Annals of Surgical Oncology

, Volume 20, Issue 4, pp 1230–1239 | Cite as

Novel Multimodality Treatment Sequencing for Extrahepatic (Mid and Distal) Cholangiocarcinoma

  • Kiran K. Turaga
  • Susan Tsai
  • Lauren A. Wiebe
  • Douglas B. Evans
  • T. Clark Gamblin
Gastrointestinal Oncology


Neoadjuvant chemoradiation has demonstrated significant advantages in the management of pancreatic adenocarcinoma. A similar tumor in a nearby anatomical location is extrahepatic cholangiocarcinoma, which has proven to be largely unresponsive to current forms of therapy. Neoadjuvant therapy for hilar cholangiocarcinoma has been combined with surgical resection and/or liver transplantation with a 25–33 % complete pathological response rate. We propose a wider application of neoadjuvant chemoradiation for patients with distal cholangiocarcinoma and present our rationale for this form of treatment sequencing.


Gemcitabine Cholangiocarcinoma Complete Pathological Response Biliary Tract Cancer Hilar Cholangiocarcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Longmire WP, McArthur MS, Bastounis EA, Hiatt J. Carcinoma of the extrahepatic biliary tract. Ann Surg. 1973;178:333–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24:115–25.PubMedCrossRefGoogle Scholar
  3. 3.
    Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis. An unusual tumor with distinctive clinical and pathological features. Am J Med. 1965;38:241–56.PubMedCrossRefGoogle Scholar
  4. 4.
    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;37:806–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet. 2005;366:1303–14.PubMedCrossRefGoogle Scholar
  6. 6.
    ACS. Bile Duct (Cholangiocarcinoma) Cancer 2011. Accessed 17 July 2011.
  7. 7.
    Evans DB, Farnell MB, Lillemoe KD, Vollmer C Jr, Strasberg SM, Schulick RD. Surgical treatment of resectable and borderline resectable pancreas cancer: expert consensus statement. Ann Surg Oncol. 2009;16:1736–44.PubMedCrossRefGoogle Scholar
  8. 8.
    Evans DB. Preoperative chemoradiation for resectable and locally advanced adenocarcinoma of the pancreas. J Gastrointest Surg. 2001;5:2–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Roy R, Maraveyas A. Chemoradiation in pancreatic adenocarcinoma: a literature review. Oncologist. 2010;15:259–69.PubMedCrossRefGoogle Scholar
  10. 10.
    Evans DB, Rich TA, Byrd DR, Cleary KR, Connelly JH, Levin B, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127:1335–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Katz MH, Wang H, Fleming JB, Sun CC, Hwang RF, Wolff RA, et al. Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol. 2009;16:836–47.PubMedCrossRefGoogle Scholar
  12. 12.
    Estrella JS, Rashid A, Fleming JB, Katz MH, Lee JE, Wolf RA, et al. Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation. Cancer. 2012;118:268–77.PubMedCrossRefGoogle Scholar
  13. 13.
    Satoi S, Yanagimoto H, Toyokawa H, Takahashi K, Matsui Y, Kitade H, et al. Surgical results after preoperative chemoradiation therapy for patients with pancreatic cancer. Pancreas. 2009;38:282–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Golcher H, Brunner T, Grabenbauer G, Merkel S, Papadopoulos T, Hohenberger W, et al. Preoperative chemoradiation in adenocarcinoma of the pancreas. A single centre experience advocating a new treatment strategy. Eur J Surg Oncol. 2008;34:756–64.PubMedCrossRefGoogle Scholar
  15. 15.
    Chandler NM, Canete JJ, Stuart KE, Callery MP. Preoperative chemoradiation in resectable pancreatic cancer. J Hepatobiliary Pancreat Surg. 2003;10:61–6.PubMedGoogle Scholar
  16. 16.
    Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7:e1000267.PubMedCrossRefGoogle Scholar
  17. 17.
    Herman JM, Swartz MJ, Hsu CC, Winter J, Pawlik TM, Sugar E, et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol. 2008;26:3503–10.PubMedCrossRefGoogle Scholar
  18. 18.
    Mohamadnejad M, DeWitt JM, Sherman S, LeBlanc JK, Pitt HA, House MG, et al. Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience. Gastrointest Endosc. 2011;73:71–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Meza-Junco J, Montano-Loza AJ, Ma M, Wong W, Sawyer MB, Bain VG. Cholangiocarcinoma: has there been any progress? Can J Gastroenterol. 2010;24:52–7.PubMedGoogle Scholar
