Skip to main content

Advertisement

SpringerLink
Log in

Progress Toward Improving Outcomes in Patients with Cholangiocarcinoma

  • Pancreas (C Forsmark, Section Editor)
  • Published:
Current Treatment Options in Gastroenterology Aims and scope Submit manuscript

Abstract

Purpose of review

To provide an update on the latest advances in treatment of cholangiocarcinoma.

Recent findings

Incidence of cholangiocarcinoma has been increasing over the past decade. A better understanding of the genetic landscape of cholangiocarcinoma and its risk factors resulted in earlier diagnosis and treatment option expansion to targeted therapy with FGFR inhibitors, and liver transplantation for early perihilar cholangiocarcinoma and early intrahepatic cholangiocarcinoma. IDH1/2 inhibition for intrahepatic cholangiocarcinoma is an emerging targeted therapy approach. Data supports benefits of adjuvant therapy for a subset of patients undergoing surgical resection. Approaches combining different treatment modalities such as chemotherapy, surgery, and radiation therapy appear to be promising.

Summary

Earlier diagnosis and genetic characterization provided additional treatment options for patients with previously incurable cholangiocarcinoma. A precision medicine approach with a focus on actionable genetic alterations and combination of treatment modalities are actively being explored and will further improve outcomes in our patients with cholangiocarcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

CCA:

Cholangiocarcinomas

iCCA:

Intrahepatic CCA

pCCA:

Perihilar CCA

dCCA:

Distal CCA

BTC:

Biliary tract cancers

PSC:

Primary sclerosing cholangitis

HCC:

Hepatocellular carcinoma

CT:

Computed tomography

MRI:

Magnetic resonance imaging

EUS:

Endoscopic ultrasound

ERC:

Endoscopic retrograde cholangiography

PTC:

Percutaneous transhepatic cholangiography

CA 19–9:

Carbohydrate antigen 19–9

IDH1:

Isocitrate dehydrogenase 1

ARID1A:

AT-rich interaction domain 1A

FGFR2:

Fibroblast growth factor receptor 2

EGFR:

Epidermal growth factor receptor

OS:

Overall survival

PVE:

Portal vein embolization

cHCC-CCA:

Combined hepatocellular-cholangiocarcinoma

ALPPS:

Associating liver partition and portal vein ligation for staged hepatectomy

NCCN:

National Comprehensive Cancer Network

AJCC:

American Joint Committee on Cancer

OLT:

Orthotopic liver transplantation

RFA:

Radiofrequency ablation

MWA:

Microwave ablation

TACE:

Transarterial chemoembolization

TARE:

Transarterial radioembolization

HAI:

Hepatic arterial infusion

SBRT:

Stereotactic body radiation therapy

RFS:

Recurrence-free survival

cTACE:

Conventional TACE

PDT:

Photodynamic therapy

PFS:

Progression free survival

BAP1:

BRCA1-associated protein 1

DDR:

DNA damage response

PARP:

The inhibitor poly (adenosine diphosphate-ribose) polymerase

PD-1:

Programmed-death-1

PD-L1:

Programmed-death ligand 1

ORR:

Objective response rate

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Mosconi S, Beretta GD, Labianca R, Zampino MG, Gatta G, Heinemann V. Cholangiocarcinoma. Crit Rev Oncol Hematol. 2009;69(3):259–70. https://doi.org/10.1016/j.critrevonc.2008.09.008.

    Article  PubMed  Google Scholar 

  2. • Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Hepatol. 2020;72(1):95–103. https://doi.org/10.1016/j.jhep.2019.09.007 This is the studydiscussing risk factors for CCA.

    Article  PubMed  Google Scholar 

  3. Yousaf A, Kim JU, Eliahoo J, Taylor-Robinson SD, Khan SA. Ablative therapy for Unresectable intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Clin Exp Hepatol. 2019;9(6):740–8. https://doi.org/10.1016/j.jceh.2019.08.001.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15(2):95–111. https://doi.org/10.1038/nrclinonc.2017.157.

