Langenbeck's Archives of Surgery

, Volume 399, Issue 6, pp 679–692 | Cite as

Multimodal treatment strategies for advanced hilar cholangiocarcinoma

  • Matthew J. Weiss
  • David Cosgrove
  • Joseph M. Herman
  • Neda Rastegar
  • Ihab Kamel
  • Timothy M. Pawlik
Review Article


Cholangiocarcinoma (CCA) is the second most common primary malignancy of the liver arising from malignant transformation and growth of biliary ductal epithelium. Approximately 50–70 % of CCAs arise at the hilar plate of the biliary tree, which are termed hilar cholangiocarcinoma (HC). Various staging systems are currently employed to classify HCs and determine resectability. Depending on the pre-operative staging, the mainstays of treatment include surgery, chemotherapy, radiation therapy, and photodynamic therapy. Surgical resection offers the only chance for cure of HC and achieving an R0 resection has demonstrated improved overall survival. However, obtaining longitudinal and radial surgical margins that are free of tumor can be difficult and frequently requires extensive resections, particularly for advanced HCs. Pre-operative interventions may be necessary to prepare patients for major hepatic resections, including endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, and portal vein embolization. Multimodal therapy that combines chemotherapy with external beam radiation, stereotactic body radiation therapy, bile duct brachytherapy, and/or photodynamic therapy are all possible strategies for advanced HC prior to resection. Orthotopic liver transplantation is another therapeutic option that can achieve complete extirpation of locally advanced HC in judiciously selected patients following standardized neoadjuvant protocols.


Cholangiocarcinoma Hilar Biliary neoplasm Multimodal treatment 


  1. 1.
    Altemeier WA, Gall EA, Zinninger MM, Hoxworth PI (1957) Sclerosing carcinoma of the major intrahepatic bile ducts. AMA Arch Surg 75(3):450–460, discussion 60–1PubMedCrossRefGoogle Scholar
  2. 2.
    Klatskin G (1965) Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis. an unusual tumor with distinctive clinical and pathological features. Am J Med 38:241–256PubMedCrossRefGoogle Scholar
  3. 3.
    Ramia JM (2013) Hilar cholangiocarcinoma. World J Gastrointest Oncol 5(7):113–114PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Suarez-Munoz MA, Fernandez-Aguilar JL, Sanchez-Perez B, Perez-Daga JA, Garcia-Albiach B, Pulido-Roa Y et al (2013) Risk factors and classifications of hilar cholangiocarcinoma. World J Gastrointest Oncol 5(7):132–138PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Welzel TM, McGlynn KA, Hsing AW, O’Brien TR, Pfeiffer RM (2006) Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst 98(12):873–875PubMedCrossRefGoogle Scholar
  6. 6.
    Choi JY, Kim MJ, Lee JM, Kim KW, Lee JY, Han JK et al (2008) Hilar cholangiocarcinoma: role of preoperative imaging with sonography, MDCT, MRI, and direct cholangiography. AJR Am J Roentgenol 191(5):1448–1457PubMedCrossRefGoogle Scholar
  7. 7.
    Ruys AT, van Beem BE, Engelbrecht MR, Bipat S, Stoker J, Van Gulik TM (2012) Radiological staging in patients with hilar cholangiocarcinoma: a systematic review and meta-analysis. Br J Radiol 85(1017):1255–1262PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Cho MS, Kim SH, Park SW, Lim JH, Choi GH, Park JS et al (2012) Surgical outcomes and predicting factors of curative resection in patients with hilar cholangiocarcinoma: 10-year single-institution experience. J Gastrointest Surg 16(9):1672–1679PubMedCrossRefGoogle Scholar
  9. 9.
    Nuzzo G, Giuliante F, Ardito F, Giovannini I, Aldrighetti L, Belli G et al (2012) Improvement in perioperative and long-term outcome after surgical treatment of hilar cholangiocarcinoma: results of an Italian multicenter analysis of 440 patients. Arch Surg 147(1):26–34PubMedCrossRefGoogle Scholar
  10. 10.
    Kobayashi A, Miwa S, Nakata T, Miyagawa S (2010) Disease recurrence patterns after R0 resection of hilar cholangiocarcinoma. Br J Surg 97(1):56–64PubMedCrossRefGoogle Scholar
  11. 11.
    Jarnagin WR, Ruo L, Little SA, Klimstra D, D’Angelica M, DeMatteo RP et al (2003) Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer 98(8):1689–1700PubMedCrossRefGoogle Scholar
  12. 12.
