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Systemic Therapy

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Intrahepatic Cholangiocarcinoma

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Abstract

Intrahepatic cholangiocarcinoma represents the second most common primary liver cancer and its incidence is rising. For patients with resected intrahepatic cholangiocarcinoma, the optimal adjuvant chemotherapy has not been determined due to the limited data from randomized trials. Most of the studies are retrospective, small, and heterogeneous in their inclusion of periampullary and biliary tract cancers. BILCAP is the only randomized phase III study that has shown adjuvant capecitabine has improved overall survival compared with observation with a significant statistical difference in the per-protocol analysis. For patients with locally advanced or metastatic intrahepatic cholangiocarcinoma, systemic chemotherapy offers improvements in quality of life and prolongs the overall survival. The phase III ABC-02 study has established the gemcitabine/cisplatin combination as a standard of care for advanced cholangiocarcinoma. There is no established second-line chemotherapy following progression although fluoropyrimidine-based therapy can be considered. Results from studies of EGFR (epithelial growth factor receptor) or VEGF (vascular endothelial growth factor) inhibitors in combination with chemotherapy have been disappointing given the lack of benefit in overall survival. There is no evidence to support the use of targeted therapy except in the clinical trial setting.

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References

  1. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer. 2002;2:10.

    Article  Google Scholar 

  2. Yeo CJ, Pitt HA, Cameron JL. Cholangiocarcinoma. Surg Clin North Am. 1990;70(6):1429–47.

    Article  CAS  Google Scholar 

  3. Bengmark S, Ekberg H, Evander A, Klofver-Stahl B, Tranberg KG. Major liver resection for hilar cholangiocarcinoma. Ann Surg. 1988;207(2):120–5.

    Article  CAS  Google Scholar 

  4. Nagorney DM, Donohue JH, Farnell MB, Schleck CD, Ilstrup DM. Outcomes after curative resections of cholangiocarcinoma. Arch Surg. 1993;128(8):871–7; discussion 7–9.

    Article  CAS  Google Scholar 

  5. Kraybill WG, Lee H, Picus J, Ramachandran G, Lopez MJ, Kucik N, et al. Multidisciplinary treatment of biliary tract cancers. J Surg Oncol. 1994;55(4):239–45.

    Article  CAS  Google Scholar 

  6. Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg. 2007;11(11):1488–96; discussion 96–7.

    Article  Google Scholar 

  7. Spolverato G, Vitale A, Cucchetti A, Popescu I, Marques HP, Aldrighetti L, et al. Can hepatic resection provide a long-term cure for patients with intrahepatic cholangiocarcinoma? Cancer. 2015;121(22):3998–4006.

    Article  Google Scholar 

  8. Yamamoto M, Takasaki K, Otsubo T, Katsuragawa H, Katagiri S. Recurrence after surgical resection of intrahepatic cholangiocarcinoma. J Hepato-Biliary-Pancreat Surg. 2001;8(2):154–7.

    Article  CAS  Google Scholar 

  9. Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7(6):593–600.

    Article  CAS  Google Scholar 

  10. Ercolani G, Vetrone G, Grazi GL, Aramaki O, Cescon M, Ravaioli M, et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg. 2010;252(1):107–14.

    Article  Google Scholar 

  11. Sur MD, In H, Sharpe SM, Baker MS, Weichselbaum RR, Talamonti MS, et al. Defining the benefit of adjuvant therapy following resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2015;22(7):2209–17.

    Article  Google Scholar 

  12. Miura JT, Johnston FM, Tsai S, George B, Thomas J, Eastwood D, et al. Chemotherapy for surgically resected intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2015;22(11):3716–23.

    Article  Google Scholar 

  13. Okamoto M, Yamagata Z, Takeda Y, Yoda Y, Kobayashi K, Fujino MA. The relationship between gallbladder disease and smoking and drinking habits in middle-aged Japanese. J Gastroenterol. 2002;37(6):455–62.

    Article  Google Scholar 

  14. Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95(8):1685–95.

    Article  Google Scholar 

  15. Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA. 2012;308(2):147–56.

    Article  CAS  Google Scholar 

  16. Primrose JN, Fox R, Palmer DH, Prasad R, Mirza D, Anthoney DA, et al. Adjuvant capecitabine for biliary tract cancer: the BILCAP randomized study. J Clin Oncol. 2017;35(15_suppl):4006.

