Cancer review: Cholangiocarcinoma

Journal of Carcinogenesis

Volumn 14, Issue 1, 2015, Pages

  Ghouri, Yezaz ^a   Mian, Idrees ^a   Blechacz, Boris ^a  

^a UNIVERSITY OF TEXAS   (United States)

Author keywords

Cholangiocarcinoma; extrahepatic cholangiocarcinoma; intrahepatic cholangiocarcinoma; perihilar cholangiocarcinoma

Indexed keywords

CA 19-9 ANTIGEN; CISPLATIN; GEMCITABINE; ANGIOPOIETIN 2; BIOLOGICAL MARKER; ERLOTINIB; NAVITOCLAX; TUMOR MARKER;

ADJUVANT CHEMORADIOTHERAPY; BILE DUCT CARCINOMA; CANCER PROGNOSIS; CANCER STAGING; CARCINOGENESIS; CHEMOEMBOLIZATION; ECHOGRAPHY; HUMAN; LIVER TRANSPLANTATION; MAGNETIC RESONANCE CHOLANGIOPANCREATOGRAPHY; METASTASIS; MOLECULARLY TARGETED THERAPY; NUCLEAR MAGNETIC RESONANCE IMAGING; PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY; POSITRON EMISSION TOMOGRAPHY; PRIMARY SCLEROSING CHOLANGITIS; RADIOFREQUENCY ABLATION; REVIEW; SURVIVAL RATE; ABLATION THERAPY; ARTICLE; CANCER MORTALITY; CANCER SURVIVAL; COMPUTER ASSISTED TOMOGRAPHY; DIFFERENTIAL DIAGNOSIS; DISTAL EXTRAHEPATIC CHOLANGIOCARCINOMA; ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY; EXTERNAL BEAM RADIOTHERAPY; EXTRAHEPATIC CHOLANGIOCARCINOMA; PANCREATICODUODENECTOMY; PATHOGENESIS; PERIHILAR CHOLANGIOCARCINOMA; PHOTODYNAMIC THERAPY; PREVALENCE; RISK FACTOR; STENT;

EID: 84937576606     PISSN: 09746773     EISSN: 14773163     Source Type: Journal    
DOI: 10.4103/1477-3163.151940     Document Type: Review

References (102)

