Skip to main content
SpringerLink
Log in

Clinical Trials and Novel/Emerging Treatment

  • Chapter
  • First Online:
Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) is increasing in incidence and presents a therapeutic challenge, as most patients present at an advanced unresectable stage and face an adverse prognosis. Recent next-generation sequencing studies indicate that these tumors are enriched with several actionable mutations, perhaps more than other gastrointestinal cancers. Morphologically, these tumors are diverse and may be mass-forming, intraductal, or periductal. Therefore, the traditional, “one-size-fits-all” approach is not ideal for this cancer. Historically, liver-directed approaches have been more commonly used in hepatocellular cancer, while systemic chemotherapy remains the primary approach for the advanced stage of ICC. This paradigm has fortunately begun to change, and patients with ICC now have multiple treatment options including liver-directed and targeted therapies based on underlying mutational profile. These novel strategies along with a multitude of ongoing clinical trials including approaches with immunotherapy offer considerable promise towards improving the clinical outcome of this cancer.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepato-Biliary-Pancreat Surg. 2003;10(4):288–91.

    Article  Google Scholar 

  2. Spolverato G, Kim Y, Alexandrescu S, et al. Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curative-intent surgical resection. Ann Surg Oncol. 2016;23(1):235–43.

    Article  PubMed  Google Scholar 

  3. Liotta L, Quante M. Adjuvant chemotherapy with Capecitabine as new standard for resected cholangiocarcinomas – a look at the BILCAP trial. Z Gastroenterol. 2018;56(7):839–40.

    Article  PubMed  Google Scholar 

  4. 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(5):1495–501.

    Article  PubMed  Google Scholar 

  5. Zheng X, Chen B, Wu JX, et al. Benefit of adjuvant radiotherapy following narrow-margin hepatectomy in patients with intrahepatic cholangiocarcinoma that adhere to major vessels. Cancer Manag Res. 2018;10:3973–81.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lee J, Yoon WS, Koom WS, Rim CH. Efficacy of stereotactic body radiotherapy for unresectable or recurrent cholangiocarcinoma: a meta-analysis and systematic review. Strahlenther Onkol. 2018;195(2):93–102.

    Article  PubMed  Google Scholar 

  7. Jia AY, Wu JX, Zhao YT, et al. Intensity-modulated radiotherapy following null-margin resection is associated with improved survival in the treatment of intrahepatic cholangiocarcinoma. J Gastrointest Oncol. 2015;6(2):126–33.

    PubMed  PubMed Central  Google Scholar 

  8. Jiang W, Zeng ZC, Tang ZY, et al. Benefit of radiotherapy for 90 patients with resected intrahepatic cholangiocarcinoma and concurrent lymph node metastases. J Cancer Res Clin Oncol. 2010;136(9):1323–31.

    Article  PubMed  Google Scholar 

  9. Liu MY, Lo CH, Lin CS, et al. Stereotactic ablative radiotherapy for patients with unresectable or medically inoperable cholangiocarcinoma. Tumori. 2017;103(3):236–41.

    Article  PubMed  Google Scholar 

  10. Mahadevan A, Dagoglu N, Mancias J, et al. Stereotactic Body Radiotherapy (SBRT) for intrahepatic and hilar cholangiocarcinoma. J Cancer. 2015;6(11):1099–104.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Barney BM, Olivier KR, Miller RC, Haddock MG. Clinical outcomes and toxicity using stereotactic body radiotherapy (SBRT) for advanced cholangiocarcinoma. Radiat Oncol (London, England). 2012;7:67.

    Article  Google Scholar 

  12. Shen Z-T, Zhou H, Li A-M, Li B, Shen J-S, Zhu X-X. Clinical outcomes and prognostic factors of stereotactic body radiation therapy for intrahepatic cholangiocarcinoma. Oncotarget. 2017;8(55):93541–50.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose-response analysis. J Clin Oncol. 2016;34(3):219–26.

    Article  CAS  PubMed  Google Scholar 

  14. Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2016;34(5):460–8.

    Article  CAS  PubMed  Google Scholar 

  15. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2000;6(3):309–16.

    Article  PubMed  Google Scholar 

  16. Zamora-Valdes D, Heimbach JK. Liver transplant for cholangiocarcinoma. Gastroenterol Clin N Am. 2018;47(2):267–80.

    Article  Google Scholar 

  17. Goldstein RM, Stone M, Tillery GW, et al. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg. 1993;166(6):768–71; discussion 771–62.

