Liver Transplantation for perihilar cholangiocarcinoma. Do we need to move forward?

Abstract

Perihilar cholangiocarcinoma (pCCA) is a challenging disease with limited options. Surgical resection and adjuvant therapy remain the only established treatment for those with resectable disease. Since the publication of the Mayo protocol in 2000, neoadjuvant chemoradiation and liver transplantation have become the standard of care in selected patients with unresectable de novo pCCA or resectable pCCA arising under primary sclerosing cholangitis. However, its application is diverse worldwide, and the need for donor organs is one of the main limitations. Also, differences in the neoadjuvant regimen used were observed. In this review, we discuss the latest results of this approach, the recommended tools for diagnostic work-up, and advances in systemic therapy to improve patient selection and long-term survival.

Keywords

Perihilar cholangiocarcinoma / liver transplantation / outcome

References

[1] De Vreede I,Burch PA.Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma.Liver Transpl2000;6:309-16

[2] Sudan D,Chinnakotla S.Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma.Am J Transplant2002;2:774-9

[3] Igami T,Ebata T.Surgical treatment of hilar cholangiocarcinoma in the “new era”: the Nagoya University experience.J Hepatobiliary Pancreat Sci2010;17:449-54

[4] Mansour JC,Crane CH,Nagino M.Hilar cholangiocarcinoma: expert consensus statement.HPB (Oxford)2015;17:691-9 PMCID:PMC4527854

[5] Ruzzenente A,Olthof PB.Perihilar Cholangiocarcinoma Collaboration GroupSurgery for bismuth-corlette type 4 perihilar cholangiocarcinoma: results from a Western Multicenter Collaborative Group.Ann Surg Oncol2021;28:7719-29 PMCID:PMC8519825

[6] Mizuno T,Yokoyama Y.Combined vascular resection for locally advanced perihilar cholangiocarcinoma.Ann Surg2022;275:382-90

[7] Mueller M,Mizuno T.Perihilar cholangiocarcinoma - novel benchmark values for surgical and oncological outcomes from 24 expert centers.Ann Surg2021;274:780-8

[8] Komaya K,Yokoyama Y.Recurrence after curative-intent resection of perihilar cholangiocarcinoma: analysis of a large cohort with a close postoperative follow-up approach.Surgery2018;163:732-8

[9] Groot Koerkamp B,Allen PJ.Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection.J Am Coll Surg2015;221:1041-9 PMCID:PMC4736142

[10] Veeze-Kuijpers B,Lameris JS,van Putten WL.The role of radiotherapy in the treatment of bile duct carcinoma.Int J Radiat Oncol Biol Phys1990;18:63-7

[11] Buskirk SJ,Schild SE,Williams HJJ.Analysis of failure after curative irradiation of extrahepatic bile duct carcinoma.Ann Surg1992;215:125-31 PMCID:PMC1242399

[12] Alden ME.The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer.Int J Radiat Oncol Biol Phys1994;28:945-51

[13] Tan EK,Heimbach JK,Rosen CB.Liver transplantation for peri-hilar cholangiocarcinoma.J Gastrointest Surg2020;24:2679-85

[14] Ricci AD,Brandi G.The DNA damage repair (DDR) pathway in biliary tract cancer (BTC): a new Pandora’s box?.ESMO Open2020;5:e001042 PMCID:PMC7526276

[15] Rizzo A,Brandi G.Durvalumab: an investigational anti-PD-L1 antibody for the treatment of biliary tract cancer.Expert Opin Investig Drugs2021;30:343-50

[16] Oh DY,Lee DW.Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study.Lancet Gastroenterol Hepatol2022;7:522-32

[17] Vogel A,Edeline J.ESMO Guidelines CommitteeElectronic address: [e-mail]. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol2023;34:127-40

[18] Cardinale V,Carpino G.Cholangiocarcinoma: increasing burden of classifications.Hepatobiliary Surg Nutr2013;2:272-80 PMCID:PMC3924690

[19] Jarnagin WR,DeMatteo RP.Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma.Ann Surg2001;234:507-17; discussion 517 PMCID:PMC1422074

[20] Rosen CB,Gores GJ.Liver transplantation for cholangiocarcinoma.Transpl Int2010;23:692-7

[21] Sapisochin G,Lerut J.Liver Transplantation for cholangiocarcinoma and mixed hepatocellular cholangiocarcinoma: working group report from the ILTS Transplant Oncology Consensus Conference.Transplantation2020;104:1125-30

[22] Angsuwatcharakon P,Moon JH.Consensus guidelines on the role of cholangioscopy to diagnose indeterminate biliary stricture.HPB (Oxford)2022;24:17-29

[23] Darwish Murad S,Therneau T.Predictors of pretransplant dropout and posttransplant recurrence in patients with perihilar cholangiocarcinoma.Hepatology2012;56:972-81 PMCID:PMC3830980

[24] Rosen CB,Heimbach JK,Nagorney DM.Neoadjuvant therapy and liver transplantation for hilar cholangiocarcinoma: is pretreatment pathological confirmation of diagnosis necessary?.J Am Coll Surg2012;215:31-8; discussion 38

[25] Hosokawa I,Furukawa K.Preoperative diagnosis of lymph node metastasis of perihilar cholangiocarcinoma using diffusion-weighted magnetic resonance imaging.Ann Surg Oncol2022;29:5502-10

[26] Lopez-Lopez V,de Vicente E.Next-generation three-dimensional modelling software for personalized surgery decision-making in perihilar cholangiocarcinoma: multicentre study.Br J Surg2021;108:e394-5

[27] Arechederra M,Amat I.Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures.Gut2022;71:1141-51 PMCID:PMC9120390

[28] Singhi AD,Chennat J.Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures.Gut2020;69:52-61 PMCID:PMC6943248