1. 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.
2. Hirohashi K, Uenishi T, Kubo S, Yamamoto T, Tanaka H, Shuto T, et al. Macroscopic types of intrahepatic cholangiocarcinoma: Clinicopathologic features and surgical outcomes. Hepatogastroenterology 2002;49:326-9.
3. Olnes MJ, Erlich R. A review and update on cholangiocarcinoma. Oncology 2004;66:167-79.
4. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115-25.
5. DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, et al. Cholangiocarcinoma: Thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007;245:755-62.
6. 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.
7. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: A true increase? J Hepatol 2004;40:472-7.
8. McLean L, Patel T. Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinoma in the United States. Liver Int 2006;26:1047-53.
9. Shin HR, Oh JK, Masuyer E, Curado MP, Bouvard V, Fang YY, et al. Epidemiology of cholangiocarcinoma: An update focusing on risk factors. Cancer Sci 2010;101:579-85.
10. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33:1353-7.
11. Bragazzi MC, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Rosanna Venere, Rossella Semeraro, et al. Cholangiocarcinoma: Epidemiology and risk factors. Transl Gastrointest Cancer 2012;1:21-32.
12. Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts, and pancreas. Cancer 1995;75:171-90.
13. Welzel TM, McGlynn KA, Hsing AW, OBrien TR, Pfeiffer RM. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst 2006;98:873-5.
14. Liu R, Cox K, Guthery SL, Book L, Witt B, Chadwick B, et al. Cholangiocarcinoma and high-grade dysplasia in young patients with primary sclerosing cholangitis. Dig Dis Sci 2014;59:2320-4.
15. Morris-Stiff G, Bhati C, Olliff S, Hubscher S, Gunson B, Mayer D, et al. Cholangiocarcinoma complicating primary sclerosing cholangitis: A 24-year experience. Dig Surg 2008;25:126-32.
16. Kerr SE, Barr Fritcher EG, Campion MB, Voss JS, Kipp BR, Halling KC, et al. Biliary dysplasia in primary sclerosing cholangitis harbors cytogenetic abnormalities similar to cholangiocarcinoma. Hum Pathol 2014;45:1797-804.
17. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 2004;99:523-6.
18. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002;89:962-70.
19. Kurathong S, Lerdverasirikul P, Wongpaitoon V, Pramoolsinsap C, Kanjanapitak A, Varavithya W, et al. Opisthorchis viverrini infection and cholangiocarcinoma. A prospective, case-controlled study. Gastroenterology 1985;89:151-6.
20. Jang KT, Hong SM, Lee KT, Lee JG, Choi SH, Heo JS, et al. Intraductal papillary neoplasm of the bile duct associated with Clonorchis sinensis infection. Virchows Arch 2008;453:589-98.
21. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A changing pattern of presentation. Ann Surg 1994;220:644-52.
22. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology 2011;54:173-84.
23. Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology 2005;128:1655-67.
24. Chen MF, Jan YY, Wang CS, Hwang TL, Jeng LB, Chen SC, et al. A reappraisal of cholangiocarcinoma in patient with hepatolithiasis. Cancer 1993;71:2461-5.
25. Liu D, Momoi H, Li L, Ishikawa Y, Fukumoto M. Microsatellite instability in thorotrast-induced human intrahepatic cholangiocarcinoma. Int J Cancer 2002;102:366-71.
26. Walker NJ, Crockett PW, Nyska A, Brix AE, Jokinen MP, Sells DM, et al. Dose-additive carcinogenicity of a defined mixture of "dioxin-like compounds". Environ Health Perspect 2005;113:43-8.
27. Gunay-Aygun M, Gahl WA, Heller T. Congenital hepatic fibrosis overview. University of Washington, Seattle, Seattle (WA); 1993.
28. Matsumoto K, Onoyama T, Kawata S, Takeda Y, Harada K, Ikebuchi Y, et al. Hepatitis B and C virus infection is a risk factor for the development of cholangiocarcinoma. Intern Med 2014;53:651-4.
29. Wu Y, Wang T, Ye S, Zhao R, Bai X, Wu Y, et al. Detection of hepatitis B virus DNA in paraffin-embedded intrahepatic and extrahepatic cholangiocarcinoma tissue in the northern Chinese population. Hum Pathol 2012;43:56-61.
30. Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: A population-based case-control study. Clin Gastroenterol Hepatol 2007;5:1221-8.
31. Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol 2012;57:69-76.
32. Li JS, Han TJ, Jing N, Li L, Zhang XH, Ma FZ, et al. Obesity and the risk of cholangiocarcinoma: A meta-analysis. Tumour Biol 2014;35:6831-8.
33. Chang JS, Tsai CR, Chen LT. Medical risk factors associated with cholangiocarcinoma in Taiwan: A population-based case-control study. PLoS One 2013;8:e69981.
34. Jing W, Jin G, Zhou X, Zhou Y, Zhang Y, Shao C, et al. Diabetes mellitus and increased risk of cholangiocarcinoma: A meta-analysis. Eur J Cancer Prev 2012;21:24-31.
35. Chaiteerakij R, Yang JD, Harmsen WS, Slettedahl SW, Mettler TA, Fredericksen ZS, et al. Risk factors for intrahepatic cholangiocarcinoma: Association between metformin use and reduced cancer risk. Hepatology 2013;57:648-55.
36. Sugawara H, Yasoshima M, Katayanagi K, Kono N, Watanabe Y, Harada K, et al. Relationship between interleukin-6 and proliferation and differentiation in cholangiocarcinoma. Histopathology 1998;33:145-53.
37. Park J, Tadlock L, Gores GJ, Patel T. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology 1999;30:1128-33.