    Article  CAS  PubMed  Google Scholar 

  18. Pascher A, Jonas S, Neuhaus P. Intrahepatic cholangiocarcinoma: indication for transplantation. J Hepato-Biliary-Pancreat Surg. 2003;10(4):282–7.

    Article  Google Scholar 

  19. Becker NS, Rodriguez JA, Barshes NR, O’Mahony CA, Goss JA, Aloia TA. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg. 2008;12(1):117–22.

    Article  PubMed  Google Scholar 

  20. Sapisochin G, Facciuto M, Rubbia-Brandt L, et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology. 2016;64(4):1178–88.

    Article  CAS  PubMed  Google Scholar 

  21. Hong JC, Jones CM, Duffy JP, 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(6):683–9.

    Article  PubMed  Google Scholar 

  22. Hong JC, Petrowsky H, Kaldas FM, et al. Predictive index for tumor recurrence after liver transplantation for locally advanced intrahepatic and hilar cholangiocarcinoma. J Am Coll Surg. 2011;212(4):514–20; discussion 520–11.

    Article  PubMed  Google Scholar 

  23. Lunsford KE, Javle M, Gaber AO, Vauthey JN, Ghobrial RM. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma – Authors’ reply. Lancet Gastroenterol Hepatol. 2018;3(8):529–30.

    Article  PubMed  Google Scholar 

  24. Lunsford KE, Javle M, Heyne K, et al. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case series. Lancet Gastroenterol Hepatol. 2018;3(5):337–48.

    Article  PubMed  Google Scholar 

  25. Vogl TJ, Naguib NN, Nour-Eldin NE, et al. Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma: results and prognostic factors governing treatment success. Int J Cancer. 2012;131(3):733–40.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. Kim JH, Yoon HK, Sung KB, et al. Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing outcomes. Cancer. 2008;113(7):1614–22.

    Article  PubMed  Google Scholar 

  28. Kiefer MV, Albert M, McNally M, et al. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer. 2011;117(7):1498–505.

    Article  CAS  PubMed  Google Scholar 

  29. Herber S, Otto G, Schneider J, et al. Transarterial chemoembolization (TACE) for inoperable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol. 2007;30(6):1156–65.

    Article  CAS  PubMed  Google Scholar 

  30. Gusani NJ, Balaa FK, Steel JL, et al. Treatment of unresectable cholangiocarcinoma with gemcitabine-based transcatheter arterial chemoembolization (TACE): a single-institution experience. J Gastrointest Surg. 2008;12(1):129–37.

    Article  PubMed  Google Scholar 

  31. Burger I, Hong K, Schulick R, et al. Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol. 2005;16(3):353–61.

    Article  PubMed  Google Scholar 

  32. Schiffman SC, Metzger T, Dubel G, et al. Precision hepatic arterial irinotecan therapy in the treatment of unresectable intrahepatic cholangiocellular carcinoma: optimal tolerance and prolonged overall survival. Ann Surg Oncol. 2011;18(2):431–8.

    Article  PubMed  Google Scholar 

  33. Poggi G, Amatu A, Montagna B, et al. OEM-TACE: a new therapeutic approach in unresectable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol. 2009;32(6):1187–92.

    Article  PubMed  Google Scholar 

  34. Aliberti C, Carandina R, Sarti D, et al. Chemoembolization with drug-eluting microspheres loaded with doxorubicin for the treatment of cholangiocarcinoma. Anticancer Res. 2017;37(4):1859–63.

    Article  CAS  PubMed  Google Scholar 

  35. Kuhlmann JB, Euringer W, Spangenberg HC, 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.

    CAS  PubMed  Google Scholar 

  36. Wu ZF, Zhang HB, Yang N, Zhao WC, Fu Y, Yang GS. Postoperative adjuvant transcatheter arterial chemoembolisation improves survival of intrahepatic cholangiocarcinoma patients with poor prognostic factors: results of a large monocentric series. Eur J Surg Oncol. 2012;38(7):602–10.

    Article  CAS  PubMed  Google Scholar 

  37. Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: technical and methodologic considerations. J Vasc Interv Radiol. 2006;17(8):1251–78.