  20. 20.
    Schwartz LH, Coakley FV, Sun Y, Blumgart LH, Fong Y, Panicek DM. Neoplastic pancreaticobiliary duct obstruction: evaluation with breath-hold MR cholangiopancreatography. AJR Am J Roentgenol. 1998;170:1491–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Seo H, Lee JM, Kim IH, Han JK, Kim SH, Jang JY, et al. Evaluation of the gross type and longitudinal extent of extrahepatic cholangiocarcinomas on contrast-enhanced multidetector row computed tomography. J Comput Assist Tomogr. 2009;33:376–82.PubMedCrossRefGoogle Scholar
  22. 22.
    Okumoto T, Sato A, Yamada T, Takase K, Matsuhashi T, Tsuda M, et al. Correct diagnosis of vascular encasement and longitudinal extension of hilar cholangiocarcinoma by four-channel multidetector-row computed tomography. Tohoku J Exp Med. 2009;217:1–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Rouse RV. Surgical Pathology Criteria is focused on the presentation of useful diagnostic criteria in an accessible format 2011. Accessed 15 July 2011.
  24. 24.
    McMasters KM, Tuttle TM, Leach SD, Rich T, Cleary KR, Evans DB, et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg. 1997;174:605–8; discussion 608–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Nelson JW, Ghafoori AP, Willett CG, et al. Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 2009; 73(1):148-53.PubMedCrossRefGoogle Scholar
  26. 26.
    Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242:451–8 (discussion 458–61).PubMedGoogle Scholar
  27. 27.
    Heimbach JK, Gores GJ, Nagorney DM, Rosen CB. Liver transplantation for perihilar cholangiocarcinoma after aggressive neoadjuvant therapy: a new paradigm for liver and biliary malignancies? Surgery. 2006;140:331–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B Jr, McCashland T, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant. 2002;2:774–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Hong JC, Jones CM, Duffy JP, Petrowsky H, Farmer DG, French S, et al. Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center. Arch Surg. 2011;146:683–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Fuller CD, Wang SJ, Choi M, Czito BG, Cornell J, Welzel TM, et al. Multimodality therapy for locoregional extrahepatic cholangiocarcinoma: a population-based analysis. Cancer. 2009;115:5175–83.PubMedCrossRefGoogle Scholar
  31. 31.
    Serafini FM, Sachs D, Bloomston M, Carey LC, Karl RC, Murr MM, et al. Location, not staging, of cholangiocarcinoma determines the role for adjuvant chemoradiation therapy. Am Surg. 2001;67:839–43; discussion 843–4.PubMedGoogle Scholar
  32. 32.
    Kim S, Kim SW, Bang YJ, Heo DS, Ha SW. Role of postoperative radiotherapy in the management of extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys. 2002;54:414–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Shinohara ET, Mitra N, Guo M, Metz JM. Radiation therapy is associated with improved survival in the adjuvant and definitive treatment of intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2008;72:1495–501.PubMedCrossRefGoogle Scholar
  34. 34.
    Kopelson G, Harisiadis L, Tretter P, Chang CH. The role of radiation therapy in cancer of the extra-hepatic biliary system: an analysis of thirteen patients and a review of the literature of the effectiveness of surgery, chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys. 1977;2:883–94.PubMedCrossRefGoogle Scholar
  35. 35.
    Brunner TB, Schwab D, Meyer T, Sauer R. Chemoradiation may prolong survival of patients with non-bulky unresectable extrahepatic biliary carcinoma. A retrospective analysis. Strahlenther Onkol. 2004;180:751–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Crane CH, Macdonald KO, Vauthey JN, Yehuda P, Brown T, Curley S, et al. Limitations of conventional doses of chemoradiation for unresectable biliary cancer. Int J Radiat Oncol Biol Phys. 2002;53:969–74.PubMedCrossRefGoogle Scholar
  37. 37.