    Cannon RM, Brock G, Buell JF (2012) Surgical resection for hilar cholangiocarcinoma: experience improves resectability. HPB 14(2):142–149PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Saxena A, Chua TC, Chu FC, Morris DL (2011) Improved outcomes after aggressive surgical resection of hilar cholangiocarcinoma: a critical analysis of recurrence and survival. Am J Surg 202(3):310–320PubMedCrossRefGoogle Scholar
  14. 14.
    Are C, Gonen M, D’Angelica M, DeMatteo RP, Fong Y, Blumgart LH et al (2006) Differential diagnosis of proximal biliary obstruction. Surgery 140(5):756–763PubMedCrossRefGoogle Scholar
  15. 15.
    Corvera CU, Blumgart LH, Darvishian F, Klimstra DS, DeMatteo R, Fong Y et al (2005) Clinical and pathologic features of proximal biliary strictures masquerading as hilar cholangiocarcinoma. J Am Coll Surg 201(6):862–869PubMedCrossRefGoogle Scholar
  16. 16.
    Gerhards MF, Vos P, van Gulik TM, Rauws EA, Bosma A, Gouma DJ (2001) Incidence of benign lesions in patients resected for suspicious hilar obstruction. Br J Surg 88(1):48–51PubMedCrossRefGoogle Scholar
  17. 17.
    Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA et al (2007) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case–control study. Clin Gastroenterol Hepatol 5(10):1221–1228PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Choi D, Lim JH, Lee KT, Lee JK, Choi SH, Heo JS et al (2006) Cholangiocarcinoma and Clonorchis sinensis infection: a case–control study in Korea. J Hepatol 44(6):1066–1073PubMedCrossRefGoogle Scholar
  19. 19.
    Parkin DM, Srivatanakul P, Khlat M, Chenvidhya D, Chotiwan P, Insiripong S et al (1991) Liver cancer in Thailand. I. A case–control study of cholangiocarcinoma. Int J Cancer 48(3):323–328PubMedCrossRefGoogle Scholar
  20. 20.
    Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ (2000) The utility of CA 19–9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol 95(1):204–207PubMedCrossRefGoogle Scholar
  21. 21.
    Juntermanns B, Radunz S, Heuer M, Hertel S, Reis H, Neuhaus JP et al (2010) Tumor markers as a diagnostic key for hilar cholangiocarcinoma. Eur J Med Res 15(8):357–361PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Park MS, Kim TK, Kim KW, Park SW, Lee JK, Kim JS et al (2004) Differentiation of extrahepatic bile duct cholangiocarcinoma from benign stricture: findings at MRCP versus ERCP. Radiology 233(1):234–240PubMedCrossRefGoogle Scholar
  23. 23.
    Silva MA, Tekin K, Aytekin F, Bramhall SR, Buckels JA, Mirza DF (2005) Surgery for hilar cholangiocarcinoma; a 10 year experience of a tertiary referral centre in the UK. Eur J Surg Oncol 31(5):533–539PubMedCrossRefGoogle Scholar
  24. 24.
    Ponchon T, Gagnon P, Berger F, Labadie M, Liaras A, Chavaillon A et al (1995) Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc 42(6):565–572PubMedCrossRefGoogle Scholar
  25. 25.
    Sugiyama M, Atomi Y, Wada N, Kuroda A, Muto T (1996) Endoscopic transpapillary bile duct biopsy without sphincterotomy for diagnosing biliary strictures: a prospective comparative study with bile and brush cytology. Am J Gastroenterol 91(3):465–467PubMedGoogle Scholar
  26. 26.
    Kubota Y, Takaoka M, Tani K, Ogura M, Kin H, Fujimura K et al (1993) Endoscopic transpapillary biopsy for diagnosis of patients with pancreaticobiliary ductal strictures. Am J Gastroenterol 88(10):1700–1704PubMedGoogle Scholar
  27. 27.
    Tamada K, Tomiyama T, Wada S, Ohashi A, Satoh Y, Ido K et al (2002) Endoscopic transpapillary bile duct biopsy with the combination of intraductal ultrasonography in the diagnosis of biliary strictures. Gut 50(3):326–331PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Domagk D, Poremba C, Dietl KH, Senninger N, Heinecke A, Domschke W et al (2002) Endoscopic transpapillary biopsies and intraductal ultrasonography in the diagnostics of bile duct strictures: a prospective study. Gut 51(2):240–244PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Farrell RJ, Agarwal B, Brandwein SL, Underhill J, Chuttani R, Pleskow DK (2002) Intraductal US is a useful adjunct to ERCP for distinguishing malignant from benign biliary strictures. Gastrointest Endosc 56(5):681–687PubMedCrossRefGoogle Scholar
  30. 30.