[29] Darwish Murad S,Harnois DM.Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.Gastroenterology2012;143:88-98.e3; quiz e14 PMCID:PMC3846443

[30] Ito T,Noguchi D.A 3-Decade, Single-Center Experience of Liver Transplantation for Cholangiocarcinoma: Impact of Era, Tumor Size, Location, and Neoadjuvant Therapy.Liver Transpl2022;28:386-96

[31] Cambridge WA,Powell JJ.Meta-analysis and meta-regression of survival after liver transplantation for unresectable perihilar cholangiocarcinoma.Ann Surg2021;273:240-50

[32] Vatner RE,Vanpouille-Box C,Formenti C.Combinations of immunotherapy and radiation in cancer therapy.Front Oncol2014;4:325 PMCID:PMC4246656

[33] Siddiqui O,Samanta Samanta,Molitoris JK.Proton beam therapy in liver malignancies.Curr Oncol Rep2020;22:30

[34] Mattiucci GC,Tringali A.A Phase I study of high-dose-rate intraluminal brachytherapy as palliative treatment in extrahepatic biliary tract cancer.Brachytherapy2015;14:401-4

[35] Yoshioka K,Oikawa H.Japanese Radiation Oncology Study Group (JROSG). Impact of intraluminal brachytherapy on survival outcome for radiation therapy for unresectable biliary tract cancer: a propensity-score matched-pair analysis.Int J Radiat Oncol Biol Phys2014;89:822-9

[36] Valle J,Palmer DH.ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.N Engl J Med2010;362:1273-81

[37] Okusaka T,Fukutomi A.Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan.Br J Cancer2010;103:469-74 PMCID:PMC2939781

[38] Loveday BPT,Dawson LA.Neoadjuvant hyperfractionated chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma in Canada.J Surg Oncol2018;117:213-9

[39] Abdelrahim M,Esmail A.Gemcitabine and cisplatin as neo-adjuvant for cholangiocarcinoma patients prior to liver transplantation: case-series.Curr Oncol2022;29:3585-94 PMCID:PMC9139862

[40] Banales JM,Lamarca A.Cholangiocarcinoma 2020: the next horizon in mechanisms and management.Nat Rev Gastroenterol Hepatol2020;17:557-88 PMCID:PMC7447603

[41] Valle JW,Nervi B.Biliary tract cancer.Lancet2021;397:428-44

[42] Macias RIR,Kendall TJ.Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions.Gut2022;71:1669-83

[43] McMillan RR,Kodali S.Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma.Am J Transplant2022;22:823-32

[44] Berchuck JE,DiToro DF.The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer.Ann Oncol2022;33:1269-83

[45] Wong M,George B.Downstaging Locally Advanced Cholangiocarcinoma Pre-Liver Transplantation: A Prospective Pilot Study.J Surg Res2019;242:23-30

[46] Mantel HT,Heimbach JK.Vascular complications after orthotopic liver transplantation after neoadjuvant therapy for hilar cholangiocarcinoma.Liver Transpl2007;13:1372-81

[47] Renard R,Couture T.Surgical repair of radiation-induced carotid stenosis.J Vasc Surg2020;72:959-67

[48] Patel DA,Suen AW,Hancock SL.Clinical manifestations of noncoronary atherosclerotic vascular disease after moderate dose irradiation.Cancer2006;106:718-25

[49] Tan EK,Heimbach JK,Zamora-Valdes D.Living donor liver transplantation for perihilar cholangiocarcinoma: outcomes and complications.J Am Coll Surg2020;231:98-110

[50] Rea DJ,Rosen CB.Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma.Ann Surg2005;242:451-8; discussion 458 PMCID:PMC1357753

[51] Ethun CG,Anderson DJ.Transplantation versus resection for hilar cholangiocarcinoma: an argument for shifting treatment paradigms for resectable disease.Ann Surg2018;267:797-805

[52] Machairas N,Prodromidou A.Liver transplantation for hilar cholangiocarcinoma: A systematic review.Transplant Rev (Orlando)2020;34:100516

[53] Wu Y,Rayhill SC.Long-term, tumor-free survival after radiotherapy combining hepatectomy-Whipple en bloc and orthotopic liver transplantation for early-stage hilar cholangiocarcinoma.Liver Transpl2008;14:279-86

[54] Duignan S,Ravichand CS.Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinoma: a single-centre national experience.HPB (Oxford)2014;16:91-8 PMCID:PMC3892320

[55] Welling TH,Wan S.Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma.Liver Transpl2014;20:81-8 PMCID:PMC4185427

[56] Marchan EM.Neoadjuvant chemoradiation followed by orthotopic liver transplantation in cholangiocarcinomas: the emory experience.J Gastrointest Oncol2016;7:248-54 PMCID:PMC4783737

[57] Zaborowski A,Fiore B.Neoadjuvant Chemoradiotherapy and liver transplantation for unresectable hilar cholangiocarcinoma: the irish experience of the mayo protocol.Transplantation2020;104:2097-104

[58] Dopazo C,Fondevila C.Applicability and results of liver transplant combined with neoadjuvant chemo-radiotherapy in the treatment of unresectable hilar cholangiocarcinoma.Cir Esp (Engl Ed)2021;99:190-9

[59] Ahmed O,Chang SH.Single-center experience of liver transplantation for perihilar cholangiocarcinoma.HPB (Oxford)2022;24:461-9

[60] Acher AW,Pawlik TM.Liver transplantation for perihilar cholangiocarcinoma: patient selection and outcomes.Expert Rev Gastroenterol Hepatol2021;15:555-66

[61] Breuer E,Doyle MB.Liver transplantation as a new standard of care in patients with perihilar cholangiocarcinoma?.Ann Surg2022;276:846-53 PMCID:PMC9983747