
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Izquierdo-Sanchez L, Lamarca A, La Casta A, Buettner S, Utpatel K, Klümpen H-J, et al. Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry [Internet]. Journal of Hepatology. Elsevier BV; 2022.
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http://hdl.handle.net/10541/625098
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