    Article  PubMed  Google Scholar 

  38. Soydal C, Kucuk ON, Bilgic S, Ibis E. Radioembolization with (90)Y resin microspheres for intrahepatic cholangiocellular carcinoma: prognostic factors. Ann Nucl Med. 2016;30(1):29–34.

    Article  CAS  PubMed  Google Scholar 

  39. Shaker TM, Chung C, Varma MK, et al. Is there a role for Yttrium-90 in the treatment of unresectable and metastatic intrahepatic cholangiocarcinoma? Am J Surg. 2018;215(3):467–70.

    Article  PubMed  Google Scholar 

  40. Saxena A, Bester L, Chua TC, Chu FC, Morris DL. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol. 2010;17(2):484–91.

    Article  PubMed  Google Scholar 

  41. Reimer P, Virarkar MK, Binnenhei M, Justinger M, Schön MR, Tatsch K. Prognostic factors in overall survival of patients with unresectable intrahepatic cholangiocarcinoma treated by means of Yttrium-90 radioembolization: results in therapy-Naïve patients. Cardiovasc Intervent Radiol. 2018;

    Google Scholar 

  42. Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer. 2008;113(8):2119–28.

    Article  CAS  PubMed  Google Scholar 

  43. Hoffmann RT, Paprottka PM, Schon A, et al. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol. 2012;35(1):105–16.

    Article  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shitara K, Ikami I, Munakata M, Muto O, Sakata Y. Hepatic arterial infusion of mitomycin C with degradable starch microspheres for unresectable intrahepatic cholangiocarcinoma. Clin Oncol (R Coll Radiol). 2008;20(3):241–6.

    Article  CAS  Google Scholar 

  46. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol. 2009;20(9):1589–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Inaba Y, Arai Y, Yamaura H, et al. Phase I/II study of hepatic arterial infusion chemotherapy with gemcitabine in patients with unresectable intrahepatic cholangiocarcinoma (JIVROSG-0301). Am J Clin Oncol. 2011;34(1):58–62.

    Article  CAS  PubMed  Google Scholar 

  48. Tanaka N, Yamakado K, Nakatsuka A, Fujii A, Matsumura K, Takeda K. Arterial chemoinfusion therapy through an implanted port system for patients with unresectable intrahepatic cholangiocarcinoma–initial experience. Eur J Radiol. 2002;41(1):42–8.

    Article  PubMed  Google Scholar 

  49. Massani M, Nistri C, Ruffolo C, et al. Intrahepatic chemotherapy for unresectable cholangiocarcinoma: review of literature and personal experience. Updat Surg. 2015;67(4):389–400.

    Article  Google Scholar 

  50. Ghiringhelli F, Lorgis V, Vincent J, Ladoire S, Guiu B. Hepatic arterial infusion of gemcitabine plus oxaliplatin as second-line treatment for locally advanced intrahepatic cholangiocarcinoma: preliminary experience. Chemotherapy. 2013;59(5):354–60.

    Article  CAS  PubMed  Google Scholar 

  51. Boehm LM, Jayakrishnan TT, Miura JT, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol. 2015;111(2):213–20.

    Article  PubMed  Google Scholar 

  52. Konstantinidis IT, Groot Koerkamp B, Do RK, et al. Unresectable intrahepatic cholangiocarcinoma: systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone. Cancer. 2016;122(5):758–65.

    Article  PubMed  Google Scholar 

  53. Cercek A, D’Angelica M, Power D, et al. Floxuridine hepatic arterial infusion associated biliary toxicity is increased by concurrent administration of systemic bevacizumab. Ann Surg Oncol. 2014;21(2):479–86.

    Article  PubMed  Google Scholar 

  54. Shindoh J. Ablative therapies for intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr. 2017;6(1):2–6.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Han K, Ko HK, Kim KW, Won HJ, Shin YM, Kim PN. Radiofrequency ablation in the treatment of unresectable intrahepatic cholangiocarcinoma: systematic review and meta-analysis. J Vasc Interv Radiol. 2015;26(7):943–8.

    Article  PubMed  Google Scholar 

  56. Bale R, Schullian P, Haidu M, Widmann G. Stereotactic radiofrequency ablation (SRFA) of intrahepatic cholangiocellular carcinomas: a minimal invasive alternative to liver resection. Wien Med Wochenschr. 2013;163(5–6):128–31.