    Article  CAS  PubMed  Google Scholar 

  5. Razumilava N, Gores GJ. Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol. 2013;11(1):13–21.e1; quiz e3–4. https://doi.org/10.1016/j.cgh.2012.09.009.

    Article  PubMed  Google Scholar 

  6. • Oneda E, Abu Hilal M, Zaniboni A. Biliary tract cancer: current medical treatment strategies. Cancers (Basel). 2020;12(5). https://doi.org/10.3390/cancers12051237 This is a comprehensive review on systemic therapy, including trials for CCA.

  7. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383(9935):2168–79. https://doi.org/10.1016/S0140-6736(13)61903-0.

    Article  PubMed  PubMed Central  Google Scholar 

  8. DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245(5):755–62. https://doi.org/10.1097/01.sla.0000251366.62632.d3.

    Article  PubMed  PubMed Central  Google Scholar 

  9. •• Mazzaferro V, Gorgen A, Roayaie S, Droz Dit Busset M, Sapisochin G. Liver resection and transplantation for intrahepatic cholangiocarcinoma. J Hepatol. 2020;72(2):364–77. https://doi.org/10.1016/j.jhep.2019.11.020 This is a review on recent advances in surgical treatment of iCCA.

    Article  PubMed  Google Scholar 

  10. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepato-Biliary-Pancreat Surg. 2003;10(4):288–91. https://doi.org/10.1007/s00534-002-0732-8.

    Article  Google Scholar 

  11. Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol. 2002;37(6):806–13. https://doi.org/10.1016/s0168-8278(02)00297-0.

    Article  PubMed  Google Scholar 

  12. Taylor-Robinson SD, Toledano MB, Arora S, Keegan TJ, Hargreaves S, Beck A, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998. Gut. 2001;48(6):816–20. https://doi.org/10.1136/gut.48.6.816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33(6):1353–7. https://doi.org/10.1053/jhep.2001.25087.

    Article  CAS  PubMed  Google Scholar 

  14. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21(5):594–9. https://doi.org/10.1634/theoncologist.2015-0446.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bertuccio P, Bosetti C, Levi F, Decarli A, Negri E, La Vecchia C. A comparison of trends in mortality from primary liver cancer and intrahepatic cholangiocarcinoma in Europe. Ann Oncol. 2013;24(6):1667–74. https://doi.org/10.1093/annonc/mds652.

    Article  CAS  PubMed  Google Scholar 

  16. Altekruse SF, Petrick JL, Rolin AI, Cuccinelli JE, Zou Z, Tatalovich Z, et al. Geographic variation of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and hepatocellular carcinoma in the United States. PLoS One. 2015;10(3):e0120574. https://doi.org/10.1371/journal.pone.0120574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Soares KC, Kamel I, Cosgrove DP, Herman JM, Pawlik TM. Hilar cholangiocarcinoma: diagnosis, treatment options, and management. Hepatobiliary Surg Nutr. 2014;3(1):18–34. https://doi.org/10.3978/j.issn.2304-3881.2014.02.05.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chi CT, Chau GY, Lee RC, Chen YY, Lei HJ, Hou MC, et al. Radiological features and outcomes of combined hepatocellular-cholangiocarcinoma in patients undergoing surgical resection. J Formos Med Assoc. 2020;119(1 Pt 1):125–33. https://doi.org/10.1016/j.jfma.2019.02.012.

    Article  PubMed  Google Scholar 

  19. Leoni S, Sansone V, Lorenzo S, Ielasi L, Tovoli F, Renzulli M, et al. Treatment of combined hepatocellular and cholangiocarcinoma. Cancers (Basel). 2020;12(4). https://doi.org/10.3390/cancers12040794.