    Lee JH, Salem R, Aslanian H, Chacho M, Topazian M (2004) Endoscopic ultrasound and fine-needle aspiration of unexplained bile duct strictures. Am J Gastroenterol 99(6):1069–1073PubMedCrossRefGoogle Scholar
  31. 31.
    Eloubeidi MA, Chen VK, Jhala NC, Eltoum IE, Jhala D, Chhieng DC et al (2004) Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma. Clin Gastroenterol Hepatol 2(3):209–213PubMedCrossRefGoogle Scholar
  32. 32.
    Byrne MF, Gerke H, Mitchell RM, Stiffler HL, McGrath K, Branch MS et al (2004) Yield of endoscopic ultrasound-guided fine-needle aspiration of bile duct lesions. Endoscopy 36(8):715–719PubMedCrossRefGoogle Scholar
  33. 33.
    Heimbach JK, Sanchez W, Rosen CB, Gores GJ (2011) Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB 13(5):356–360PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Choi ER, Chung YH, Lee JK, Lee KT, Lee KH, Choi DW et al (2011) Preoperative evaluation of the longitudinal extent of borderline resectable hilar cholangiocarcinoma by intraductal ultrasonography. J Gastroenterol Hepatol 26(12):1804–1810PubMedCrossRefGoogle Scholar
  35. 35.
    Watadani T, Akahane M, Yoshikawa T, Ohtomo K (2008) Preoperative assessment of hilar cholangiocarcinoma using multidetector-row CT: correlation with histopathological findings. Radiat Med 26(7):402–407PubMedCrossRefGoogle Scholar
  36. 36.
    Aloia TA, Charnsangavej C, Faria S, Ribero D, Abdalla EK, Vauthey JN et al (2007) High-resolution computed tomography accurately predicts resectability in hilar cholangiocarcinoma. Am J Surg 193(6):702–706PubMedCrossRefGoogle Scholar
  37. 37.
    Cha JH, Han JK, Kim TK, Kim AY, Park SJ, Choi BI et al (2000) Preoperative evaluation of Klatskin tumor: accuracy of spiral CT in determining vascular invasion as a sign of unresectability. Abdom Imaging 25(5):500–507PubMedCrossRefGoogle Scholar
  38. 38.
    Chen HW, Lai EC, Pan AZ, Chen T, Liao S, Lau WY (2009) Preoperative assessment and staging of hilar cholangiocarcinoma with 16-multidetector computed tomography cholangiography and angiography. Hepato-Gastroenterology 56(91–92):578–583PubMedGoogle Scholar
  39. 39.
    Sai JK, Suyama M, Kubokawa Y, Watanabe S, Maehara T (2009) Early detection of extrahepatic bile-duct carcinomas in the nonicteric stage by using MRCP followed by EUS. Gastrointest Endosc 70(1):29–36PubMedCrossRefGoogle Scholar
  40. 40.
    Cherqui D, Benoist S, Malassagne B, Humeres R, Rodriguez V, Fagniez PL (2000) Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg 135(3):302–308PubMedCrossRefGoogle Scholar
  41. 41.
    Farges O, Regimbeau JM, Fuks D, Le Treut YP, Cherqui D, Bachellier P et al (2013) Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg 100(2):274–283PubMedCrossRefGoogle Scholar
  42. 42.
    Grandadam S, Compagnon P, Arnaud A, Olivie D, Malledant Y, Meunier B et al (2010) Role of preoperative optimization of the liver for resection in patients with hilar cholangiocarcinoma type III. Ann Surg Oncol 17(12):3155–3161PubMedCrossRefGoogle Scholar
  43. 43.
    Tsai HM, Chuang CH, Lin XZ, Chen CY (2009) Factors relating to the short term effectiveness of percutaneous biliary drainage for hilar cholangiocarcinoma. World J Gastroenterol 15(41):5206–5210PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Young AL, Igami T, Senda Y, Adair R, Farid S, Toogood GJ et al (2011) Evolution of the surgical management of perihilar cholangiocarcinoma in a Western centre demonstrates improved survival with endoscopic biliary drainage and reduced use of blood transfusion. HPB 13(7):483–493PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Belghiti J, Ogata S (2005) Preoperative optimization of the liver for resection in patients with hilar cholangiocarcinoma. HPB 7(4):252–253PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Lai EC, Chu KM, Lo CY, Mok FP, Fan ST, Lo CM et al (1992) Surgery for malignant obstructive jaundice: analysis of mortality. Surgery 112(5):891–896PubMedGoogle Scholar
  47. 47.