38. Sripa B, Mairiang E, Thinkhamrop B, Laha T, Kaewkes S, Sithithaworn P, et al. Advanced periductal fibrosis from infection with the carcinogenic human liver fluke Opisthorchis viverrini correlates with elevated levels of interleukin-6. Hepatology 2009;50:1273-81.
39. Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 2000;60:184-90.
40. Ohnishi S, Ma N, Thanan R, Pinlaor S, Hammam O, Murata M, et al. DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid Med Cell Longev 2013;2013:387014.
41. Torok NJ, Higuchi H, Bronk S, Gores GJ. Nitric oxide inhibits apoptosis downstream of cytochrome C release by nitrosylating caspase 9. Cancer Res 2002;62:1648-53.
42. Malhi H, Gores GJ. Cholangiocarcinoma: Modern advances in understanding a deadly old disease. J Hepatol 2006;45:856-67.
43. Kang BK, Jung BK, Lee YS, Hwang IK, Lim H, Cho J, et al. A case of Fasciola hepatica infection mimicking cholangiocarcinoma and ITS-1 sequencing of the worm. Korean J Parasitol 2014;52:193-6.
44. Kim YH, Kang KJ, Kwon JH. Four cases of hepatic fascioliasis mimicking cholangiocarcinoma. Korean J Hepatol 2005;11:169-75.
45. Vosskuhl K, Negm AA, Framke T, Weismuller T, Manns MP, Wedemeyer H, et al. Measurement of IgG4 in bile: A new approach for the diagnosis of IgG4-associated cholangiopathy. Endoscopy 2012;44:48-52.
46. Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WM, Taylor-Robinson SD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: Consensus document. Gut 2002;51 Suppl 6:VI1-9.
47. Lee HY, Kim SH, Lee JM, Kim SW, Jang JY, Han JK, et al. Preoperative assessment of resectability of hepatic hilar cholangiocarcinoma: Combined CT and cholangiography with revised criteria. Radiology 2006;239:113-21.
48. Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2011;8:512-22.
49. Blechacz BR, Gores GJ. Cholangiocarcinoma. Clin Liver Dis 2008;12:131-50, ix.
50. Harewood GC, Baron TH, Stadheim LM, Kipp BR, Sebo TJ, Salomao DR. Prospective, blinded assessment of factors influencing the accuracy of biliary cytology interpretation. Am J Gastroenterol 2004;99:1464-9.
51. Kipp BR, Stadheim LM, Halling SA, Pochron NL, Harmsen S, Nagorney DM, et al. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol 2004;99:1675-81.
52. Halling KC, Kipp BR. Fluorescence in situ hybridization in diagnostic cytology. Hum Pathol 2007;38:1137-44.
53. Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 2004;24:139-54.
54. Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 2005;50:1734-40.
55. Metzger J, Negm AA, Plentz RR, Weismuller TJ, Wedemeyer J, Karlsen TH, et al. Urine proteomic analysis differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders. Gut 2013;62:122-30.
56. Voigtlander T, David S, Thamm K, Schlue J, Metzger J, Manns MP, et al. Angiopoietin-2 and biliary diseases: Elevated serum, but not bile levels are associated with cholangiocarcinoma. PLoS One 2014;9:e97046.
57. de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, et al. Intrahepatic cholangiocarcinoma: An international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011;29:3140-5.
58. Spolverato G, Ejaz A, Kim Y, Sotiropoulos GC, Pau A, Alexandrescu S, et al. Tumor size predicts vascular invasion and histologic grade among patients undergoing resection of intrahepatic cholangiocarcinoma. J Gastrointest Surg 2014;18:1284-91.
59. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014;60:1268-89.
60. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed, Springer; 2010.
61. Nathan H, Aloia TA, Vauthey JN, Abdalla EK, Zhu AX, Schulick RD, et al. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2009;16:14-22.
62. Farges O, Fuks D, Le Treut YP, Azoulay D, Laurent A, Bachellier P, et al. AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma: By the AFC-IHCC-2009 study group. Cancer 2011;117:2170-7.
63. Yamasaki S. Intrahepatic cholangiocarcinoma: Macroscopic type and stage classification. J Hepatobiliary Pancreat Surg 2003;10:288-91.
64. Uenishi T, Ariizumi S, Aoki T, Ebata T, Ohtsuka M, Tanaka E, et al. Proposal of a new staging system for mass-forming intrahepatic cholangiocarcinoma: A multicenter analysis by the Study Group for Hepatic Surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci 2014;21:499-508.
65. Ercolani G, Zanello M, Grazi GL, Cescon M, Ravaioli M, Del Gaudio M, et al. Changes in the surgical approach to hilar cholangiocarcinoma during an 18-year period in a Western single center. J Hepatobiliary Pancreat Sci 2010;17:329-37.
66. Klempnauer J, Ridder GJ, von Wasielewski R, Werner M, Weimann A, Pichlmayr R. Resectional surgery of hilar cholangiocarcinoma: A multivariate analysis of prognostic factors. J Clin Oncol 1997;15:947-54.
67. Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Pedersen R, Kremers W, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006;82:1703-7.
68. Park J, Kim MH, Kim KP, Park do H, Moon SH, Song TJ, et al. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: A large-scale observational study. Gut Liver 2009;3:298-305.
69. Ebata T, Kosuge T, Hirano S, Unno M, Yamamoto M, Miyazaki M, et al. Proposal to modify the International Union Against Cancer staging system for perihilar cholangiocarcinomas. Br J Surg 2014;101:79-88.
70. Zaydfudim VM, Clark CJ, Kendrick ML, Que FG, Reid-Lombardo KM, Donohue JH, et al. Correlation of staging systems to survival in patients with resected hilar cholangiocarcinoma. Am J Surg 2013;206:159-65.