  20. Annunziata S, Caldarella C, Pizzuto DA, Galiandro F, Sadeghi R, Giovanella L, et al. Diagnostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography in the evaluation of the primary tumor in patients with cholangiocarcinoma: a meta-analysis. Biomed Res Int. 2014;2014:247693. https://doi.org/10.1155/2014/247693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Malikowski T, Levy MJ, Gleeson FC, Storm AC, Vargas Valls EJ, Topazian MD, et al. EUS-FNA is effective for lymph node staging in patients with cholangiocarcinoma. Hepatology. 2019. https://doi.org/10.1002/hep.31077.

  22. Xu X, Li L, Zhang XN. Correlation analysis of preoperative magnetic resonance cholangiopancreatography and prognosis in hilar cholangiocarcinoma. Clin Invest Med. 2019;42(4):E14–e21. https://doi.org/10.25011/cim.v42i4.33113.

    Article  CAS  PubMed  Google Scholar 

  23. Eaton JE, Welle CL, Bakhshi Z, Sheedy SP, Idilman IS, Gores GJ, et al. Early cholangiocarcinoma detection with magnetic resonance imaging versus ultrasound in primary sclerosing cholangitis. Hepatology. 2020. https://doi.org/10.1002/hep.31575.

  24. Heimbach JK, Sanchez W, Rosen CB, Gores GJ. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB (Oxford). 2011;13(5):356–60. https://doi.org/10.1111/j.1477-2574.2011.00298.x.

    Article  Google Scholar 

  25. •• Athauda A, Fong C, Lau DK, Javle M, Abou-Alfa GK, Morizane C, et al. Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation. Cancer Treat Rev. 2020;86:101998. https://doi.org/10.1016/j.ctrv.2020.101998 This is a comprehensive review on the molecular targeted therapy and immunotherapy for biliary tract cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003–10. https://doi.org/10.1038/ng.3375.

    Article  CAS  PubMed  Google Scholar 

  27. Lowery MA, Ptashkin R, Jordan E, Berger MF, Zehir A, Capanu M, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res. 2018;24(17):4154–61. https://doi.org/10.1158/1078-0432.Ccr-18-0078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN, Padmanabhan N, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 2017;7(10):1116–35. https://doi.org/10.1158/2159-8290.Cd-17-0368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Montal R, Sia D, Montironi C, Leow WQ, Esteban-Fabró R, Pinyol R, et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol. 2020. https://doi.org/10.1016/j.jhep.2020.03.008.

  30. Machairas N, Lang H, Jayant K, Raptis DA, Sotiropoulos GC. Intrahepatic cholangiocarcinoma: limitations for resectability, current surgical concepts and future perspectives. Eur J Surg Oncol. 2020. https://doi.org/10.1016/j.ejso.2020.01.028.

  31. de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011;29(23):3140–5. https://doi.org/10.1200/jco.2011.35.6519.

    Article  PubMed  Google Scholar 

  32. Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248(1):84–96. https://doi.org/10.1097/SLA.0b013e318176c4d3.

    Article  PubMed  Google Scholar 

  33. Conci S, Ruzzenente A, Vigano L, Ercolani G, Fontana A, Bagante F, et al. Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery. Ann Surg Oncol. 2018;25(12):3719–27. https://doi.org/10.1245/s10434-018-6669-1.

    Article  PubMed  Google Scholar 

  34. Cillo U, Fondevila C, Donadon M, Gringeri E, Mocchegiani F, Schlitt HJ, et al. Surgery for cholangiocarcinoma. Liver Int. 2019;39(Suppl 1):143–55. https://doi.org/10.1111/liv.14089.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Narula N, Aloia TA. Portal vein embolization in extended liver resection. Langenbeck's Arch Surg. 2017;402(5):727–35. https://doi.org/10.1007/s00423-017-1591-8.