    Clements WD, Diamond T, McCrory DC, Rowlands BJ (1993) Biliary drainage in obstructive jaundice: experimental and clinical aspects. Br J Surg 80(7):834–842PubMedCrossRefGoogle Scholar
  48. 48.
    Makino H, Shimizu H, Ito H, Kimura F, Ambiru S, Togawa A et al (2006) Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy. World J Gastroenterol 12(13):2053–2059PubMedGoogle Scholar
  49. 49.
    Yamano T, Hirai R, Hato S, Uemura T, Shimizu N (2002) Delayed liver regeneration with negative regulation of hepatocyte growth factor and positive regulation of transforming growth factor-beta1 mRNA after portal branch ligation in biliary obstructed rats. Surgery 131(2):163–171PubMedCrossRefGoogle Scholar
  50. 50.
    Kennedy TJ, Yopp A, Qin Y, Zhao B, Guo P, Liu F et al (2009) Role of preoperative biliary drainage of liver remnant prior to extended liver resection for hilar cholangiocarcinoma. HPB 11(5):445–451PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Yokoyama Y, Nagino M, Nishio H, Ebata T, Igami T, Nimura Y (2007) Recent advances in the treatment of hilar cholangiocarcinoma: portal vein embolization. J Hepato-Biliary-Pancreat Surg 14(5):447–454CrossRefGoogle Scholar
  52. 52.
    Farges O, Belghiti J, Kianmanesh R, Regimbeau JM, Santoro R, Vilgrain V et al (2003) Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 237(2):208–217PubMedCentralPubMedGoogle Scholar
  53. 53.
    Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN (2002) Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 137(6):675–680, discussion 80–1PubMedCrossRefGoogle Scholar
  54. 54.
    Makuuchi M, Thai BL, Takayasu K, Takayama T, Kosuge T, Gunven P et al (1990) Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 107(5):521–527PubMedGoogle Scholar
  55. 55.
    Hemming AW, Reed AI, Howard RJ, Fujita S, Hochwald SN, Caridi JG et al (2003) Preoperative portal vein embolization for extended hepatectomy. Ann Surg 237(5):686–691, discussion 91–3PubMedCentralPubMedGoogle Scholar
  56. 56.
    van Lienden KP, van den Esschert JW, de Graaf W, Bipat S, Lameris JS, van Gulik TM et al (2013) Portal vein embolization before liver resection: a systematic review. Cardiovasc Intervent Radiol 36(1):25–34PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Yi B, Xu AM, Lai EC, Qu ZQ, Cheng QB, Liu C et al (2010) Preoperative portal vein embolization for hilar cholangiocarcinoma—a comparative study. Hepato-Gastroenterology 57(104):1341–1346PubMedGoogle Scholar
  58. 58.
    Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y (2006) Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 243(3):364–372PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Ribero D, Abdalla EK, Madoff DC, Donadon M, Loyer EM, Vauthey JN (2007) Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome. Br J Surg 94(11):1386–1394PubMedCrossRefGoogle Scholar
  60. 60.
    Bismuth H, Nakache R, Diamond T (1992) Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 215(1):31–38PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Paul A, Kaiser GM, Molmenti EP, Schroeder T, Vernadakis S, Oezcelik A et al (2011) Klatskin tumors and the accuracy of the Bismuth-Corlette classification. Am Surg 77(12):1695–1699PubMedGoogle Scholar
  62. 62.
    Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ et al (2001) Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234(4):507–517, discussion 17–9PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Matsuo K, Rocha FG, Ito K, D’Angelica MI, Allen PJ, Fong Y et al (2012) The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am Coll Surg 215(3):343–355PubMedCrossRefGoogle Scholar
  64. 64.
    Burke EC, Jarnagin WR, Hochwald SN, Pisters PW, Fong Y, Blumgart LH (1998) Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 228(3):385–394PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Deoliveira ML, Schulick RD, Nimura Y, Rosen C, Gores G, Neuhaus P et al (2011) New staging system and a registry for perihilar cholangiocarcinoma. Hepatology 53(4):1363–1371PubMedCrossRefGoogle Scholar
  66. 66.