    Article  Google Scholar 

  17. Edeline J, Bonnetain F, Phelip JM, Watelet J, Hammel P, Joly J-P, et al. Gemox versus surveillance following surgery of localized biliary tract cancer: results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial. J Clin Oncol. 2017;35(4_suppl):225.

    Article  Google Scholar 

  18. Kubicka S, Rudolph KL, Tietze MK, Lorenz M, Manns M. Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepato-Gastroenterology. 2001;48(39):783–9.

    CAS  PubMed  Google Scholar 

  19. Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Lenauer A, et al. Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol. 2001;12(2):183–6.

    Article  CAS  Google Scholar 

  20. Park JS, Oh SY, Kim SH, Kwon HC, Kim JS, Jin-Kim H, et al. Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study. Jpn J Clin Oncol. 2005;35(2):68–73.

    Article  Google Scholar 

  21. Novarino AM, Satolli MA, Chiappino I, Giacobino A, Napoletano R, Ceccarelli M, et al. FOLFOX-4 regimen or single-agent gemcitabine as first-line chemotherapy in advanced biliary tract cancer. Am J Clin Oncol. 2013;36(5):466–71.

    Article  CAS  Google Scholar 

  22. Takada T, Kato H, Matsushiro T, Nimura Y, Nagakawa T, Nakayama T. Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology. 1994;51(5):396–400.

    Article  CAS  Google Scholar 

  23. Ducreux M, Rougier P, Fandi A, Clavero-Fabri MC, Villing AL, Fassone F, et al. Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin. Ann Oncol. 1998;9(6):653–6.

    Article  CAS  Google Scholar 

  24. Sanz-Altamira PM, Ferrante K, Jenkins RL, Lewis WD, Huberman MS, Stuart KE. A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma. Cancer. 1998;82(12):2321–5.

    Article  CAS  Google Scholar 

  25. Choi CW, Choi IK, Seo JH, Kim BS, Kim JS, Kim CD, et al. Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol. 2000;23(4):425–8.

    Article  CAS  Google Scholar 

  26. Chen JS, Jan YY, Lin YC, Wang HM, Chang WC, Liau CT. Weekly 24 h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract carcinomas. Anti-Cancer Drugs. 1998;9(5):393–7.

    Article  CAS  Google Scholar 

  27. Malik IA, Aziz Z. Prospective evaluation of efficacy and toxicity of 5-fu and folinic acid (Mayo Clinic regimen) in patients with advanced cancer of the gallbladder. Am J Clin Oncol. 2003;26(2):124–6.

    Article  CAS  Google Scholar 

  28. Patt YZ, Hassan MM, Aguayo A, Nooka AK, Lozano RD, Curley SA, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004;101(3):578–86.

    Article  CAS  Google Scholar 

  29. Knox JJ, Hedley D, Oza A, Feld R, Siu LL, Chen E, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol. 2005;23(10):2332–8.

    Article  CAS  Google Scholar 

  30. Koeberle D, Saletti P, Borner M, Gerber D, Dietrich D, Caspar CB, et al. Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2008;26(22):3702–8.

    Article  CAS  Google Scholar 

  31. Riechelmann RP, Townsley CA, Chin SN, Pond GR, Knox JJ. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer. 2007;110(6):1307–12.

    Article  CAS  Google Scholar 

  32. Meyerhardt JA, Zhu AX, Stuart K, Ryan DP, Blaszkowsky L, Lehman N, et al. Phase-II study of gemcitabine and cisplatin in patients with metastatic biliary and gallbladder cancer. Dig Dis Sci. 2008;53(2):564–70.

    Article  CAS  Google Scholar 

  33. Andre T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F, Avenin D, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol. 2004;15(9):1339–43.

    Article  CAS  Google Scholar 

  34. Kim ST, Park JO, Lee J, Lee KT, Lee JK, Choi SH, et al. A phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer. 2006;106(6):1339–46.

    Article  CAS  Google Scholar 

  35. Harder J, Riecken B, Kummer O, Lohrmann C, Otto F, Usadel H, et al. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer. 2006;95(7):848–52.

    Article  CAS  Google Scholar 

  36. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  38. Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer. 2010;103(4):469–74.