    Article  Google Scholar 

  36. Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg. 2006;243(3):364–72. https://doi.org/10.1097/01.sla.0000201482.11876.14.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Baili E, Tsilimigras DI, Filippou D, Ioannidis A, Bakopoulos A, Machairas N, et al. Associating liver partition and portal vein ligation for staged hepatectomy in patients with primary liver malignancies: a systematic review of the literature. J buon. 2019;24(4):1371–81.

    PubMed  Google Scholar 

  38. Schnitzbauer AA, Lang SA, Goessmann H, Nadalin S, Baumgart J, Farkas SA, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg. 2012;255(3):405–14. https://doi.org/10.1097/SLA.0b013e31824856f5.

    Article  PubMed  Google Scholar 

  39. Li J, Moustafa M, Linecker M, Lurje G, Capobianco I, Baumgart J, et al. ALPPS for locally advanced intrahepatic cholangiocarcinoma: did aggressive surgery lead to the oncological benefit? An international multi-center study. Ann Surg Oncol. 2020. https://doi.org/10.1245/s10434-019-08192-z.

  40. Benson AB, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Anaya DA, et al. Guidelines insights: hepatobiliary cancers, version 2.2019. J Natl Compr Cancer Netw. 2019;17(4):302–10. https://doi.org/10.6004/jnccn.2019.0019.

    Article  CAS  Google Scholar 

  41. Ratti F, Cipriani F, Ariotti R, Gagliano A, Paganelli M, Catena M, et al. Safety and feasibility of laparoscopic liver resection with associated lymphadenectomy for intrahepatic cholangiocarcinoma: a propensity score-based case-matched analysis from a single institution. Surg Endosc. 2016;30(5):1999–2010. https://doi.org/10.1007/s00464-015-4430-4.

    Article  PubMed  Google Scholar 

  42. Olthof PB, Aldrighetti L, Alikhanov R, Cescon M, Groot Koerkamp B, Jarnagin WR, et al. Portal vein embolization is associated with reduced liver failure and mortality in high-risk resections for perihilar cholangiocarcinoma. Ann Surg Oncol. 2020. https://doi.org/10.1245/s10434-020-08258-3.

  43. Olthof PB, Coelen RJS, Wiggers JK, Groot Koerkamp B, Malago M, Hernandez-Alejandro R, et al. High mortality after ALPPS for perihilar cholangiocarcinoma: case-control analysis including the first series from the international ALPPS registry. HPB (Oxford). 2017;19(5):381–7. https://doi.org/10.1016/j.hpb.2016.10.008.

    Article  Google Scholar 

  44. Lang H, Baumgart J, Mittler J. Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) registry: what have we learned? Gut Liver. 2020. https://doi.org/10.5009/gnl19233.

  45. Sakamoto Y, Matsumura M, Yamashita S, Ohkura N, Hasegawa K, Kokudo N. Partial TIPE ALPPS for perihilar cancer. Ann Surg. 2018;267(2):e18–20. https://doi.org/10.1097/sla.0000000000002484.

    Article  PubMed  Google Scholar 

  46. Komaya K, Ebata T, Shirai K, Ohira S, Morofuji N, Akutagawa A, et al. Recurrence after resection with curative intent for distal cholangiocarcinoma. Br J Surg. 2017;104(4):426–33. https://doi.org/10.1002/bjs.10452.

    Article  CAS  PubMed  Google Scholar 

  47. Chua TC, Mittal A, Arena J, Sheen A, Gill AJ, Samra JS. Resection margin influences survival after pancreatoduodenectomy for distal cholangiocarcinoma. Am J Surg. 2017;213(6):1072–6. https://doi.org/10.1016/j.amjsurg.2016.09.049.

    Article  PubMed  Google Scholar 

  48. Waseem D, Tushar P. Intrahepatic, perihilar and distal cholangiocarcinoma: management and outcomes. Ann Hepatol. 2017;16(1):133–9. https://doi.org/10.5604/16652681.1226927.