    Parikh AA, Abdalla EK, Vauthey JN (2005) Operative considerations in resection of hilar cholangiocarcinoma. HPB 7(4):254–258PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Ruys AT, Busch OR, Gouma DJ, van Gulik TM (2012) Staging laparoscopy for hilar cholangiocarcinoma: is it still worthwhile? Indian J Surg Oncol 3(2):147–153PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Connor S, Barron E, Wigmore SJ, Madhavan KK, Parks RW, Garden OJ (2005) The utility of laparoscopic assessment in the preoperative staging of suspected hilar cholangiocarcinoma. J Gastrointest Surg 9(4):476–480PubMedCrossRefGoogle Scholar
  69. 69.
    Weber SM, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR (2002) Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg 235(3):392–399PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Barlow AD, Garcea G, Berry DP, Rajesh A, Patel R, Metcalfe MS et al (2013) Staging laparoscopy for hilar cholangiocarcinoma in 100 patients. Langenbecks Arch Surg/Deutsche Gesellschaft fur Chirurgie 398(7):983–988CrossRefGoogle Scholar
  71. 71.
    Zheng-Rong L, Hai-Bo Y, Xin C, Chuan-Xin W, Zuo-Jin L, Bing T et al (2011) Resection and drainage of hilar cholangiocarcinoma: an 11-year experience of a single center in mainland China. Am Surg 77(5):627–633PubMedGoogle Scholar
  72. 72.
    Schiffman SC, Reuter NP, McMasters KM, Scoggins CR, Martin RC (2012) Overall survival peri-hilar cholangiocarcinoma: R1 resection with curative intent compared to primary endoscopic therapy. J Surg Oncol 105(1):91–96PubMedCrossRefGoogle Scholar
  73. 73.
    Rocha FG, Matsuo K, Blumgart LH, Jarnagin WR (2010) Hilar cholangiocarcinoma: the Memorial Sloan-Kettering Cancer Center experience. J Hepato-Biliary-Pancreat Sci 17(4):490–496CrossRefGoogle Scholar
  74. 74.
    Miyazaki M, Ito H, Nakagawa K, Ambiru S, Shimizu H, Shimizu Y et al (1998) Aggressive surgical approaches to hilar cholangiocarcinoma: hepatic or local resection? Surgery 123(2):131–136PubMedCrossRefGoogle Scholar
  75. 75.
    de Jong MC, Marques H, Clary BM, Bauer TW, Marsh JW, Ribero D et al (2012) The impact of portal vein resection on outcomes for hilar cholangiocarcinoma: a multi-institutional analysis of 305 cases. Cancer 118(19):4737–4747PubMedCrossRefGoogle Scholar
  76. 76.
    Ikeyama T, Nagino M, Oda K, Ebata T, Nishio H, Nimura Y (2007) Surgical approach to Bismuth type I and II hilar cholangiocarcinomas: audit of 54 consecutive cases. Ann Surg 246(6):1052–1057PubMedCrossRefGoogle Scholar
  77. 77.
    Neuhaus P, Jonas S, Settmacher U, Thelen A, Benckert C, Lopez-Hanninen E et al (2003) Surgical management of proximal bile duct cancer: extended right lobe resection increases resectability and radicality. Langenbecks Arch Surg/Deutsche Gesellschaft fur Chirurgie 388(3):194–200CrossRefGoogle Scholar
  78. 78.
    Capussotti L, Vigano L, Ferrero A, Muratore A (2008) Local surgical resection of hilar cholangiocarcinoma: is there still a place? HPB 10(3):174–178PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD et al (2007) Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245(5):755–762PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Ito F, Agni R, Rettammel RJ, Been MJ, Cho CS, Mahvi DM et al (2008) Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence. Ann Surg 248(2):273–279PubMedCrossRefGoogle Scholar
  81. 81.
    Shi Z, Yang MZ, He QL, Ou RW, Chen YT (2009) Addition of hepatectomy decreases liver recurrence and leads to long survival in hilar cholangiocarcinoma. World J Gastroenterol 15(15):1892–1896PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Cheng QB, Yi B, Wang JH, Jiang XQ, Luo XJ, Liu C et al (2012) Resection with total caudate lobectomy confers survival benefit in hilar cholangiocarcinoma of Bismuth type III and IV. Eur J Surg Oncol 38(12):1197–1203PubMedCrossRefGoogle Scholar
  83. 83.
    Kow AW, Wook CD, Song SC, Kim WS, Kim MJ, Park HJ et al (2012) Role of caudate lobectomy in type III A and III B hilar cholangiocarcinoma: a 15-year experience in a tertiary institution. World J Surg 36(5):1112–1121PubMedCrossRefGoogle Scholar
  84. 84.