    Article  CAS  Google Scholar 

  39. Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomized trials. Ann Oncol. 2014;25(2):391–8.

    Article  CAS  Google Scholar 

  40. Manzione L, Romano R, Germano D. Chemotherapy with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer: a single-institution experience. Oncology. 2007;73(5–6):311–5.

    Article  CAS  Google Scholar 

  41. Andre T, Reyes-Vidal JM, Fartoux L, Ross P, Leslie M, Rosmorduc O, et al. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J Cancer. 2008;99(6):862–7.

    Article  CAS  Google Scholar 

  42. Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T, Arnold D, et al. Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2016;27(suppl 5):v28–37.

    Article  CAS  Google Scholar 

  43. Williams KJ, Picus J, Trinkhaus K, Fournier CC, Suresh R, James JS, et al. Gemcitabine with carboplatin for advanced biliary tract cancers: a phase II single-institution study. HPB (Oxford). 2010;12(6):418–26.

    Article  Google Scholar 

  44. Bridgewater J, Palmer D, Cunningham D, Iveson T, Gillmore R, Waters J, et al. Outcome of second-line chemotherapy for biliary tract cancer. Eur J Cancer. 2013;49(6):1511.

    Article  CAS  Google Scholar 

  45. He S, Shen J, Sun X, Liu L, Dong J. A phase II FOLFOX-4 regimen as second-line treatment in advanced biliary tract cancer refractory to gemcitabine/cisplatin. J Chemother. 2014;26(4):243–7.

    Article  CAS  Google Scholar 

  46. Zheng Y, Tu X, Zhao P, Jiang W, Liu L, Tong Z, et al. A randomized phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin. Br J Cancer. 2018;119(3):291–5.

    Article  CAS  Google Scholar 

  47. 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  Google Scholar 

  48. Andersen JB. Molecular pathogenesis of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2015;22(2):101–13.

    Article  Google Scholar 

  49. Churi CR, Shroff R, Wang Y, Rashid A, Kang HC, Weatherly J, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9(12):e115383.

    Article  Google Scholar 

  50. Ross JS, Wang K, Gay L, Al-Rohil R, Rand JV, Jones DM, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist. 2014;19(3):235–42.

    Article  CAS  Google Scholar 

  51. 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(2):418–25.

    Article  CAS  Google Scholar 

  52. 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(3):356–65.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  55. Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardiere C, Boucher E, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomized, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28.

    Article  CAS  Google Scholar 

  56. Chen JS, Hsu C, Chiang NJ, Tsai CS, Tsou HH, Huang SF, 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  Google Scholar 

  57. Brechon M, Dior M, Dreanic J, Brieau B, Guillaumot MA, Brezault C, et al. Addition of antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers. Investig New Drugs. 2018;36(1):156–62.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  59. Sirica AE. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol. 2008;14(46):7033–58.

    Article  CAS  Google Scholar 

  60. Borbath I, Ceratti A, Verslype C, Demols A, Delaunoit T, Laurent S, 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  Google Scholar 

  61. Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, 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  Google Scholar 

  62. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003–10.

    Article  CAS  Google Scholar 

  63. Tiong KH, Mah LY, Leong CO. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis. 2013;18(12):1447–68.

    Article  CAS  Google Scholar 

  64. Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014;59(4):1427–34.

    Article  CAS  Google Scholar 

  65. Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R, Bryce AH, et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet. 2014;10(2):e1004135.

    Article  Google Scholar 

  66. Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3(6):636–47.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  68. Lowery MA, Bou-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. American Society of Clinical Oncology Annual Meeting. 2017; Abstract 4015.

    Google Scholar 

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Authors and Affiliations

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

    Ning Jin & Laith Abushahin

  2. Division of Medical Oncology, Department of Internal Medicine, Columbus, OH, USA

    Laith Abushahin

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  1. Ning Jin
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Correspondence to Ning Jin .

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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

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Jin, N., Abushahin, L. (2019). Systemic Therapy. In: Pawlik, T., Cloyd, J., Dillhoff, M. (eds) Intrahepatic Cholangiocarcinoma. Springer, Cham. https://doi.org/10.1007/978-3-030-22258-1_8

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  • DOI: https://doi.org/10.1007/978-3-030-22258-1_8

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