    Article  PubMed  Google Scholar 

  49. Cambridge WA, Fairfield C, Powell JJ, Harrison EM, Soreide K, Wigmore SJ, et al. Meta-analysis and meta-regression of survival after liver transplantation for unresectable perihilar cholangiocarcinoma. Ann Surg. 2020. https://doi.org/10.1097/SLA.0000000000003801.

  50. Abreu P, Gorgen A, Oldani G, Hibi T, Sapisochin G. Recent advances in liver transplantation for cancer: the future of transplant oncology. J HEP Rep. 2019;1(5):377–91. https://doi.org/10.1016/j.jhepr.2019.07.004.

    Article  Google Scholar 

  51. Tan EK, Rosen CB, Heimbach JK, Gores GJ, Zamora-Valdes D, Taner T. Living donor liver transplantation for perihilar cholangiocarcinoma: outcomes and complication. J Am Coll Surg. 2020. https://doi.org/10.1016/j.jamcollsurg.2019.12.037.

  52. Lee DD, Croome KP, Musto KR, Melendez J, Tranesh G, Nakhleh R, et al. Liver transplantation for intrahepatic cholangiocarcinoma. Liver Transpl. 2018;24(5):634–44. https://doi.org/10.1002/lt.25052.

    Article  PubMed  Google Scholar 

  53. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation. 2000;69(8):1633–7. https://doi.org/10.1097/00007890-200004270-00019.

    Article  CAS  PubMed  Google Scholar 

  54. •• Zamora-Valdes D, Heimbach JK. Liver transplant for cholangiocarcinoma. Gastroenterol Clin N Am. 2018;47(2):267–80. https://doi.org/10.1016/j.gtc.2018.01.002 This article discusses outcomes of liver transplantation for pCCA and iCCA.

    Article  Google Scholar 

  55. Sapisochin G, Facciuto M, Rubbia-Brandt L, Marti J, Mehta N, Yao FY, et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology. 2016;64(4):1178–88. https://doi.org/10.1002/hep.28744.

    Article  CAS  PubMed  Google Scholar 

  56. Facciuto ME, Singh MK, Lubezky N, Selim MA, Robinson D, Kim-Schluger L, et al. Tumors with intrahepatic bile duct differentiation in cirrhosis: implications on outcomes after liver transplantation. Transplantation. 2015;99(1):151–7. https://doi.org/10.1097/tp.0000000000000286.

    Article  PubMed  Google Scholar 

  57. Sapisochin G, Rodríguez de Lope C, Gastaca M, Ortiz de Urbina J, Suarez MA, Santoyo J, et al. “Very early” intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am J Transplant. 2014;14(3):660–7. https://doi.org/10.1111/ajt.12591.

    Article  CAS  PubMed  Google Scholar 

  58. Koay EJ, Odisio BC, Javle M, Vauthey JN, Crane CH. Management of unresectable intrahepatic cholangiocarcinoma: how do we decide among the various liver-directed treatments? Hepatobiliary Surg Nutr. 2017;6(2):105–16. https://doi.org/10.21037/hbsn.2017.01.16.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Currie BM, Soulen MC. Decision making: intra-arterial therapies for cholangiocarcinoma-TACE and TARE. Semin Interv Radiol. 2017;34(2):92–100. https://doi.org/10.1055/s-0037-1602591.

    Article  Google Scholar 

  60. Zhang SJ, Hu P, Wang N, Shen Q, Sun AX, Kuang M, et al. Thermal ablation versus repeated hepatic resection for recurrent intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2013;20(11):3596–602. https://doi.org/10.1245/s10434-013-3035-1.

    Article  PubMed  Google Scholar 

  61. Izzo F, Granata V, Grassi R, Fusco R, Palaia R, Delrio P, et al. Radiofrequency ablation and microwave ablation in liver tumors: an update. Oncologist. 2019;24(10):e990–e1005. https://doi.org/10.1634/theoncologist.2018-0337.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Xu C, Li L, Xu W, Du C, Yang L, Tong J, et al. Ultrasound-guided percutaneous microwave ablation versus surgical resection for recurrent intrahepatic cholangiocarcinoma: intermediate-term results. Int J Hyperth. 2019;36(1):351–8. https://doi.org/10.1080/02656736.2019.1571247.

