Cholangiocarcinoma (CCA), or tumor of the biliary tree, is a rare and heterogeneous group of malignancies associated with a very poor prognosis. Depending on their localization along the biliary tree, CCAs are classified as intrahepatic, perihilar, and distal, and these subtypes are now considered different entities that differ in tumor biology, the staging system, management, and prognosis. When diagnosed, an evaluation by a multidisciplinary team is essential; the team must decide on the best therapeutic option. Surgical resection of tumors with negative margins is the best option for all subtypes of CCA, although this is only achieved in less than 50% of cases. Five-year survival rates have increased in the recent past owing to improvements in imaging techniques, which permits resectability to be predicted more accurately, and in surgery. Chemotherapy and radiotherapy are relatively ineffective in treating nonoperable tumors and the resistance of CCA to these therapies is a major problem. Although the combination of gemcitabine plus platinum derivatives is the pharmacological treatment most widely used, to date there is no standard chemotherapy, and new combinations with targeted drugs are currently being tested in ongoing clinical trials. This review summarizes the biology, clinical management, and pharmacological perspectives of these complex tumors. 1. Primary and Metastatic Liver Cancer Primary liver cancer accounts for approximately 10–12% of deaths due to cancer. Although the incidence of this group of cancers is lower than 6% of new cancers diagnosed each year worldwide, the prognosis is usually very poor. The most frequent of these tumors are adenocarcinomas, which include hepatocellular carcinoma (HCC) derived from parenchymal cells—accounting for almost 85% of liver adenocarcinomas and cholangiocarcinoma (CCA), derived from biliary epithelial cells and accounting for the remaining 15%. Other rare primary liver tumors include hemangiosarcoma, derived from endothelial cells, and hepatoblastoma, derived from embryonic or fetal hepatocyte precursors. Even less frequent primary liver cancers are fibrosarcoma and lymphosarcoma. It should also be considered that the liver is highly vulnerable to tumor invasion from extrahepatic metastasis. The large size of the liver, its abundant blood supply, and its double-source vascularization explain why it is the second most common seat of metastasis after lymph nodes. Among the tumors that most frequently metastasize to the liver are colorectal cancer, breast cancer, melanoma, and lung cancer. 2.
References
[1]
P. Bertuccio, C. Bosetti, F. Levi, A. Decarli, E. Negri, and C. La Vecchia, “A comparison of trends in mortality from primary liver cancer and intrahepatic cholangiocarcinoma in Europe,” Annals of Oncology, vol. 24, pp. 1667–1674, 2013.
[2]
Y. Shaib and H. B. El-Serag, “The prevalence and risk factors of functional dyspepsia in a multiethnic population in the United States,” American Journal of Gastroenterology, vol. 99, no. 11, pp. 2210–2216, 2004.
[3]
M. Shimoda and K. Kubota, “Multi-disciplinary treatment for cholangiocellular carcinoma,” World Journal of Gastroenterology, vol. 13, no. 10, pp. 1500–1504, 2007.
[4]
N. Razumilava and G. J. Gores, “Classification, diagnosis, and management of cholangiocarcinoma,” Clinical Gastroenterology and Hepatology, vol. 11, pp. 13.e1–21.e1, 2013.
[5]
C. Sempoux, G. Jibara, S. C. Ward et al., “Intrahepatic cholangiocarcinoma: new insights in Pathology,” Seminars in Liver Disease, vol. 31, no. 1, pp. 49–60, 2011.
[6]
V. Cardinale, G. Carpino, L. Reid, E. Gaudio, and D. Alvaro, “Multiple cells of origin in cholangiocarcinoma underlie biological, epidemiological and clinical heterogeneity,” World Journal of Gastrointestinal Oncology, vol. 4, pp. 94–102, 2012.
[7]
B. Fan, Y. Malato, D. F. Calvisi, et al., “Cholangiocarcinomas can originate from hepatocytes in mice,” Journal of Clinical Investigation, vol. 122, pp. 2911–2915, 2012.