71. Deoliveira ML, Schulick RD, Nimura Y, Rosen C, Gores G, Neuhaus P, et al. New staging system and a registry for perihilar cholangiocarcinoma. Hepatology 2011;53:1363-71.
72. Hong SM, Pawlik TM, Cho H, Aggarwal B, Goggins M, Hruban RH, et al. Depth of tumor invasion better predicts prognosis than the current American Joint Committee on Cancer T classification for distal bile duct carcinoma. Surgery 2009;146:250-7.
73. Murakami Y, Uemura K, Sudo T, Hashimoto Y, Kondo N, Nakagawa N, et al. Perineural invasion in extrahepatic cholangiocarcinoma: Prognostic impact and treatment strategies. J Gastrointest Surg 2013;17:1429-39.
74. Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, et al. Intrahepatic cholangiocarcinoma: Rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008;248:84-96.
75. Guglielmi A, Ruzzenente A, Campagnaro T, Pachera S, Valdegamberi A, Nicoli P, et al. Intrahepatic cholangiocarcinoma: Prognostic factors after surgical resection. World J Surg 2009;33:1247-54.
76. Lang H, Sotiropoulos GC, Sgourakis G, Schmitz KJ, Paul A, Hilgard P, et al. Operations for intrahepatic cholangiocarcinoma: Single-institution experience of 158 patients. J Am Coll Surg 2009;208:218-28.
77. Morimoto Y, Tanaka Y, Ito T, Nakahara M, Nakaba H, Nishida T, et al. Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2003;10:432-40.
78. 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.
79. Petrowsky H, Hong JC. Current surgical management of hilar and intrahepatic cholangiocarcinoma: The role of resection and orthotopic liver transplantation. Transplant Proc 2009;41:4023-35.
80. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: A systematic review and meta-analysis. J Clin Oncol 2012;30:1934-40.
81. National Comprehensive Cancer Network (NCCN) clinical Practise Guidelines in Oncology. Hepatobiliary Cancers 2014. Available from: http://www.nccn.org/professionals/physician-gls/pdf/hepatobiliary.pdf Version 2.2015. [Last cited on 2014 Feb].
82. 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;103:469-74.
83. Kuhlmann JB, Euringer W, Spangenberg HC, Breidert M, Blum HE, Harder J, et al. Treatment of unresectable cholangiocarcinoma: Conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy. Eur J Gastroenterol Hepatol 2012;24:437-43.
84. Boehm LM, Jayakrishnan TT, Miura JT, Zacharias AJ, Johnston FM, Turaga KK, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol 2015;111:213-20.
85. Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A, et al. Recommendations for liver transplantation for hepatocellular carcinoma: An international consensus conference report. Lancet Oncol 2012;13:e11-22.
86. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An update. Hepatology 2011;53:1020-2.
87. Sapisochin G, Rodriguez de Lope C, Gastaca M, Ortiz de Urbina J, Suarez MA, Santoyo J, et al. "Very early" intrahepatic cholangiocarcinoma in cirrhotic patients: Should liver transplantation be reconsidered in these patients? Am J Transplant 2014;14:660-7.
88. Sotiropoulos GC, Kaiser GM, Lang H, Molmenti EP, Beckebaum S, Fouzas I, et al. Liver transplantation as a primary indication for intrahepatic cholangiocarcinoma: A single-center experience. Transplant Proc 2008;40:3194-5.
89. Fu BS, Zhang T, Li H, Yi SH, Wang GS, Xu C, et al. The role of liver transplantation for intrahepatic cholangiocarcinoma: A single-center experience. Eur Surg Res 2011;47:218-21.
90. Ghali P, Marotta PJ, Yoshida EM, Bain VG, Marleau D, Peltekian K, et al. Liver transplantation for incidental cholangiocarcinoma: Analysis of the Canadian experience. Liver Transpl 2005;11:1412-6.
91. Robles R, Figueras J, Turrion VS, Margarit C, Moya A, Varo E, et al. Liver transplantation for peripheral cholangiocarcinoma: Spanish experience. Transplant Proc 2003;35:1823-4.
92. Hoffmann RT, Paprottka PM, Schon A, Bamberg F, Haug A, Durr EM, et al. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: Factors associated with prolonged survival. Cardiovasc Intervent Radiol 2012;35:105-16.
93. Razumilava N, Gores GJ. Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol 2013;11:13-211.
94. Rosen CB, Heimbach JK, Gores GJ. Liver transplantation for cholangiocarcinoma. Transpl Int 2010;23:692-7.
95. van der Gaag NA, Rauws EA, van Eijck CH, Bruno MJ, van der Harst E, Kubben FJ, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010;362:129-37.
96. Liberato MJ, Canena JM. Endoscopic stenting for hilar cholangiocarcinoma: Efficacy of unilateral and bilateral placement of plastic and metal stents in a retrospective review of 480 patients. BMC Gastroenterol 2012;12:103.
97. Ortner ME, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: A randomized prospective study. Gastroenterology 2003;125:1355-63.
98. Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 2012;142:1021-31 e15.
99. 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, randomised, phase 3 study. Lancet Oncol 2012;13:181-8.
100. Takahashi H, Ojima H, Shimizu H, Furuse J, Furukawa H, Shibata T. Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma. Jpn J Clin Oncol 2014;44:570-8.
101. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014;383:2168-79.
102. Mertens JC, Fingas CD, Christensen JD, Smoot RL, Bronk SF, Werneburg NW, et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 2013;73:897-907.