    Article  PubMed  Google Scholar 

  57. Butros SR, Shenoy-Bhangle A, Mueller PR, Arellano RS. Radiofrequency ablation of intrahepatic cholangiocarcinoma: feasability, local tumor control, and long-term outcome. Clin Imaging. 2014;38(4):490–4.

    Article  PubMed  Google Scholar 

  58. Fu Y, Yang W, Wu W, Yan K, Xing BC, Chen MH. Radiofrequency ablation in the management of unresectable intrahepatic cholangiocarcinoma. J Vasc Interv Radiol. 2012;23(5):642–9.

    Article  PubMed  Google Scholar 

  59. Haidu M, Dobrozemsky G, Schullian P, et al. Stereotactic radiofrequency ablation of unresectable intrahepatic cholangiocarcinomas: a retrospective study. Cardiovasc Intervent Radiol. 2012;35(5):1074–82.

    Article  PubMed  Google Scholar 

  60. Kim JH, Won HJ, Shin YM, Kim KA, Kim PN. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Roentgenol. 2011;196(2):W205–9.

    Article  PubMed  Google Scholar 

  61. Kim JH, Won HJ, Shin YM, Kim PN, Lee SG, Hwang S. Radiofrequency ablation for recurrent intrahepatic cholangiocarcinoma after curative resection. Eur J Radiol. 2011;80(3):e221–5.

    Article  PubMed  Google Scholar 

  62. Xu HX, Wang Y, Lu MD, Liu LN. Percutaneous ultrasound-guided thermal ablation for intrahepatic cholangiocarcinoma. Br J Radiol. 2012;85(1016):1078–84.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Giorgio A, Calisti G, DE Stefano G, et al. Radiofrequency ablation for intrahepatic cholangiocarcinoma: retrospective analysis of a single centre experience. Anticancer Res. 2011;31(12):4575–80.

    PubMed  Google Scholar 

  64. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81.

    Article  CAS  PubMed  Google Scholar 

  65. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer. 2007;96(6):896–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rogers JE, Law L, Nguyen VD, et al. Second-line systemic treatment for advanced cholangiocarcinoma. J Gastrointest Oncol. 2014;5(6):408–13.

    PubMed  PubMed Central  Google Scholar 

  67. Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol. 2014;25(12):2328–38.

    Article  CAS  PubMed  Google Scholar 

  68. Borbath I, Ceratti A, Verslype C, et al. Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology. Ann Oncol. 2013;24(11):2824–9.

    Article  CAS  PubMed  Google Scholar 

  69. Burris H, Mellinghoff I, Maher E, et al. Abstract PL04-05: the first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas. Mol Cancer Ther. 2015;14(12 Supplement 2):PL04–5.

    Google Scholar 

  70. Chen JS, Hsu C, Chiang NJ, et al. A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. Ann Oncol. 2015;26(5):943–9.

    Article  CAS  PubMed  Google Scholar 

  71. Chiorean EG, Ramasubbaiah R, Yu M, et al. Phase II trial of erlotinib and docetaxel in advanced and refractory hepatocellular and biliary cancers: Hoosier Oncology Group GI06-101. Oncologist. 2012;17(1):13.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Gruenberger B, Schueller J, Heubrandtner U, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol. 2010;11(12):1142–8.

    Article  CAS  PubMed  Google Scholar 

  73. Hezel AF, Noel MS, Allen JN, et al. Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer. Br J Cancer. 2014;111(3):430–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36(3):276–82.

    Article  CAS  PubMed  Google Scholar 

  75. Jensen LH, Lindebjerg J, Ploen J, Hansen TF, Jakobsen A. Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer. Ann Oncol. 2012;23(9):2341–6.

    Article  CAS  PubMed  Google Scholar 

  76. Lee J, Park SH, Chang HM, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13(2):181–8.

    Article  CAS  PubMed  Google Scholar 

  77. Leone F, Marino D, Cereda S, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer. 2016;122(4):574–81.

    Article  CAS  PubMed  Google Scholar 

  78. Malka D, Cervera P, Foulon S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Paule B, Herelle MO, Rage E, et al. Cetuximab plus gemcitabine-oxaliplatin (GEMOX) in patients with refractory advanced intrahepatic cholangiocarcinomas. Oncology. 2007;72(1–2):105–10.

    Article  CAS  PubMed  Google Scholar 

  80. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol. 2006;24(19):3069–74.