[8]
S. Sekiya and A. Suzuki, “Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes,” Journal of Clinical Investigation, vol. 122, pp. 3914–3918, 2012.
[9]
D. Sia, Y. Hoshida, A. Villanueva, et al., “Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes,” Gastroenterology, vol. 144, pp. 829–840, 2013.
[10]
S. B. Edge, D. R. Byrd, C. C. Compton, A. G. Fritz, F. L. Greene, and A. Trotti, AJCC Cancer Staging Manual, Springer, New York, NY, USA, 7th edition, 2010.
[11]
M. C. de Jong, H. Nathan, G. C. Sotiropoulos et al., “Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment,” Journal of Clinical Oncology, vol. 29, no. 23, pp. 3140–3145, 2011.
[12]
B. Juntermanns, G. C. Sotiropoulos, S. Radunz, et al., “Comparison of the sixth and the seventh editions of the UICC classification for perihilar cholangiocarcinoma,” Annals of Surgical Oncology, vol. 20, pp. 277–284, 2013.
[13]
D. Ribero, G. Nuzzo, M. Amisano et al., “Comparison of the prognostic accuracy of the sixth and seventh editions of the TNM classification for intrahepatic cholangiocarcinoma,” HPB, vol. 13, no. 3, pp. 198–205, 2011.
[14]
L. McLean and T. Patel, “Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinoma in the United States,” Liver International, vol. 26, no. 9, pp. 1047–1053, 2006.
[15]
J. E. Everhart and C. E. Ruhl, “Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas,” Gastroenterology, vol. 136, no. 4, pp. 1134–1144, 2009.
[16]
K. S？reide, H. K？rner, J. Havnen, and J. A. S？reide, “Bile duct cysts in adults,” British Journal of Surgery, vol. 91, no. 12, pp. 1538–1548, 2004.
[17]
M. L. DeOliveira, S. C. Cunningham, J. L. Cameron et al., “Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution,” Annals of Surgery, vol. 245, no. 5, pp. 755–762, 2007.
[18]
T. Patel, “Worldwide trends in mortality from biliary tract malignancies,” BMC Cancer, vol. 2, article 10, 2002.
[19]
S. D. Taylor-Robinson, M. B. Toledano, S. Arora et al., “Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998,” Gut, vol. 48, no. 6, pp. 816–820, 2001.
[20]
T. Patel, “Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States,” Hepatology, vol. 33, no. 6, pp. 1353–1357, 2001.
[21]
H. Nathan, T. M. Pawlik, C. L. Wolfgang, M. A. Choti, J. L. Cameron, and R. D. Schulick, “Trends in survival after surgery for cholangiocarcinoma: a 30-Year population-based SEER database analysis,” Journal of Gastrointestinal Surgery, vol. 11, no. 11, pp. 1488–1497, 2007.
[22]
S. A. Khan, S. Emadossadaty, N. G. Ladep et al., “Rising trends in cholangiocarcinoma: is the ICD classification system misleading us?” Journal of Hepatology, vol. 56, no. 4, pp. 848–854, 2012.
[23]
B. R. A. Blechacz and G. J. Gores, “Cholangiocarcinoma,” Clinics in Liver Disease, vol. 12, no. 1, pp. 131–150, 2008.
[24]
H.-R. Shin, C.-U. Lee, H.-J. Park et al., “Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a case-control study in Pusan, Korea,” International Journal of Epidemiology, vol. 25, no. 5, pp. 933–940, 1996.
[25]
G. L. Tyson and H. B. El-Serag, “Risk factors for cholangiocarcinoma,” Hepatology, vol. 54, no. 1, pp. 173–184, 2011.
[26]
Y. H. Shaib, H. B. El-Serag, J. A. Davila, R. Morgan, and K. A. Mcglynn, “Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study,” Gastroenterology, vol. 128, no. 3, pp. 620–626, 2005.
[27]
W. C. Palmer and T. Patel, “Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma,” Journal of Hepatology, vol. 57, no. 1, pp. 69–76, 2012.