    Article  CAS  Google Scholar 

  63. Yang J, Wang J, Zhou H, Zhou Y, Wang Y, Jin H, et al. Efficacy and safety of endoscopic radiofrequency ablation for unresectable extrahepatic cholangiocarcinoma: a randomized trial. Endoscopy. 2018;50(8):751–60. https://doi.org/10.1055/s-0043-124870.

    Article  PubMed  Google Scholar 

  64. Tsurusaki M, Murakami T. Surgical and locoregional therapy of HCC: TACE. Liver Cancer. 2015;4(3):165–75. https://doi.org/10.1159/000367739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Park SY, Kim JH, Yoon HJ, Lee IS, Yoon HK, Kim KP. Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma. Clin Radiol. 2011;66(4):322–8. https://doi.org/10.1016/j.crad.2010.11.002.

    Article  PubMed  Google Scholar 

  66. Kuhlmann JB, Euringer W, Spangenberg HC, Breidert M, Blum HE, Harder J, et al. Treatment of unresectable cholangiocarcinoma: conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy. Eur J Gastroenterol Hepatol. 2012;24(4):437–43. https://doi.org/10.1097/MEG.0b013e3283502241.

    Article  CAS  PubMed  Google Scholar 

  67. Lv WF, Lu D, He YS, Xiao JK, Zhou CZ, Cheng DL. Liver abscess formation following transarterial chemoembolization: clinical features, risk factors, bacteria spectrum, and percutaneous catheter drainage. Medicine (Baltimore). 2016;95(17):e3503. https://doi.org/10.1097/md.0000000000003503.

    Article  CAS  Google Scholar 

  68. Najran P, Lamarca A, Mullan D, McNamara MG, Westwood T, Hubner RA, et al. Update on treatment options for advanced bile duct tumours: radioembolisation for advanced cholangiocarcinoma. Curr Oncol Rep. 2017;19(7):50. https://doi.org/10.1007/s11912-017-0603-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Al-Adra DP, Gill RS, Axford SJ, Shi X, Kneteman N, Liau SS. Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis. Eur J Surg Oncol. 2015;41(1):120–7. https://doi.org/10.1016/j.ejso.2014.09.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kohler M, Harders F, Lohofer F, Paprottka PM, Schaarschmidt BM, Theysohn J, et al. Prognostic factors for overall survival in advanced intrahepatic cholangiocarcinoma treated with Yttrium-90 radioembolization. J Clin Med. 2019;9(1). https://doi.org/10.3390/jcm9010056.

  71. Zervoudakis A, Boucher T, Kemeny NE. Treatment options in colorectal liver metastases: hepatic arterial infusion. Visc Med. 2017;33(1):47–53. https://doi.org/10.1159/000454693.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Cercek A, Boerner T, Tan BR, Chou JF, Gönen M, Boucher TM, et al. Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2019;6(1):60–7. https://doi.org/10.1001/jamaoncol.2019.3718.

    Article  PubMed Central  Google Scholar 

  73. Higaki T, Aramaki O, Moriguchi M, Nakayama H, Midorikawa Y, Takayama T. Arterial infusion of cisplatin plus S-1 against unresectable intrahepatic cholangiocarcinoma. Biosci Trends. 2018;12(1):73–8. https://doi.org/10.5582/bst.2017.01320.

    Article  CAS  PubMed  Google Scholar 

  74. Wang X, Hu J, Cao G, Zhu X, Cui Y, Ji X, et al. Phase II study of hepatic arterial infusion chemotherapy with oxaliplatin and 5-fluorouracil for advanced perihilar cholangiocarcinoma. Radiology. 2017;283(2):580–9. https://doi.org/10.1148/radiol.2016160572.