    Dinant S, Gerhards MF, Busch OR, Obertop H, Gouma DJ, Van Gulik TM (2005) The importance of complete excision of the caudate lobe in resection of hilar cholangiocarcinoma. HPB 7(4):263–267PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Regimbeau JM, Fuks D, Le Treut YP, Bachellier P, Belghiti J, Boudjema K et al (2011) Surgery for hilar cholangiocarcinoma: a multi-institutional update on practice and outcome by the AFC-HC study group. J Gastrointest Surg 15(3):480–488PubMedCrossRefGoogle Scholar
  86. 86.
    Miyazaki M, Kimura F, Shimizu H, Yoshidome H, Otuka M, Kato A et al (2010) One hundred seven consecutive surgical resections for hilar cholangiocarcinoma of Bismuth types II, III, IV between 2001 and 2008. J Hepato-Biliary-Pancreat Sci 17(4):470–475CrossRefGoogle Scholar
  87. 87.
    Wu XS, Dong P, Gu J, Li ML, Wu WG, Lu JH et al (2013) Combined portal vein resection for hilar cholangiocarcinoma: a meta-analysis of comparative studies. J Gastrointest Surg 17(6):1107–1115PubMedCrossRefGoogle Scholar
  88. 88.
    Hemming AW, Mekeel K, Khanna A, Baquerizo A, Kim RD (2011) Portal vein resection in management of hilar cholangiocarcinoma. J Am Coll Surg 212(4):604–613, discussion 13–6PubMedCrossRefGoogle Scholar
  89. 89.
    Miyazaki M, Kato A, Ito H, Kimura F, Shimizu H, Ohtsuka M et al (2007) Combined vascular resection in operative resection for hilar cholangiocarcinoma: does it work or not? Surgery 141(5):581–588PubMedCrossRefGoogle Scholar
  90. 90.
    Abbas S, Sandroussi C (2013) Systematic review and meta-analysis of the role of vascular resection in the treatment of hilar cholangiocarcinoma. HPB 15(7):492–503PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Neuhaus P, Jonas S, Bechstein WO, Lohmann R, Radke C, Kling N et al (1999) Extended resections for hilar cholangiocarcinoma. Ann Surg 230(6):808–818, discussion 19PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Ramos E (2013) Principles of surgical resection in hilar cholangiocarcinoma. World J Gastrointest Oncol 5(7):139–146PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Neuhaus P, Thelen A, Jonas S, Puhl G, Denecke T, Veltzke-Schlieker W et al (2012) Oncological superiority of hilar en bloc resection for the treatment of hilar cholangiocarcinoma. Ann Surg Oncol 19(5):1602–1608PubMedCrossRefGoogle Scholar
  94. 94.
    Shimizu H, Sawada S, Kimura F, Yoshidome H, Ohtsuka M, Kato A et al (2009) Clinical significance of biliary vascular anatomy of the right liver for hilar cholangiocarcinoma applied to left hemihepatectomy. Ann Surg 249(3):435–439PubMedCrossRefGoogle Scholar
  95. 95.
    Zervos EE, Osborne D, Goldin SB, Villadolid DV, Thometz DP, Durkin A et al (2005) Stage does not predict survival after resection of hilar cholangiocarcinomas promoting an aggressive operative approach. Am J Surg 190(5):810–815PubMedCrossRefGoogle Scholar
  96. 96.
    de Jong MC, Hong SM, Augustine MM, Goggins MG, Wolfgang CL, Hirose K et al (2011) Hilar cholangiocarcinoma: tumor depth as a predictor of outcome. Arch Surg 146(6):697–703PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R et al (2009) Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study—the UK ABC-01 Study. Br J Cancer 101(4):621–627PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Murakami Y, Uemura K, Sudo T, Hashimoto Y, Nakashima A, Kondo N et al (2011) Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol 18(3):651–658PubMedCrossRefGoogle Scholar
  99. 99.
    Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakamura H et al (2009) Gemcitabine-based adjuvant chemotherapy improves survival after aggressive surgery for hilar cholangiocarcinoma. J Gastrointest Surg 13(8):1470–1479PubMedCrossRefGoogle Scholar
  100. 100.
    Dumitrascu T, Chirita D, Ionescu M, Popescu I (2013) Resection for hilar cholangiocarcinoma: analysis of prognostic factors and the impact of systemic inflammation on long-term outcome. J Gastrointest Surg 17(5):913–924PubMedCrossRefGoogle Scholar
  101. 101.