[28]
T. M. Welzel, B. I. Graubard, S. Zeuzem, H. B. El-Serag, J. A. Davila, and K. A. Mcglynn, “Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-medicare database,” Hepatology, vol. 54, no. 2, pp. 463–471, 2011.
[29]
E. Lozano, L. Sanchez-Vicente, M. J. Monte, et al., “Co-carcinogenic effects of intrahepatic bile acid accumulation in cholangiocarcinoma development,” Molecular Cancer Research, vol. 12, no. 1, pp. 91–100, 2014.
[30]
A. N. Rota, H. K. Weindling, and P. G. Goodman, “Cholangiocarcinoma associated with thorium dioxide (thorotrast): report of a case,” Michigan Medicine, vol. 70, no. 25, pp. 911–915, 1971.
[31]
M. Jaiswal, N. F. LaRusso, L. J. Burgart, and G. J. Gores, “Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism,” Cancer Research, vol. 60, no. 1, pp. 184–190, 2000.
[32]
B. Blechacz and G. J. Gores, “Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment,” Hepatology, vol. 48, no. 1, pp. 308–321, 2008.
[33]
S. Pinlaor, B. Sripa, N. Ma et al., “Nitrative and oxidative DNA damage in intrahepatic cholangiocarcinoma patients in relation to tumor invasion,” World Journal of Gastroenterology, vol. 11, no. 30, pp. 4644–4649, 2005.
[34]
K. Itatsu, M. Sasaki, J. Yamaguchi et al., “Cyclooxygenase-2 is involved in the up-regulation of matrix metalloproteinase-9 in cholangiocarcinoma induced by tumor necrosis factor-α,” American Journal of Pathology, vol. 174, no. 3, pp. 829–841, 2009.
[35]
J. S. Goydos, A. M. Brumfield, E. Frezza, A. Booth, M. T. Lotze, and S. E. Carty, “Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker,” Annals of Surgery, vol. 227, no. 3, pp. 398–404, 1998.
[36]
H. Isomoto, J. L. Mott, S. Kobayashi et al., “Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing,” Gastroenterology, vol. 132, no. 1, pp. 384–396, 2007.
[37]
S. Kobayashi, N. W. Werneburg, S. F. Bronk, S. H. Kaufmann, and G. J. Gores, “Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells,” Gastroenterology, vol. 128, no. 7, pp. 2054–2065, 2005.
[38]
J. Park, L. Tadlock, G. J. Gores, and T. Patel, “Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line,” Hepatology, vol. 30, no. 5, pp. 1128–1133, 1999.
[39]
Y. Yamagiwa, F. Meng, and T. Patel, “Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes,” Life Sciences, vol. 78, no. 21, pp. 2494–2502, 2006.
[40]
K. Endo, B.-I. Yoon, C. Pairojkul, A. J. Demetris, and A. E. Sirica, “ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions,” Hepatology, vol. 36, no. 2, pp. 439–450, 2002.
[41]
K. Nakazawa, Y. Dobashi, S. Suzuki, H. Fujii, Y. Takeda, and A. Ooi, “Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers,” Journal of Pathology, vol. 206, no. 3, pp. 356–365, 2005.
[42]
D. Yoshikawa, H. Ojima, M. Iwasaki et al., “Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma,” British Journal of Cancer, vol. 98, no. 2, pp. 418–425, 2008.
[43]
A. E. Sirica, S. Radaeva, and N. Caran, “NEU overexpression in the furan rat model of cholangiocarcinogenesis compared with biliary ductal cell hyperplasia,” American Journal of Pathology, vol. 151, no. 6, pp. 1685–1694, 1997.
[44]
W. Treekitkarnmongkol and T. Suthiphongchai, “High expression of ErbB2 contributes to cholangiocarcinoma cell invasion and proliferation through AKT/p70S6K,” World Journal of Gastroenterology, vol. 16, no. 32, pp. 4047–4054, 2010.
[45]
J. H. Yoon, H. Higuchi, N. W. Werneburg, S. H. Kaufmann, and G. J. Gores, “Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line,” Gastroenterology, vol. 122, no. 4, pp. 985–993, 2002.