    Article  PubMed  Google Scholar 

  75. Frakulli R, Buwenge M, Macchia G, Cammelli S, Deodato F, Cilla S, et al. Stereotactic body radiation therapy in cholangiocarcinoma: a systematic review. Br J Radiol. 2019;92(1097):20180688. https://doi.org/10.1259/bjr.20180688.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Pereira SP, Jitlal M, Duggan M, Lawrie E, Beare S, O'Donoghue P, et al. PHOTOSTENT-02: porfimer sodium photodynamic therapy plus stenting versus stenting alone in patients with locally advanced or metastatic biliary tract cancer. ESMO Open. 2018;3(5):e000379. https://doi.org/10.1136/esmoopen-2018-000379.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81. https://doi.org/10.1056/NEJMoa0908721.

    Article  CAS  PubMed  Google Scholar 

  78. Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al. ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol. 2019;37(15_suppl):4003. https://doi.org/10.1200/JCO.2019.37.15_suppl.4003.

    Article  Google Scholar 

  79. Tella SH, Kommalapati A, Borad MJ, Mahipal A. Second-line therapies in advanced biliary tract cancers. Lancet Oncol. 2020;21(1):e29–41. https://doi.org/10.1016/S1470-2045(19)30733-8.

    Article  CAS  PubMed  Google Scholar 

  80. Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663–73. https://doi.org/10.1016/S1470-2045(18)30915-X.

    Article  CAS  PubMed  Google Scholar 

  81. Lamarca A, Ross P, Wasan HS, Hubner RA, McNamara MG, Lopes A, et al. Advanced intrahepatic cholangiocarcinoma: post hoc analysis of the ABC-01, −02, and −03 clinical trials. J Natl Cancer Inst. 2020;112(2):200–10. https://doi.org/10.1093/jnci/djz071.

    Article  PubMed  Google Scholar 

  82. Nakachi K, Konishi M, Ikeda M, Mizusawa J, Eba J, Okusaka T, et al. A randomized phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan clinical oncology group study (JCOG1202, ASCOT). Jpn J Clin Oncol. 2018;48(4):392–5. https://doi.org/10.1093/jjco/hyy004.

    Article  PubMed  Google Scholar 

  83. Phelip JM, Edeline J, Blanc JF, Barbier E, Michel P, Bourgeois V, et al. Modified FOLFIRINOX versus CisGem first-line chemotherapy for locally advanced non resectable or metastatic biliary tract cancer (AMEBICA)-PRODIGE 38: study protocol for a randomized controlled multicenter phase II/III study. Dig Liver Dis. 2019;51(2):318–20. https://doi.org/10.1016/j.dld.2018.11.018.

    Article  CAS  PubMed  Google Scholar 

  84. Perkhofer L, Berger AW, Beutel AK, Gallmeier E, Angermeier S, Fischer, et al. Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study. BMC Cancer. 2019;19(1):990. https://doi.org/10.1186/s12885-019-6142-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. •• Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671–84. https://doi.org/10.1016/s1470-2045(20)30109-1 This is the study that demonstrated benefits of targeting FGRF2 derangments in patient with CCA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hoy SM. Pemigatinib: first approval. Drugs. 2020;80(9):923–9. https://doi.org/10.1007/s40265-020-01330-y.

    Article  PubMed  Google Scholar 

  87. Cao J, Hu J, Liu S, Meric-Bernstam F, Abdel-Wahab R, Xu J, et al. Intrahepatic cholangiocarcinoma: genomic heterogeneity between eastern and Western patients. JCO Precision Oncol. 2020:557–69. https://doi.org/10.1200/PO.18.00414.

  88. Mazzaferro V, El-Rayes BF, Droz Dit Busset M, Cotsoglou C, Harris WP, Damjanov N, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120(2):165–71. https://doi.org/10.1038/s41416-018-0334-0.