    Sanz-Altamira PM, Ferrante K, Jenkins RL, Lewis WD, Huberman MS, Stuart KE (1998) A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma. Cancer 82(12):2321–2325PubMedCrossRefGoogle Scholar
  102. 102.
    Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F et al (2005) Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer 92(9):1650–1654PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Andersen JB, Thorgeirsson SS (2014) A perspective on molecular therapy in cholangiocarcinoma: present status and future directions. Hepatic Oncol 1(1):143–157CrossRefGoogle Scholar
  104. 104.
    Ross JS, Wang K, Gay L, Al-Rohil R, Rand JV, Jones DM et al (2014) New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 19(3):235–242PubMedCrossRefGoogle Scholar
  105. 105.
    Tada S, Fujikawa T, Tanaka A, Abe T, Yoshimoto Y, Maekawa H et al (2012) A case of unresectable hilar cholangiocarcinoma successfully treated by gemcitabine and S-1 combination chemotherapy. Gan to Kagaku Ryoho Cancer Chemother 39(8):1279–1282Google Scholar
  106. 106.
    Grendar J, Grendarova P, Sinha R, Dixon E (2014) Neoadjuvant therapy for downstaging of locally advanced hilar cholangiocarcinoma: a systematic review. HPB 16(4):297–303PubMedCrossRefGoogle Scholar
  107. 107.
    McMasters KM, Tuttle TM, Leach SD, Rich T, Cleary KR, Evans DB et al (1997) Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 174(6):605–608, discussion 8–9PubMedCrossRefGoogle Scholar
  108. 108.
    Nelson JW, Ghafoori AP, Willett CG, Tyler DS, Pappas TN, Clary BM et al (2009) Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 73(1):148–153PubMedCrossRefGoogle Scholar
  109. 109.
    Gerhards MF, Gonzalez DG, ten Hoopen-Neumann H, van Gulik TM, de Wit LT, Gouma DJ (2000) Prevention of implantation metastases after resection of proximal bile duct tumours with pre-operative low dose radiation therapy. Eur J Surg Oncol 26(5):480–485PubMedCrossRefGoogle Scholar
  110. 110.
    Gerhards MF, van Gulik TM, Gonzalez Gonzalez D, Rauws EA, Gouma DJ (2003) Results of postoperative radiotherapy for resectable hilar cholangiocarcinoma. World J Surg 27(2):173–179PubMedGoogle Scholar
  111. 111.
    Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H et al (2000) Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma. Int J Radiat Oncol Biol Phys 46(3):581–587PubMedCrossRefGoogle Scholar
  112. 112.
    Cheon YK, Lee TY, Lee SM, Yoon JY, Shim CS (2012) Longterm outcome of photodynamic therapy compared with biliary stenting alone in patients with advanced hilar cholangiocarcinoma. HPB 14(3):185–193PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Witzigmann H, Berr F, Ringel U, Caca K, Uhlmann D, Schoppmeyer K et al (2006) Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to r1/r2 resection. Ann Surg 244(2):230–239PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Dumoulin FL, Gerhardt T, Fuchs S, Scheurlen C, Neubrand M, Layer G et al (2003) Phase II study of photodynamic therapy and metal stent as palliative treatment for nonresectable hilar cholangiocarcinoma. Gastrointest Endosc 57(7):860–867PubMedCrossRefGoogle Scholar
  115. 115.
    Quyn AJ, Ziyaie D, Polignano FM, Tait IS (2009) Photodynamic therapy is associated with an improvement in survival in patients with irresectable hilar cholangiocarcinoma. HPB 11(7):570–577PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Wiedmann M, Caca K, Berr F, Schiefke I, Tannapfel A, Wittekind C et al (2003) Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: a phase II pilot study. Cancer 97(11):2783–2790PubMedCrossRefGoogle Scholar
  117. 117.
    Iwatsuki S, Todo S, Marsh JW, Madariaga JR, Lee RG, Dvorchik I et al (1998) Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg 187(4):358–364PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Meyer CG, Penn I, James L (2000) Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 69(8):1633–1637PubMedCrossRefGoogle Scholar
  119. 119.
    Shimoda M, Farmer DG, Colquhoun SD, Rosove M, Ghobrial RM, Yersiz H et al (2001) Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature. Liver Transpl 7(12):1023–1033PubMedCrossRefGoogle Scholar
  120. 120.
