Abstract
A majority of patients diagnosed with malignancy of the intrahepatic bile ducts, (cholangiocarcinoma) or the extrahepatic bile ducts, either present initially with extensive unresectable disease, or will either develop recurrent disease after surgical resection. These patients will need systemic treatment with chemotherapy to palliate symptoms and prolong survival. Many challenges are faced with the development of effective chemotherapy regimens for these patients.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ishizawa T, Mise Y, Aoki T et al (2010) Surgical technique: new advances for expanding indications and increasing safety in liver resection for HCC: the Eastern perspective. J Hepatobiliary Pancreat Sci 17:389–393
LaFemina J, Jarnagin WR (2012) Surgical management of proximal bile duct cancers. Langenbecks Arch Surg 397:869–879
Kawakubo K, Isayama H, Mizuno S et al (2013) One-step, simultaneous triple endoscopic nasobiliary drainage for hilar biliary stricture. Dig Endosc 25:76–79
Valle JW (2010) Advances in the treatment of metastatic or unresectable biliary tract cancer. Ann Oncol 21(Suppl 7):vii345–vii348
de Jong MC, Nathan H, Sotiropoulos GC et al (2011) Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 29:3140–3145
Gerhardt T, Rings D, Hoblinger A et al (2010) Combination of bilateral metal stenting and trans-stent photodynamic therapy for palliative treatment of hilar cholangiocarcinoma. Z Gastroenterol 48:28–32
Nathan H, Aloia TA, Vauthey JN et al (2009) A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol 16:14–22
Blechacz B, Komuta M, Roskams T et al (2011) Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 8:512–522
Aishima S, Fujita N, Mano Y et al (2009) Different roles of S100P overexpression in intrahepatic cholangiocarcinoma: carcinogenesis of perihilar type and aggressive behavior of peripheral type. Am J Surg Pathol 35:590–598
Chung YE, Kim MJ, Park YN et al (2009) Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation. Radiographics 29:683–700
Inui K, Yoshino J, Miyoshi H (2009) Differential diagnosis and treatment of biliary strictures. Clin Gastroenterol Hepatol 7:S79–S83
Motosugi U, Ichikawa T, Nakajima H et al (2009) Cholangiolocellular carcinoma of the liver: imaging findings. J Comput Assist Tomogr 33:682–688
Kim SH, Lee WJ, Lim HK et al (2007) Sclerosing hepatic carcinoma: helical CT features. Abdom Imaging 32:725–729
Gu XJ, Wang BF, Liu R (2012) Application of (1)(8)F-fluorodeoxyglucose positron emission tomography/computed tomography in preoperative assessment of hilar cholangiocarcinoma. Zhonghua Yi Xue Za Zhi 92:1409–1412
Alvaro D, Bragazzi MC, Benedetti A et al (2011) Cholangiocarcinoma in Italy: a national survey on clinical characteristics, diagnostic modalities and treatment. Results from the “Cholangiocarcinoma” committee of the Italian Association for the Study of Liver disease. Dig Liver Dis 43:60–65
Lee SW, Kim HJ, Park JH et al (2010) Clinical usefulness of 18F-FDG PET-CT for patients with gallbladder cancer and cholangiocarcinoma. J Gastroenterol 45:560–566
Wehbe H, Henson R, Meng F et al (2006) Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res 66:10517–10524
Fava G, Alpini G, Rychlicki C et al (2008) Leptin enhances cholangiocarcinoma cell growth. Cancer Res 68:6752–6761
Marin JJ, Romero MR, Briz O (2010) Molecular bases of liver cancer refractoriness to pharmacological treatment. Curr Med Chem 17:709–740
Namwat N, Amimanan P, Loilome W et al (2008) Characterization of 5-fluorouracil-resistant cholangiocarcinoma cell lines. Chemotherapy 54:343–351
Kongpetch S, Kukongviriyapan V, Prawan A et al (2012) Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. PLoS ONE 7:e34994
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Valle J, Wasan H, Palmer DH et al (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281
Lin MH, Chen JS, Chen HH et al (2003) A phase II trial of gemcitabine in the treatment of advanced bile duct and periampullary carcinomas. Chemotherapy 49:154–158
Alberts SR, Al-Khatib H, Mahoney MR et al (2005) Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Cancer 103:111–118
Sasaki T, Isayama H, Nakai Y et al (2012) Multicenter phase II study of S-1 monotherapy as second-line chemotherapy for advanced biliary tract cancer refractory to gemcitabine. Invest New Drugs 30:708–713