    Article  CAS  PubMed  Google Scholar 

  81. Rubovszky G, Lang I, Ganofszky E, et al. Cetuximab, gemcitabine and capecitabine in patients with inoperable biliary tract cancer: a phase 2 study. Eur J Cancer. 2013;49(18):3806–12.

    Article  CAS  PubMed  Google Scholar 

  82. Sohal DP, Mykulowycz K, Uehara T, et al. A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma. Ann Oncol. 2013;24(12):3061–5.

    Article  CAS  PubMed  Google Scholar 

  83. Vogel A, Kasper S, Weichert W, et al. Panitumumab in combination with gemcitabine/cisplatin (GemCis) for patients with advanced KRAS WT biliary tract cancer: a randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol. 2015;33(15_suppl):4082.

    Article  Google Scholar 

  84. Bengala C, Bertolini F, Malavasi N, et al. Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial. Br J Cancer. 2010;102(1):68–72.

    Article  CAS  PubMed  Google Scholar 

  85. El-Khoueiry AB, Rankin CJ, Ben-Josef E, et al. SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Investig New Drugs. 2012;30(4):1646–51.

    Article  CAS  Google Scholar 

  86. Lee JK, Capanu M, O’Reilly EM, et al. A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas. Br J Cancer. 2013;109(4):915–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Moehler M, Ehrlich A, Ruckes C, et al. 2322 safety and efficacy of Afatinib with gemcitabine/cisplatin in chemo-naïve patients with metastatic biliary tract cancer: an open-label, uncontrolled phase Ib trial. Eur J Cancer. 2015;51:S440.

    Article  Google Scholar 

  88. Moehler M, Maderer A, Schimanski C, et al. Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme. Eur J Cancer. 2014;50(18):3125–35.

    Article  CAS  PubMed  Google Scholar 

  89. Neuzillet C, Seitz J-F, Fartoux L, et al. Sunitinib as second-line treatment in patients with advanced intrahepatic cholangiocarcinoma (SUN-CK phase II trial): safety, efficacy, and updated translational results. J Clin Oncol. 2015;33(3_suppl):343.

    Article  Google Scholar 

  90. Ramanathan RK, Belani CP, Singh DA, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol. 2009;64(4):777–83.

    Article  CAS  PubMed  Google Scholar 

  91. Santoro A, Gebbia V, Pressiani T, et al. A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study. Ann Oncol. 2015;26(3):542–7.

    Article  CAS  PubMed  Google Scholar 

  92. Yi JH, Thongprasert S, Lee J, et al. A phase II study of sunitinib as a second-line treatment in advanced biliary tract carcinoma: a multicentre, multinational study. Eur J Cancer. 2012;48(2):196–201.

    Article  CAS  PubMed  Google Scholar 

  93. Zhu AX, Meyerhardt JA, Blaszkowsky LS, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010;11(1):48–54.

    Article  CAS  PubMed  Google Scholar 

  94. Ahn DH, Li J, Wei L, et al. Results of an abbreviated phase-II study with the Akt inhibitor MK-2206 in patients with advanced biliary cancer. Sci Rep. 2015;5:12122.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Bekaii-Saab T, Phelps MA, Li X, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol. 2011;29(17):2357–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bridgewater J, Lopes A, Beare S, et al. A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study. BMC Cancer. 2016;16:153.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Goyal L, Zheng H, Yurgelun MB, et al. A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Cancer. 2017;123(11):1979–88.

    Article  CAS  PubMed  Google Scholar 

  98. Ioka T, Ikeda M, Fukutomi A, et al. 2382 a proof-of-concept study of MEK inhibitor trametinib monotherapy in patients with biliary tract cancers. Eur J Cancer. 2015;51:S464.

    Article  Google Scholar 

  99. Iyer RV, Pokuri VK, Groman A, et al. A multicenter phase II study of gemcitabine, Capecitabine, and bevacizumab for locally advanced or metastatic biliary tract cancer. Am J Clin Oncol. 2018;41(7):649–55.

    Article  CAS  PubMed  Google Scholar 

  100. Valle JW, Wasan H, Lopes A, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol. 2015;16(8):967–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. El-Khoueiry AB, Rankin C, Siegel AB, et al. S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma. Br J Cancer. 2014;110(4):882–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jensen LH, Fernebro E, Ploen J, Eberhard J, Lindebjerg J, Jakobsen AKM. Randomized phase II crossover trial exploring the clinical benefit from targeting EGFR or VEGF with combination chemotherapy in patients with non-resectable biliary tract cancer. J Clin Oncol. 2015;33(15_suppl):4071.