    Article  CAS  PubMed  Google Scholar 

  89. Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36(3):276–82. https://doi.org/10.1200/jco.2017.75.5009.

    Article  CAS  PubMed  Google Scholar 

  90. •• O'Rourke CJ, Munoz-Garrido P, Andersen JB. Molecular targets in cholangiocarcinoma. Hepatology. 2020. https://doi.org/10.1002/hep.31278 This is a review of the therapeutic potential of different classes of molecular targets in CCA.

  91. •• Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796–807. https://doi.org/10.1016/s1470-2045(20)30157-1 This is the study that demonstrated benefits of targeting IDH1 mutations in patient with CCA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chen XX, Yin Y, Cheng JW, Huang A, Hu B, Zhang X, et al. BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways. Cell Death Dis. 2018;9(10):1036. https://doi.org/10.1038/s41419-018-1087-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Moeini A, Sia D, Bardeesy N, Mazzaferro V, Llovet JM. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin Cancer Res. 2016;22(2):291–300. https://doi.org/10.1158/1078-0432.Ccr-14-3296.

    Article  PubMed  Google Scholar 

  94. Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013;45(12):1470–3. https://doi.org/10.1038/ng.2813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. George TJ, DeRemer DL, Parekh HD, Lee J-H, Markham MJ, Daily KC, et al. Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma. J Clin Oncol. 2020;38(4_suppl):TPS591-TPS. https://doi.org/10.1200/JCO.2020.38.4_suppl.TPS591.

    Article  Google Scholar 

  96. Jakubowski CD, Azad NS. Immune checkpoint inhibitor therapy in biliary tract cancer (cholangiocarcinoma). Chin Clin Oncol. 2020;9(1):2. https://doi.org/10.21037/cco.2019.12.10.

    Article  PubMed  Google Scholar 

  97. Kriegsmann M, Roessler S, Kriegsmann K, Renner M, Longuespée R, Albrecht T, et al. Programmed cell death ligand 1 (PD-L1, CD274) in cholangiocarcinoma - correlation with clinicopathological data and comparison of antibodies. BMC Cancer. 2019;19(1):72. https://doi.org/10.1186/s12885-018-5254-0.

    Article  PubMed  PubMed Central  Google Scholar 

  98. • Piha-Paul SA, Oh DY, Ueno M, Malka D, Chung HC, Nagrial A, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020. https://doi.org/10.1002/ijc.33013 This article discusses efficacy and safety of immunotherapy for patients with biliary cancers.

  99. Arkenau HT, Martin-Liberal J, Calvo E, Penel N, Krebs MG, Herbst RS, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced or metastatic biliary tract cancer: nonrandomized, open-label, phase I trial (JVDF). Oncologist. 2018;23(12):1407–e136. https://doi.org/10.1634/theoncologist.2018-0044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lin J, Shi W, Zhao S, Hu J, Hou Z, Yao M, et al. Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): preliminary data and correlation with next-generation sequencing. J Clin Oncol. 2018;36(4_suppl):500. https://doi.org/10.1200/JCO.2018.36.4_suppl.500.

    Article  Google Scholar 

Download references

Funding

This work was supported by NIDDK K08 (DK122114-01; NR); Gilead Research Scholar Award (NR).

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    Hiroko Kawasaki MD & Yuko Akazawa MD

  2. Department of Internal Medicine, University of Michigan, 109 Zina Pitcher Pl., BSRB, 2062, Ann Arbor, MI, 48109, USA

    Nataliya Razumilava MD

Authors
  1. Hiroko Kawasaki MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuko Akazawa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nataliya Razumilava MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nataliya Razumilava MD.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Pancreas

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawasaki, H., Akazawa, Y. & Razumilava, N. Progress Toward Improving Outcomes in Patients with Cholangiocarcinoma. Curr Treat Options Gastro 19, 153–168 (2021). https://doi.org/10.1007/s11938-021-00333-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11938-021-00333-2

Keywords

Search

Navigation