Thongprasert S, Napapan S, Charoentum C et al (2005) Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol 16:279–281
Knox JJ, Hedley D, Oza A et al (2005) Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 23:2332–2338
Jang JS, Lim HY, Hwang IG et al (2010) Gemcitabine and oxaliplatin in patients with unresectable biliary cancer including gall bladder cancer: a Korean Cancer Study Group phase II trial. Cancer Chemother Pharmacol 65:641–647
Gruenberger B, Schueller J, Heubrandtner U et al (2010) Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 11:1142–1148
Nehls O, Oettle H, Hartmann JT et al (2008) Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer 98:309–315
Patt YZ, Hassan MM, Aguayo A et al (2004) Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer 101:578–586
Feisthammel J, Schoppmeyer K, Mossner J et al (2007) Irinotecan with 5-FU/FA in advanced biliary tract adenocarcinomas: a multicenter phase II trial. Am J Clin Oncol 30:319–324
Furuse J, Kasuga A, Takasu A et al (2012) Role of chemotherapy in treatments for biliary tract cancer. J Hepatobiliary Pancreat Sci 19:337–341
Eckmann KR, Patel DK, Landgraf A et al (2011) Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: a retrospective analysis. Gastrointest Cancer Res 4:155–160
Lubner SJ, Mahoney MR, Kolesar JL et al (2010) Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol 28:3491–3497
Bengala C, Bertolini F, Malavasi N et al (2010) Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial. Br J Cancer 102:68–72
El-Khoueiry AB, Rankin CJ, Ben-Josef E et al (2012) SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs 30:1646–1651
Ramanathan RK, Belani CP, Singh DA et al (2009) A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 64:777–783
Bekaii-Saab T, Phelps MA, Li X et al (2011) Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol 29:2357–2363
Philip PA, Mahoney MR, Allmer C et al (2006) Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 24:3069–3074
Jensen LH, Lindebjerg J, Ploen J et al (2012) Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer. Ann Oncol 23:2341–2346
Lee J, Park SH, Chang HM et al (2012) Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 13:181–188
Yi JH, Thongprasert S, Lee J et al (2012) A phase II study of sunitinib as a second-line treatment in advanced biliary tract carcinoma: a multicentre, multinational study. Eur J Cancer 48:196–201
Zhu AX, Meyerhardt JA, Blaszkowsky LS et al (2010) 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 11:48–54
Utispan K, Sonongbua J, Thuwajit P et al (2012) Periostin activates integrin alpha5beta1 through a PI3 K/AKTdependent pathway in invasion of cholangiocarcinoma. Int J Oncol 41:1110–1118
Mertens JC, Fingas CD, Christensen JD et al (2013) Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 73:897–907
Fingas CD, Mertens JC, Razumilava N et al (2012) Targeting PDGFR-beta in cholangiocarcinoma. Liver Int 32:400–409
Sia D, Hoshida Y, Villanueva A et al (2013) Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144:829–840
Andersen JB, Thorgeirsson SS (2012) Genetic profiling of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 28:266–272
Andersen JB, Spee B, Blechacz BR et al (2012) Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 142:1021–1031 e15
Yoshikawa D, Ojima H, Iwasaki M et al (2008) Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer 98:418–425
Yoshikawa D, Ojima H, Kokubu A et al (2009) Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma. Br J Cancer 100:1257–1266
Boonjaraspinyo S, Boonmars T, Wu Z et al (2012) Platelet-derived growth factor may be a potential diagnostic and prognostic marker for cholangiocarcinoma. Tumour Biol 33:1785–1802
Fingas CD, Bronk SF, Werneburg NW et al (2011) Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells. Hepatology 54:2076–2088
Yoon JH, Werneburg NW, Higuchi H et al (2002) Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism. Cancer Res 62:6500–6505
Jan YY, Yeh TS, Yeh JN et al (2004) Expression of epidermal growth factor receptor, apomucins, matrix metalloproteinases, and p53 in rat and human cholangiocarcinoma: appraisal of an animal model of cholangiocarcinoma. Ann Surg 240:89–94
Terada T, Ashida K, Endo K et al (1998) c-erbB-2 protein is expressed in hepatolithiasis and cholangiocarcinoma. Histopathology 33:325–331