    Deodato F, Clemente G, Mattiucci GC, Macchia G, Costamagna G, Giuliante F, et al. Chemoradiation and brachytherapy in biliary tract carcinoma: long-term results. Int J Radiat Oncol Biol Phys. 2006;64:483–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Ghafoori AP, Nelson JW, Willett CG, Chino J, Tyler DS, Hurwitz HI, et al. Radiotherapy in the treatment of patients with unresectable extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2011;81:654–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.PubMedGoogle Scholar
  40. 40.
    Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27:5513–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.PubMedCrossRefGoogle Scholar
  42. 42.
    Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008;113:2046–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304:1073–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Pelzer U, Kubica K, Stieler J, Schwaner I, Heil G, Gorner M, et al. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. J Clin Oncol. 2008;26(May 20 suppl):Abstract 4508.Google Scholar
  45. 45.
    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;362:1273–81.PubMedCrossRefGoogle Scholar
  46. 46.
    Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist. 2008;13:415–23.PubMedCrossRefGoogle Scholar
  47. 47.
    Zen Y, Pedica F, Patcha VR, Capelli P, Zamboni G, Casaril A, et al. Mucinous cystic neoplasms of the liver: a clinicopathological study and comparison with intraductal papillary neoplasms of the bile duct. Mod Pathol. 2011;24:1079–89.PubMedCrossRefGoogle Scholar
  48. 48.
    Nakanishi Y, Zen Y, Kondo S, Itoh T, Itatsu K, Nakanuma Y. Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm. Hum Pathol. 2008;39:1153–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Itatsu K, Zen Y, Ohira S, Ishikawa A, Sato Y, Harada K, et al. Immunohistochemical analysis of the progression of flat and papillary preneoplastic lesions in intrahepatic cholangiocarcinogenesis in hepatolithiasis. Liver Int. 2007;27:1174–84.PubMedCrossRefGoogle Scholar
  50. 50.
    Argani P, Shaukat A, Kaushal M, Wilentz RE, Su GH, Sohn TA, et al. Differing rates of loss of DPC4 expression and of p53 overexpression among carcinomas of the proximal and distal bile ducts. Cancer. 2001;91:1332–41.PubMedCrossRefGoogle Scholar
  51. 51.
    Miller G, Socci ND, Dhall D, D’Angelica M, DeMatteo RP, Allen PJ, et al. Genome wide analysis and clinical correlation of chromosomal and transcriptional mutations in cancers of the biliary tract. J Exp Clin Cancer Res. 2009;28:62.PubMedCrossRefGoogle Scholar
  52. 52.
    Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98:418–25.PubMedCrossRefGoogle Scholar
  53. 53.
    Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol. 2005;206:356–65.PubMedCrossRefGoogle Scholar
  54. 54.
    Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut. 2003;52:706–12.PubMedCrossRefGoogle Scholar
  55. 55.
    Yoon JH, Werneburg NW, Higuchi H, Canbay AE, Kaufmann SH, Akgul C, et al. Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism. Cancer Res. 2002;62:6500–5.PubMedGoogle Scholar
  56. 56.
    Benckert C, Jonas S, Cramer T, Von Marschall Z, Schäfer G, Peters M, et al. Transforming growth factor beta 1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells. Cancer Res. 2003;63:1083–92.PubMedGoogle Scholar
  57. 57.
    Briggs CD, Neal CP, Mann CD, Steward WP, Manson MM, Berry DP. Prognostic molecular markers in cholangiocarcinoma: a systematic review. Eur J Cancer. 2009;45:33–47.PubMedCrossRefGoogle Scholar
  58. 58.
    El-Khoueiry AB, Rankin CJ, Ben-Josef E, Lenz HJ, Gold PJ, Hamilton RD, et al. SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs. 2012;30:1646–51.PubMedCrossRefGoogle Scholar
  59. 59.
    Alden ME, Mohiuddin M. The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys. 1994;28:945–51.PubMedCrossRefGoogle Scholar
  60. 60.
    Foo ML, Gunderson LL, Bender CE, Buskirk SJ. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1997;39:929–35.PubMedCrossRefGoogle Scholar
  61. 61.
    Czito BG, Hong TJ, Cohen DP, Petros WP, Tyler DS, Pappas TN, et al. A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract. Cancer Invest. 2006;24:9–17.PubMedCrossRefGoogle Scholar