[46]
V. Keitel, R. Reinehr, M. Reich, et al., “TGR5 (Gpbar-1) is expressed in cholangiocarcinomas and confers apopotosis resistance in isolated cholangiocytes,” Zeitschrift für Gastroenterologie, vol. 50, pp. 5–24, 2012.
[47]
M. Trauner, “The nuclear bile acid receptor FXR as a novel therapeutic target in cholestatic liver diseases: hype or hope?” Hepatology, vol. 40, no. 1, pp. 260–263, 2004.
[48]
F. Yang, X. Huang, T. Yi, Y. Yen, D. D. Moore, and W. Huang, “Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor,” Cancer Research, vol. 67, no. 3, pp. 863–867, 2007.
[49]
I. Kim, K. Morimura, Y. Shah, Q. Yang, J. M. Ward, and F. J. Gonzalez, “Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice,” Carcinogenesis, vol. 28, no. 5, pp. 940–946, 2007.
[50]
B. K. Park, Y.-H. Paik, J. Y. Park et al., “The clinicopathologic significance of the expression of vascular endothelial growth factor-C in intrahepatic cholangiocarcinoma,” American Journal of Clinical Oncology, vol. 29, no. 2, pp. 138–142, 2006.
[51]
A. Mancino, M. G. Mancino, S. S. Glaser et al., “Estrogens stimulate the proliferation of human cholangiocarcinoma by inducing the expression and secretion of vascular endothelial growth factor,” Digestive and Liver Disease, vol. 41, no. 2, pp. 156–163, 2009.
[52]
T. Terada, Y. Nakanuma, and A. E. Sirica, “Immunohistochemical demonstration of MET overexpression in human intrahepatic cholangiocarcinoma and in hepatolithiasis,” Human Pathology, vol. 29, no. 2, pp. 175–180, 1998.
[53]
K. Leelawat, S. Leelawat, P. Tepaksorn et al., “Involvement of c-met/hepatocyte growth factor pathway in cholangiocarcinoma cell invasion and its therapeutic inhibition with small interfering RNA specific for c-met,” Journal of Surgical Research, vol. 136, no. 1, pp. 78–84, 2006.
[54]
P. Angulo, D. H. Pearce, C. D. Johnson et al., “Magnetic resonance cholangiography in patients with biliary disease: Its role in primary sclerosing cholangitis,” Journal of Hepatology, vol. 33, no. 4, pp. 520–527, 2000.
[55]
M. S. Peterson, T. Murakami, and R. L. Baron, “MR imaging patterns of gadolinium retention within liver neoplasms,” Abdominal Imaging, vol. 23, no. 6, pp. 592–599, 1998.
[56]
J. Rimola, A. Forner, M. Reig et al., “Cholangiocarcinoma in cirrhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma,” Hepatology, vol. 50, no. 3, pp. 791–798, 2009.
[57]
V. Vilgrain, “Staging cholangiocarcinoma by imaging studies,” HPB, vol. 10, no. 2, pp. 106–109, 2008.
[58]
Y. E. Chung, M.-J. Kim, Y. N. Park et al., “Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation,” Radiographics, vol. 29, no. 3, pp. 683–700, 2009.
[59]
C. U. Corvera, L. H. Blumgart, T. Akhurst et al., “18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer,” Journal of the American College of Surgeons, vol. 206, no. 1, pp. 57–65, 2008.
[60]
B. Juntermanns, G. M. Kaiser, H. Reis et al., “Klatskin-mimicking lesions: still a diagnostical and therapeutical dilemma?” Hepato-Gastroenterology, vol. 58, no. 106, pp. 265–269, 2011.
[61]
P. Yachimski and D. S. Pratt, “Cholangiocarcinoma: natural history, treatment, and strategies for surveillance in high-risk patients,” Journal of Clinical Gastroenterology, vol. 42, no. 2, pp. 178–190, 2008.