Lai GH, Zhang Z, Shen XN et al (2005) erbB-2/neu transformed rat cholangiocytes recapitulate key cellular and molecular features of human bile duct cancer. Gastroenterology 129:2047–2057
Kiguchi K, Carbajal S, Chan K et al (2001) Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 61:6971–6976
Leone F, Cavalloni G, Pignochino Y et al (2006) Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin Cancer Res 12:1680–1685
Zhang Z, Oyesanya RA, Campbell DJ et al (2010) Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy. Hepatology 52:975–986
Sirica AE, Lai GH, Endo K et al (2002) Cyclooxygenase-2 and ERBB-2 in cholangiocarcinoma: potential therapeutic targets. Semin Liver Dis 22:303–313
Sirica AE, Lai GH, Zhang Z (2001) Biliary cancer growth factor pathways, cyclo-oxygenase-2 and potential therapeutic strategies. J Gastroenterol Hepatol 16:363–372
Han C, Demetris AJ, Stolz DB et al (2006) Modulation of Stat3 activation by the cytosolic phospholipase A2alpha and cyclooxygenase-2-controlled prostaglandin E2 signaling pathway. J Biol Chem 281:24831–24846
Han C, Wu T (2005) Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor receptor and Akt. J Biol Chem 280:24053–24063
Zhang Z, Lai GH, Sirica AE (2004) Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated by Akt inactivation and Bax translocation. Hepatology 39:1028–1037
Dobashi A, Imazu H, Tatsumi N et al (2013) Quantitative analysis of VEGF-C mRNA of extrahepatic cholangiocarcinoma with real-time PCR using samples obtained during endoscopic retrograde cholangiopancreatography. Scand J Gastroenterol 48:848–855
Benckert C, Jonas S, Cramer T et al (2003) Transforming growth factor beta 1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells. Cancer Res 63:1083–1092
Sugiyama H, Onuki K, Ishige K et al (2011) Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells. J Gastroenterol 46:779–789
Wiedmann MW, Mossner J (2010) Molecular targeted therapy of biliary tract cancer–results of the first clinical studies. Curr Drug Targets 11:834–850
Meng F, Yamagiwa Y, Taffetani S et al (2005) IL-6 activates serum and glucocorticoid kinase via p38alpha mitogen-activated protein kinase pathway. Am J Physiol Cell Physiol 289:C971–C981
Tan FL, Ooi A, Huang D et al (2010) p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion. Int J Cancer 126:2353–2361
Horiuchi H, Kawamata H, Furihata T et al (2004) A MEK inhibitor (U0126) markedly inhibits direct liver invasion of orthotopically inoculated human gallbladder cancer cells in nude mice. J Exp Clin Cancer Res 23:599–606
Horiuchi H, Kawamata H, Fujimori T et al (2003) A MEK inhibitor (U0126) prolongs survival in nude mice bearing human gallbladder cancer cells with K-ras mutation: analysis in a novel orthotopic inoculation model. Int J Oncol 23:957–963
Radaeva S, Ferreira-Gonzalez A, Sirica AE (1999) Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: a link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. Hepatology 29:1453–1462
Terada T, Nakanuma Y, Sirica AE (1998) Immunohistochemical demonstration of MET overexpression in human intrahepatic cholangiocarcinoma and in hepatolithiasis. Hum Pathol 29:175–180
Socoteanu MP, Mott F, Alpini G et al (2008) c-Met targeted therapy of cholangiocarcinoma. World J Gastroenterol 14:2990–2994
Ge X, Wang Y, Wang Y et al (2013) NK4 gene therapy inhibits HGF/Met-induced growth of human cholangiocarcinoma cells. Dig Dis Sci 58:1636–1643
Tannapfel A, Sommerer F, Benicke M et al (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52:706–712
El Khatib M, Kalnytska A, Palagani V et al (2013) Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma. Hepatology 57:1035–1045
Omenetti A, Diehl AM (2011) Hedgehog signaling in cholangiocytes. Curr Opin Gastroenterol 27:268–275
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Thomas, M.B. (2014). Systemic Therapy: Current Strategies and New Directions. In: Herman, J., Pawlik, T., Thomas, Jr., C. (eds) Biliary Tract and Gallbladder Cancer. Medical Radiology(). Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40558-7_18
Download citation
DOI: https://doi.org/10.1007/978-3-642-40558-7_18
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-40557-0
Online ISBN: 978-3-642-40558-7
eBook Packages: MedicineMedicine (R0)