    Darwish Murad S, Kim WR, Therneau T, Gores GJ, Rosen CB, Martenson JA et al (2012) Predictors of pretransplant dropout and posttransplant recurrence in patients with perihilar cholangiocarcinoma. Hepatology 56(3):972–981PubMedCrossRefGoogle Scholar
  121. 121.
    Rosen CB, Heimbach JK, Gores GJ (2010) Liver transplantation for cholangiocarcinoma. Transpl Int 23(7):692–697PubMedCrossRefGoogle Scholar
  122. 122.
    Hong JC, Jones CM, Duffy JP, Petrowsky H, Farmer DG, French S et al (2011) Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center. Arch Surg 146(6):683–689PubMedCrossRefGoogle Scholar
  123. 123.
    Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK et al (2005) Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 242(3):451–458, discussion 8–61PubMedCentralPubMedGoogle Scholar
  124. 124.
    Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM et al (2012) Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 143(1):88–98, e3; quiz e14PubMedCrossRefGoogle Scholar
  125. 125.
    Chauhan A, House MG, Pitt HA, Nakeeb A, Howard TJ, Zyromski NJ et al (2011) Post-operative morbidity results in decreased long-term survival after resection for hilar cholangiocarcinoma. HPB 13(2):139–147PubMedCentralPubMedCrossRefGoogle Scholar
  126. 126.
    van Gulik TM, Ruys AT, Busch OR, Rauws EA, Gouma DJ (2011) Extent of liver resection for hilar cholangiocarcinoma (Klatskin tumor): how much is enough? Dig Surg 28(2):141–147PubMedCrossRefGoogle Scholar
  127. 127.
    Shimizu H, Kimura F, Yoshidome H, Ohtsuka M, Kato A, Yoshitomi H et al (2010) Aggressive surgical resection for hilar cholangiocarcinoma of the left-side predominance: radicality and safety of left-sided hepatectomy. Ann Surg 251(2):281–286PubMedCrossRefGoogle Scholar
  128. 128.
    Unno M, Katayose Y, Rikiyama T, Yoshida H, Yamamoto K, Morikawa T et al (2010) Major hepatectomy for perihilar cholangiocarcinoma. J Hepato-Biliary-Pancreat Sci 17(4):463–469CrossRefGoogle Scholar
  129. 129.
    Lee SG, Song GW, Hwang S, Ha TY, Moon DB, Jung DH et al (2010) Surgical treatment of hilar cholangiocarcinoma in the new era: the Asan experience. J Hepato-Biliary-Pancreat Sci 17(4):476–489CrossRefGoogle Scholar
  130. 130.
    El-Khoueiry AB, Rankin C, Siegel AB, Iqbal S, Gong IY, Micetich KC, Kayaleh OR, Lenz HJ, Blanke CD (2014) S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma. Br J Cancer 110:882–887PubMedCrossRefGoogle Scholar
  131. 131.
    Rubovszky G, Lang I et al (2013) Cetuximab, gemcitabine and capecitabine in patients with inoperable biliary tract cancer: a phase 2 study. Eur J Cancer 49(18):3806–3812PubMedCrossRefGoogle Scholar
  132. 132.
    Jensen LH, Lindebjerg J, Ploen J et al (2012) Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer. Ann Oncol 23(9):2341–2346PubMedCrossRefGoogle Scholar
  133. 133.
    Lubner SJ, Mahoney MR, Kolesar JL et al (2010) Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol 28:3491–3497PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    El-Khoueiry AB, Rankin CJ, Ben-Josef E, Lenz HJ, Gold PJ, Hamilton RD, Govindarajan R, Eng C, Blanke CD (2012) SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs 30(4):1646–1651PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Valle JM et al (2014) ABC-04: A phase 1b trial of cisplatin, gemcitabine, and selumetinib in patients with advanced biliary tract cancer. J Clin Oncol 32:5s (abstr 4002)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Matthew J. Weiss
    • 1
  • David Cosgrove
    • 2
  • Joseph M. Herman
    • 3
  • Neda Rastegar
    • 4
  • Ihab Kamel
    • 4
  • Timothy M. Pawlik
    • 1
  1. 1.Division of Surgical Oncology, Department of SurgeryThe Johns Hopkins HospitalBaltimoreUSA
  2. 2.Department of Medical OncologyThe Johns Hopkins HospitalBaltimoreUSA
  3. 3.Department of Radiation OncologyThe Johns Hopkins HospitalBaltimoreUSA
  4. 4.Department of RadiologyThe Johns Hopkins HospitalBaltimoreUSA

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