    Article  Google Scholar 

  103. Lubner SJ, Mahoney MR, Kolesar JL, et al. 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. 2010;28(21):3491–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Shroff RT, Yarchoan M, O’Connor A, et al. The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Br J Cancer. 2017;116(11):1402–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sun W, Normolle DP, Bahary N, et al. A phase 2 trial of regorafenib as a single agent in patients with chemotherapy-refractory advanced and metastatic biliary adenocarcinoma/cholangiocarcinoma. J Clin Oncol. 2017;35(15_suppl):4081.

    Article  Google Scholar 

  106. Luo X, Jia W, Huang Z, et al. Effectiveness and safety of sorafenib in the treatment of unresectable and advanced intrahepatic cholangiocarcinoma: a pilot study. Oncotarget. 2017;8(10):17246–57.

    Article  PubMed  Google Scholar 

  107. Lowery MA, O’Reilly EM, Harding JJ, et al. A phase I trial of binimetinib in combination with gemcitabine (G) and cisplatin (C) patients (pts) with untreated advanced biliary cancer (ABC). J Clin Oncol. 2015;33(15_suppl):e15125.

    Article  Google Scholar 

  108. Bridgewater JA, Goodman KA, Kalyan A, Mulcahy MF. Biliary tract cancer: epidemiology, radiotherapy, and molecular profiling. Am Soc Clin Oncol Educ Book. 2016;35:e194–203.

    Article  PubMed  Google Scholar 

  109. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17(1):72–9.

    Article  CAS  PubMed  Google Scholar 

  110. Javle M, Bekaii-Saab T, Jain A, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016;122(24):3838–47.

    Article  CAS  PubMed  Google Scholar 

  111. Goyal L, Govindan A, Sheth RA, et al. Prognosis and Clinicopathologic features of patients with advanced stage Isocitrate Dehydrogenase (IDH) mutant and IDH wild-type intrahepatic cholangiocarcinoma. Oncologist. 2015;20(9):1019–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhu AX, Borger DR, Kim Y, et al. Genomic profiling of intrahepatic cholangiocarcinoma: refining prognosis and identifying therapeutic targets. Ann Surg Oncol. 2014;21(12):3827–34.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lowery MA, Abou-Alfa GK, Burris HA, et al. Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: results from the cholangiocarcinoma dose escalation and expansion cohorts. J Clin Oncol. 2017;35(15_suppl):4015.

    Article  Google Scholar 

  114. Abdel-Wahab R, Ali SM, Borad MJ, et al. Variations in DNA repair genomic alterations and tumor mutation burden in biliary tract cancer (BTC) subtypes. J Clin Oncol. 2018;36(4_suppl):263.

    Article  Google Scholar 

  115. Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. BioEssays. 2004;26(8):882–93.

    Article  CAS  PubMed  Google Scholar 

  116. Turk AA, Deming DA, Lubner SJ, et al. A phase I study of veliparib (Vel) in combination with oxaliplatin (Ox) and capecitabine (Cap) in advanced solid tumors. J Clin Oncol. 2018;36(4_suppl):314.

    Article  Google Scholar 

  117. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17(12):e542–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Dijkstra KK, Voabil P, Schumacher TN, Voest EE. Genomics- and transcriptomics-based patient selection for cancer treatment with immune checkpoint inhibitors: a review. JAMA Oncol. 2016;2(11):1490–5.

    Article  PubMed  Google Scholar 

  120. Chong DQ, Zhu AX. The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget. 2016;7(29):46750–67.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Kim ST, Jang KT, Lee J, et al. Molecular subgroup analysis of clinical outcomes in a phase 3 study of gemcitabine and Oxaliplatin with or without Erlotinib in advanced biliary tract cancer. Transl Oncol. 2015;8(1):40–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lavingia V, Fakih M. Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief review. J Gastrointest Oncol. 2016;7(6):E98–E102.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Loaiza-Bonilla A, Clayton E, Furth E, O’Hara M, Morrissette J. Dramatic response to dabrafenib and trametinib combination in a BRAF V600E-mutated cholangiocarcinoma: implementation of a molecular tumour board and next-generation sequencing for personalized medicine. Ecancermedicalscience. 2014;8:479.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Efficacy of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer (ATC). J Clin Oncol. 2017;35(15_suppl):6023.