[62]
B. Juntermanns, S. Radunz, M. Heuer et al., “Tumor markers as a diagnostic key for hilar cholangiocarcinoma,” European Journal of Medical Research, vol. 15, no. 8, pp. 357–361, 2010.
[63]
A. H. Patel, D. M. Harnois, G. G. Klee, N. F. Larusso, and G. J. Gores, “The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis,” American Journal of Gastroenterology, vol. 95, no. 1, pp. 204–207, 2000.
[64]
D. Alvaro, “Serum and bile biomarkers for cholangiocarcinoma,” Current Opinion in Gastroenterology, vol. 25, no. 3, pp. 279–284, 2009.
[65]
M. Gatto and D. Alvaro, “New insights on cholangiocarcinoma,” World Journal of Gastrointestinal Oncology, vol. 2, pp. 136–145, 2010.
[66]
S. Marubashi, K. Gotoh, H. Takahashi, et al., “Prediction of the postoperative prognosis of intrahepatic cholangiocarcinoma (ICC): importance of preoperatively-determined anatomic invasion level and number of tumors,” Digestive Diseases and Sciences. In press.
[67]
H. Li, J. S. Wu, X. T. Wang, et al., “Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis,” Journal of Gastrointestinal Surgery, vol. 18, no. 1, pp. 194–199, 2013.
[68]
C. B. Rosen, J. K. Heimbach, and G. J. Gores, “Liver transplantation for cholangiocarcinoma,” Transplant International, vol. 23, no. 7, pp. 692–697, 2010.
[69]
D. J. Rea, J. K. Heimbach, C. B. Rosen et al., “Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma,” Annals of Surgery, vol. 242, no. 3, pp. 451–461, 2005.
[70]
R. J. Salgia, A. G. Singal, S. Fu, S. Pelletier, and J. A. Marrero, “Improved post-transplant survival in the United States for patients with cholangiocarcinoma after 2000,” Digestive Diseases and Sciences. In press.
[71]
J. H. Kim, H. J. Won, Y. M. Shin, K.-A. Kim, and P. N. Kim, “Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma,” American Journal of Roentgenology, vol. 196, no. 2, pp. W205–W209, 2011.
[72]
P. H. P. Davids, A. K. Groen, E. A. J. Rauws, G. N. J. Tytgat, and K. Huibregtse, “Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction,” Te Lancet, vol. 340, no. 8834-8835, pp. 1488–1492, 1992.
[73]
D. J. Grunhagen, D. F. Dunne, R. P. Sturgess, et al., “Metal stents: a bridge to surgery in hilar cholangiocarcinoma,” HPB, vol. 15, pp. 372–378, 2013.
[74]
E. Liapi and J.-F. H. Geschwind, “Transcatheter and ablative therapeutic approaches for solid malignancies,” Journal of Clinical Oncology, vol. 25, no. 8, pp. 978–986, 2007.
[75]
M. V. Kiefer, M. Albert, M. McNally et al., “Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol,” Cancer, vol. 117, no. 7, pp. 1498–1505, 2011.
[76]
R.-T. Hoffmann, P. M. Paprottka, A. Sch？n et al., “Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival,” CardioVascular and Interventional Radiology, vol. 35, no. 1, pp. 105–116, 2012.
[77]
M. Penz, G. V. Kornek, M. Raderer et al., “Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer,” Annals of Oncology, vol. 12, no. 2, pp. 183–186, 2001.
[78]
N. Tsavaris, C. Kosmas, P. Gouveris et al., “Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer,” Investigational New Drugs, vol. 22, no. 2, pp. 193–198, 2004.
[79]
T. Okusaka, H. Ishii, A. Funakoshi et al., “Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer,” Cancer Chemotherapy and Pharmacology, vol. 57, no. 5, pp. 647–653, 2006.
[80]
Y. Z. Patt, M. M. Hassan, A. Aguayo et al., “Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma,” Cancer, vol. 101, no. 3, pp. 578–586, 2004.
[81]
J. Furuse, T. Okusaka, N. Boku et al., “S-1 monotherapy as first-line treatment in patients with advanced biliary tract cancer: a multicenter phase II study,” Cancer Chemotherapy and Pharmacology, vol. 62, no. 5, pp. 849–855, 2008.
[82]
J. J. Knox, D. Hedley, A. Oza et al., “Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial,” Journal of Clinical Oncology, vol. 23, no. 10, pp. 2332–2338, 2005.
[83]
J. Y. Cho, Y. H. Paik, Y. S. Chang et al., “Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma,” Cancer, vol. 104, no. 12, pp. 2753–2758, 2005.
[84]
R. V. Iyer, J. Gibbs, B. Kuvshinoff et al., “A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: a single-institution prospective study,” Annals of Surgical Oncology, vol. 14, no. 11, pp. 3202–3209, 2007.
[85]
S. Iqbal, C. Rankin, H.-J. Lenz et al., “A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: southwest Oncology Group study S0202,” Cancer Chemotherapy and Pharmacology, vol. 68, no. 6, pp. 1595–1602, 2011.
[86]
T. Sasaki, H. Isayama, Y. Nakai et al., “Multicenter, phase ii study of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer,” Cancer Chemotherapy and Pharmacology, vol. 65, no. 6, pp. 1101–1107, 2010.
[87]
S. Thongprasert, S. Napapan, C. Charoentum, and S. Moonprakan, “Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma,” Annals of Oncology, vol. 16, no. 2, pp. 279–281, 2005.
[88]
S. T. Kim, J. O. Park, J. Lee et al., “A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer,” Cancer, vol. 106, no. 6, pp. 1339–1346, 2006.
[89]
T. André, C. Tournigand, O. Rosmorduc et al., “Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study,” Annals of Oncology, vol. 15, no. 9, pp. 1339–1343, 2004.
[90]
J. Harder, B. Riecken, O. Kummer et al., “Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer,” British Journal of Cancer, vol. 95, no. 7, pp. 848–852, 2006.
[91]
J.-S. Jang, H. Y. Lim, I. G. Hwang et al., “Gemcitabine and oxaliplatin in patients with unresectable biliary cancer including gall bladder cancer: a Korean Cancer Study Group phase II trial,” Cancer Chemotherapy and Pharmacology, vol. 65, no. 4, pp. 641–647, 2010.
[92]
T. Sasaki, H. Isayama, Y. Nakai, et al., “A randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine monotherapy for advanced biliary tract cancer,” Cancer Chemotherapy and Pharmacology, vol. 71, pp. 973–979, 2013.
[93]
J. Valle, H. Wasan, D. H. Palmer et al., “Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer,” The New England Journal of Medicine, vol. 362, no. 14, pp. 1273–1281, 2010.
[94]
T. Okusaka, K. Nakachi, A. Fukutomi et al., “Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan,” British Journal of Cancer, vol. 103, no. 4, pp. 469–474, 2010.
[95]
S. R. Alberts, H. Al-Khatib, M. R. Mahoney et al., “Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a north central cancer treatment group phase II trial,” Cancer, vol. 103, no. 1, pp. 111–118, 2005.
[96]
N. Karachaliou, A. Polyzos, N. Kentepozidis et al., “A multicenter phase II trial with irinotecan plus oxaliplatin as first-line treatment for inoperable/metastatic cancer of the biliary tract,” Oncology, vol. 78, no. 5-6, pp. 356–360, 2010.
[97]
U. Lassen, L. H. Jensen, M. Sorensen, K. S. Rohrberg, Z. Ujmajuridze, and A. Jakobsen, “A Phase I-II dose escalation study of fixed-dose rate gemcitabine, oxaliplatin and capecitabine every two weeks in advanced cholangiocarcinomas,” Acta Oncologica, vol. 50, no. 3, pp. 448–454, 2011.
[98]
H. Ueno, T. Okusaka, M. Ikeda, Y. Takezako, and C. Morizane, “Phase II study of S-1 in patients with advanced biliary tract cancer,” British Journal of Cancer, vol. 91, no. 10, pp. 1769–1774, 2004.
[99]
S. Kondo, T. Takada, M. Miyazaki et al., “Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment,” Journal of Hepato-Biliary-Pancreatic Surgery, vol. 15, no. 1, pp. 41–54, 2008.
[100]
J. M. Llovet, S. Ricci, V. Mazzaferro et al., “Sorafenib in advanced hepatocellular carcinoma,” The New England Journal of Medicine, vol. 359, no. 4, pp. 378–390, 2008.
[101]
C. Bengala, F. Bertolini, N. Malavasi et al., “Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial,” British Journal of Cancer, vol. 102, no. 1, pp. 68–72, 2010.
[102]
A. B. El-Khoueiry, C. J. Rankin, E. Ben-Josef et al., “SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma,” Investigational New Drugs, vol. 30, no. 4, pp. 1646–1651, 2012.
[103]
J. H. Yi, S. Thongprasert, J. Lee et al., “A phase II study of sunitinib as a second-line treatment in advanced biliary tract carcinoma: a multicentre, multinational study,” European Journal of Cancer, vol. 48, no. 2, pp. 196–201, 2012.
[104]
T. Bekaii-Saab, M. A. Phelps, X. Li et al., “Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers,” Journal of Clinical Oncology, vol. 29, no. 17, pp. 2357–2363, 2011.
[105]
P. A. Philip, M. R. Mahoney, C. Allmer et al., “Phase II study of erlotinib in patients with advanced biliary cancer,” Journal of Clinical Oncology, vol. 24, no. 19, pp. 3069–3074, 2006.
[106]
R. K. Ramanathan, C. P. Belani, D. A. Singh et al., “A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer,” Cancer Chemotherapy and Pharmacology, vol. 64, no. 4, pp. 777–783, 2009.
[107]
S. J. Lubner, M. R. Mahoney, J. L. Kolesar 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,” Journal of Clinical Oncology, vol. 28, no. 21, pp. 3491–3497, 2010.
[108]
B. Gruenberger, J. Schueller, U. Heubrandtner et al., “Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study,” The Lancet Oncology, vol. 11, no. 12, pp. 1142–1148, 2010.
[109]
A. X. Zhu, J. A. Meyerhardt, L. S. Blaszkowsky 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,” The Lancet Oncology, vol. 11, no. 1, pp. 48–54, 2010.
[110]
L. H. Jensen, J. Lindebjerg, J. Ploen, T. F. Hansen, and A. Jakobsen, “Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer,” Annals of Oncology, vol. 23, pp. 2341–2346, 2012.
[111]
J. Lee, S. H. Park, H.-M. Chang et al., “Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study,” The Lancet Oncology, vol. 13, no. 2, pp. 181–188, 2012.
[112]
J. K. Lee, M. Capanu, E. M. O'Reilly, et al., “A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas,” British Journal of Cancer, vol. 109, pp. 915–919, 2013.
[113]
N. Shafizadeh, J. P. Grenert, V. Sahai, and S. Kakar, “Epidermal growth factor receptor and HER-2/neu status by immunohistochemistry and fluorescence in situ hybridization in adenocarcinomas of the biliary tree and gallbladder,” Human Pathology, vol. 41, no. 4, pp. 485–492, 2010.
[114]
A. Jimeno, B. Rubio-Viqueira, M. L. Amador et al., “Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents,” Cancer Research, vol. 65, no. 8, pp. 3003–3010, 2005.
[115]
M. Wiedmann, J. Feisthammel, T. Blüthner et al., “Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib,” Anti-Cancer Drugs, vol. 17, no. 7, pp. 783–795, 2006.
[116]
D. Yoshikawa, H. Ojima, A. Kokubu et al., “Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma,” British Journal of Cancer, vol. 100, no. 8, pp. 1257–1266, 2009.
[117]
P. Martinez-Becerra, J. Vaquero, M. R. Romero, et al., “No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors,” Molecular Pharmacology, vol. 9, pp. 1693–1704, 2012.
[118]
M. Heise, A. Lautem, J. Knapstein et al., “Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance,” BMC Cancer, vol. 12, article 109, 2012.
[119]
E. Herraez, E. Lozano, R. I. Macias, et al., “Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib,” Hepatology, vol. 58, pp. 1065–1073, 2013.
[120]
J. J. Marin, “Plasma membrane transporters in modern liver pharmacology,” Scientifica, vol. 2012, Article ID 428139, 15 pages, 2012.
[121]
K. N. Lazaridis, L. Pham, P. Tietz et al., “Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter,” Journal of Clinical Investigation, vol. 100, no. 11, pp. 2714–2721, 1997.
[122]
J. J. Criado, R. I. R. Macias, M. Medarde, M. J. Monte, M. A. Serrano, and J. J. G. Marin, “Synthesis and characterization of the new cytostatic complex cis-diammineplatinum(II)-chlorocholylglycinate,” Bioconjugate Chemistry, vol. 8, no. 4, pp. 453–458, 1997.
[123]
J. J. G. Marin, M. F. Palomero, M. C. Herrera, R. I. R. Macias, J. J. Criado, and M. A. Serrano, “In vitro cytostatic activity and DNA-interaction of the new liver organotropic complex chloro-bis-cholylglycinate-platinum(II),” Anticancer Research, vol. 18, no. 3, pp. 1641–1647, 1998.
[124]
J. J. Criado, M. F. Domínguez, M. Medarde, E. R. Fernández, R. I. R. Macías, and J. J. G. Marín, “Structural characterization, kinetic studies, and in vitro biological activity of new cis-diamminebis-cholylglycinate(O,O′) Pt(II) and cis-diamminebis-ursodeoxycholate(O,O′) Pt(II) complexes,” Bioconjugate Chemistry, vol. 11, no. 2, pp. 167–174, 2000.
[125]
J. J. Marin, R. I. Macias, J. J. Criado, A. Bueno, M. J. Monte, and M. A. Serrano, “DNA interaction and cytostatic activity of the new liver organotropic complex of cisplatin with glycocholic acid: Bamet-R2,” International Journal of Cancer, vol. 78, pp. 346–352, 1998.
[126]
M. F. Dominguez, R. I. R. Macias, I. Izco-Basurko et al., “Low in vivo toxicity of a novel cisplatin-ursodeoxycholic derivative (Bamet-UD2) with enhanced cytostatic activity versus liver tumors,” Journal of Pharmacology and Experimental Therapeutics, vol. 297, no. 3, pp. 1106–1112, 2001.
[127]
R. I. R. Macias, M. J. Monte, M. Y. El-Mir, G. R. Villanueva, and J. J. G. Marin, “Transport and biotransformation of the new cytostatic complex cis- diammineplatinum(II)-chlorocholylglycinate (Bamet-R2) by the rat liver,” Journal of Lipid Research, vol. 39, no. 9, pp. 1792–1798, 1998.
[128]
E. Lozano, M. J. Monte, S. Jimenez, et al., “La proteína ASBT podría utilizarse en el tratamiento del colangiocarcinoma como diana para la vectorización de derivados citostáticos de ácidos biliares,” in Gastroenterologia Y Hepatologia, pp. 195–196, 2012.
[129]
J. Trojan and S. Zeuzem, “Tivantinib in hepatocellular carcinoma,” Expert Opinion on Investigational Drugs, vol. 22, pp. 141–147, 2013.
[130]
M. Nagilla, R. L. Brown, and E. E. Cohen, “Cabozantinib for the treatment of advanced medullary thyroid cancer,” Advances in Therapy, vol. 29, pp. 925–934, 2012.
[131]
T. Wu, J. Leng, C. Han, and A. J. Demetris, “The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells,” Molecular Cancer Therapeutics, vol. 3, no. 3, pp. 299–307, 2004.
[132]
C. N. Yeh, K. C. Chiang, H. H. Juang, et al., “Reappraisal of the therapeutic role of celecoxib in cholangiocarcinoma,” PLoS ONE, vol. 8, Article ID e69928, 2013.