  62. 62.
    Vern-Gross TZ, Shivnani AT, Chen K, Lee CM, Tward JD, MacDonald OK, et al. Survival outcomes in resected extrahepatic cholangiocarcinoma: effect of adjuvant radiotherapy in a surveillance, epidemiology, and end results analysis. Int J Radiat Oncol Biol Phys. 2011;81:189–98.PubMedCrossRefGoogle Scholar
  63. 63.
    Fernandez-Ruiz M, Guerra-Vales JM, Colina-Ruizdelgado F. Comorbidity negatively influences prognosis in patients with extrahepatic cholangiocarcinoma. World J Gastroenterol. 2009;15:5279–86.PubMedCrossRefGoogle Scholar
  64. 64.
    Sakamoto Y, Shimada K, Nara S, Esaki M, Ojima H, Sano T, et al. Surgical management of infrahilar/suprapancreatic cholangiocarcinoma: an analysis of the surgical procedures, surgical margins, and survivals of 77 patients. J Gastrointest Surg. 2010;14:335–43.PubMedCrossRefGoogle Scholar
  65. 65.
    Alexopoulou A, Soultati A, Dourakis SP, Vasilieva L, Archimandritis AJ. Cholangiocarcinoma: a 7-year experience at a single center in Greece. World J Gastroenterol. 2008;14:6213–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Allen PJ, Reiner AS, Gonen M, Klimstra DK, Blumgart LH, Brennan MF, et al. Extrahepatic cholangiocarcinoma: a comparison of patients with resected proximal and distal lesions. HPB (Oxford). 2008;10:341–6.CrossRefGoogle Scholar
  67. 67.
    Wakai T, Shirai Y, Tsuchiya Y, Nomura T, Akazawa K, Hatakeyama K. Combined major hepatectomy and pancreaticoduodenectomy for locally advanced biliary carcinoma: long-term results. World J Surg. 2008;32:1067–74.PubMedCrossRefGoogle Scholar
  68. 68.
    Hernandez J, Cowgill SM, Al-Saadi S, Villadolid D, Ross S, Kraemer E, et al. An aggressive approach to extrahepatic cholangiocarcinomas is warranted: margin status does not impact survival after resection. Ann Surg Oncol. 2008;15:807–14.PubMedCrossRefGoogle Scholar
  69. 69.
    Shi QF, Liang TB, Qin YS, Wang WL, Shen Y, Zhang M, et al. Evaluation of surgical approach for extrahepatic cholangiocarcinoma. Hepatobiliary Pancreat Dis Int. 2007;6:622–6.PubMedGoogle Scholar
  70. 70.
    Woo SM, Ryu JK, Lee SH, Yoo JW, Park JK, Kim YT, et al. Recurrence and prognostic factors of ampullary carcinoma after radical resection: comparison with distal extrahepatic cholangiocarcinoma. Ann Surg Oncol. 2007;14:3195–201.PubMedCrossRefGoogle Scholar
  71. 71.
    Sasaki R, Takeda Y, Funato O, Nitta H, Kawamura H, Uesugi N, et al. Significance of ductal margin status in patients undergoing surgical resection for extrahepatic cholangiocarcinoma. World J Surg. 2007;31:1788–96.PubMedCrossRefGoogle Scholar
  72. 72.
    Wakai T, Shirai Y, Moroda T, Yokoyama N, Hatakeyama K. Impact of ductal resection margin status on long-term survival in patients undergoing resection for extrahepatic cholangiocarcinoma. Cancer. 2005;103:1210–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Blom D, Schwartz SI. Surgical treatment and outcomes in carcinoma of the extrahepatic bile ducts: the University of Rochester experience. Arch Surg. 2001;136:209–15.PubMedCrossRefGoogle Scholar
  74. 74.
    Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–73 (discussion 473–5).PubMedCrossRefGoogle Scholar
  75. 75.
    Nagorney DM, Donohue JH, Farnell MB, Schleck CD, Ilstrup DM. Outcomes after curative resections of cholangiocarcinoma. Arch Surg. 1993;128:871–7 (discussion 877–9).PubMedCrossRefGoogle Scholar
  76. 76.
    Evander A, Fredlund P, Hoevels J, Ihse I, Bengmark S. Evaluation of aggressive surgery for carcinoma of the extrahepatic bile ducts. Ann Surg. 1980;191:23–9.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2012

Authors and Affiliations

  • Kiran K. Turaga
    • 1
  • Susan Tsai
    • 1
  • Lauren A. Wiebe
    • 2
  • Douglas B. Evans
    • 1
  • T. Clark Gamblin
    • 1
  1. 1.Department of Surgery, Dvision of Surgical OncologyMedical College of WisconsinMilwaukeeUSA
  2. 2.Department of Medicine, Division of Hematology OncologyMedical College of WisconsinMilwaukeeUSA

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