    Article  Google Scholar 

  125. Al-Shamsi HO, Anand D, Shroff RT, et al. BRCA-associated protein 1 mutant cholangiocarcinoma: an aggressive disease subtype. J Gastrointest Oncol. 2016;7(4):556–61.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Kwak TW, Kim DH, Jeong Y-I, Kang DH. Antitumor activity of vorinostat-incorporated nanoparticles against human cholangiocarcinoma cells. J Nanobiotechnol. 2015;13:60.

    Article  CAS  Google Scholar 

  127. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Koster BD, de Gruijl TD, van den Eertwegh AJ. Recent developments and future challenges in immune checkpoint inhibitory cancer treatment. Curr Opin Oncol. 2015;27(6):482–8.

    Article  CAS  PubMed  Google Scholar 

  131. Goeppert B, Frauenschuh L, Zucknick M, et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer. 2013;109(10):2665–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.

    Article  CAS  PubMed  Google Scholar 

  133. Fukunaga A, Miyamoto M, Cho Y, et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28(1):e26–31.

    Article  PubMed  Google Scholar 

  134. Wang Y, Ding M, Zhang Q, et al. Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis. J Cancer. 2017;8(1):74–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chen DS, Mellman I. Elements of cancer immunity and the cancer–immune set point. Nature. 2017;541:321.

    Article  CAS  PubMed  Google Scholar 

  136. Herbst RS, Soria J-C, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bonneville R, Krook MA, Kautto EA, Miya J, Wing MR, Chen HZ, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;2017.

    Google Scholar 

  138. Silva VW, Askan G, Daniel TD, et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin Clin Oncol. 2016;5(5):62.

    Article  PubMed  Google Scholar 

  139. Diaz LA, Marabelle A, Delord J-P, et al. Pembrolizumab therapy for microsatellite instability-high (MSI-H) colorectal cancer (CRC) and non-CRC. J Clin Oncol. 2017;35(15_suppl):3071.

    Article  Google Scholar 

  140. Aruga A. Vaccination of biliary tract cancer patients with four peptides derived from cancer-testis antigens. Oncoimmunology. 2013;2(7):e24882.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Yoshitomi M, Yutani S, Matsueda S, et al. Personalized peptide vaccination for advanced biliary tract cancer: IL-6, nutritional status and pre-existing antigen-specific immunity as possible biomarkers for patient prognosis. Exp Ther Med. 2012;3(3):463–9.

    Article  CAS  PubMed  Google Scholar 

  142. Shimizu K, Kotera Y, Aruga A, Takeshita N, Takasaki K, Yamamoto M. Clinical utilization of postoperative dendritic cell vaccine plus activated T-cell transfer in patients with intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2012;19(2):171–8.

    Article  PubMed  Google Scholar 

  143. Kida A, Mizukoshi E, Tamai T, et al. Immune responses against tumor-associated antigen-derived cytotoxic T lymphocyte epitopes in cholangiocarcinoma patients. Liver Int. 2018;38(11):2040–50.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jonathan D. Mizrahi

  2. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Reham Abdel-Wahab & Milind Javle

  3. Clinical Oncology Department, Faculty of Medicine, Assiut University, Asyut, Egypt

    Reham Abdel-Wahab

Authors
  1. Jonathan D. Mizrahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reham Abdel-Wahab
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Milind Javle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Milind Javle .

Editor information

Editors and Affiliations

  1. Wexner Medical Center, The Ohio State University, Columbus, OH, USA

    Timothy M. Pawlik

  2. Wexner Medical Center, The Ohio State University, Columbus, OH, USA

    Jordan M. Cloyd

  3. Wexner Medical Center, The Ohio State University, Columbus, OH, USA

    Mary Dillhoff

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mizrahi, J.D., Abdel-Wahab, R., Javle, M. (2019). Clinical Trials and Novel/Emerging Treatment. In: Pawlik, T., Cloyd, J., Dillhoff, M. (eds) Intrahepatic Cholangiocarcinoma. Springer, Cham. https://doi.org/10.1007/978-3-030-22258-1_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-22258-1_13

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-22257-4

  • Online ISBN: 978-3-030-22258-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation