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Gallbladder Cancer: Current and Emerging Therapies

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Abstract

Despite its rare prevalence, gallbladder cancer (GBC) is associated with a poor prognosis. Patients typically experience vague symptoms and present with advanced stages of disease. Gallstones are the most prevalent risk factors. Tumors that are associated with gallstones have a different pathogenesis compared to those originating from anomalous pancreaticobiliary duct junction or on a background of adenomatous polyps. Approximately 10–30% of patients will qualify for surgical resection, which is the only potentially curable treatment. Patients with resected, node- or margin-positive disease are candidates for adjuvant therapy. Options include fluoropyrimidine-based chemoradiation with or without chemotherapy, as well as fluoropyrimidine- or gemcitabine-based chemotherapy alone. For patients with advanced disease, prognosis is poor despite treatment, which includes fluoropyrimidine- or gemcitabine-based chemotherapy, with or without fluoropyrimidine chemoradiation. Targeted biologic therapy, such as inhibitors of VEGF, EGFR, and HER2, as well as pathways with aberrant expression, have been evaluated in the setting of advanced disease. Unfortunately, the trials are underpowered. Further studies are in dire need.

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References

  1. Yang G, Zhang L, Li R, Wang L. The role of micrornas in gallbladder cancer. Mol Clin Oncol. 2016;5(1):7–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Higuchi R, Ota T, Araida T, Kajiyama H, Yazawa T, Furukawa T, et al. Surgical approaches to advanced gallbladder cancer: a 40-year single-institution study of prognostic factors and resectability. Ann Surg Oncol. 2014;21(13):4308–16.

    Article  PubMed  Google Scholar 

  3. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109.

    PubMed  PubMed Central  Google Scholar 

  4. Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol. 2003;4(3):167–76.

    Article  PubMed  Google Scholar 

  5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.

    Article  PubMed  Google Scholar 

  6. Zatonski WA, Lowenfels AB, Boyle P, Maisonneuve P, Bueno de Mesquita HB, Ghadirian P, et al. Epidemiologic aspects of gallbladder cancer: a case-control study of the search program of the international agency for research on cancer. J Natl Cancer Inst. 1997;89(15):1132–8.

    Article  CAS  PubMed  Google Scholar 

  7. Silva MA, Tekin K, Aytekin F, Bramhall SR, Buckels JA, Mirza DF. Surgery for hilar cholangiocarcinoma; a 10 year experience of a tertiary referral centre in the UK. Eur J Surg Oncol. 2005;31(5):533–9.

    Article  CAS  PubMed  Google Scholar 

  8. Liebe R, Milkiewicz P, Krawczyk M, Bonfrate L, Portincasa P, Krawczyk M. Modifiable factors and genetic predisposition associated with gallbladder cancer. A concise review. J Gastrointestin Liver Dis. 2015;24(3):339–48.

    PubMed  Google Scholar 

  9. Cariati A, Piromalli E, Cetta F. Gallbladder cancers: associated conditions, histological types, prognosis, and prevention. Eur J Gastroenterol Hepatol. 2014;26(5):562–9.

    Article  PubMed  Google Scholar 

  10. Andrea C, Enzo A. Cholesterol gallstones larger than 3 cm appear to be associated with gallbladder cancer: identification of a high risk group of patients that could benefit from preventive cholecystectomy. Ann Surg. 2016;263(3):e56.

    Article  PubMed  Google Scholar 

  11. Zatonski WA, La Vecchia C, Przewozniak K, Maisonneuve P, Lowenfels AB, Boyle P. Risk factors for gallbladder cancer: a polish case-control study. Int J Cancer. 1992;51(5):707–11.

    Article  CAS  PubMed  Google Scholar 

  12. Friedman GD. Natural history of asymptomatic and symptomatic gallstones. Am J Surg. 1993;165(4):399–404.

    Article  CAS  PubMed  Google Scholar 

  13. Schnelldorfer T. Porcelain gallbladder: a benign process or concern for malignancy? J Gastrointest Surg. 2013;17(6):1161–8.

    Article  PubMed  Google Scholar 

  14. Okamoto M, Okamoto H, Kitahara F, Kobayashi K, Karikome K, Miura K, et al. Ultrasonographic evidence of association of polyps and stones with gallbladder cancer. Am J Gastroenterol. 1999;94(2):446–50.

    Article  CAS  PubMed  Google Scholar 

  15. Aloia TA, Jarufe N, Javle M, Maithel SK, Roa JC, Adsay V, et al. Gallbladder cancer: expert consensus statement. HPB. 2015;17(8):681–90.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Voyles CR, Smadja C, Shands WC, Blumgart LH. Carcinoma in choledochal cysts. Age-related incidence. Arch Surg. 1983;118(8):986–8.

    Article  CAS  PubMed  Google Scholar 

  17. Elnemr A, Ohta T, Kayahara M, Kitagawa H, Yoshimoto K, Tani T, et al. Anomalous pancreaticobiliary ductal junction without bile duct dilatation in gallbladder cancer. Hepato-Gastroenterology. 2001;48(38):382–6.

    CAS  PubMed  Google Scholar 

  18. Sogaard KK, Erichsen R, Lund JL, Farkas DK, Sorensen HT. Cholangitis and subsequent gastrointestinal cancer risk: a Danish population-based cohort study. Gut. 2014;63(2):356–61.

    Article  PubMed  Google Scholar 

  19. Nagaraja V, Eslick GD. Systematic review with meta-analysis: the relationship between chronic salmonella typhi carrier status and gall-bladder cancer. Aliment Pharmacol Ther. 2014;39(8):745–50.

    Article  CAS  PubMed  Google Scholar 

  20. Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol. 2008;48(4):598–605.

    Article  PubMed  Google Scholar 

  21. Kobayashi T, Harada K, Miwa K, Nakanuma Y. Helicobacter genus DNA fragments are commonly detectable in bile from patients with extrahepatic biliary diseases and associated with their pathogenesis. Dig Dis Sci. 2005;50(5):862–7.

    Article  CAS  PubMed  Google Scholar 

  22. Rai R, Sharma KL, Misra S, Kumar A, Mittal B. Cyp17 polymorphism (rs743572) is associated with increased risk of gallbladder cancer in tobacco users. Tumour Biol. 2014;35(7):6531–7.

    Article  CAS  PubMed  Google Scholar 

  23. Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, et al. Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis. Br J Cancer. 2015;112(3):580–93.

    Article  CAS  PubMed  Google Scholar 

  24. Shebl FM, Andreotti G, Meyer TE, Gao YT, Rashid A, Yu K, et al. Metabolic syndrome and insulin resistance in relation to biliary tract cancer and stone risks: a population-based study in Shanghai, China. Br J Cancer. 2011;105(9):1424–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yun SP, Shin N, Seo HI. Clinical outcomes of small cell neuroendocrine carcinoma and adenocarcinoma of the gallbladder. World J Gastroenterol. 2015;21(1):269–75.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Barreto SG, Dutt A, Chaudhary A. A genetic model for gallbladder carcinogenesis and its dissemination. Ann Oncol. 2014;25(6):1086–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.

    Article  CAS  PubMed  Google Scholar 

  28. Marks EI, Yee NS. Molecular genetics and targeted therapeutics in biliary tract carcinoma. World J Gastroenterol. 2016;22(4):1335–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Legan M, Luzar B, Marolt VF, Cor A. Expression of cyclooxygenase-2 is associated with p53 accumulation in premalignant and malignant gallbladder lesions. World J Gastroenterol. 2006;12(21):3425–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wistuba II, Albores-Saavedra J. Genetic abnormalities involved in the pathogenesis of gallbladder carcinoma. J Hepato-Biliary-Pancreat Surg. 1999;6(3):237–44.

    Article  CAS  Google Scholar 

  31. Legan M, Luzar B, Ferlan-Marolt V, Cor A. Cyclooxygenase-2 expression determines neo-angiogenesis in gallbladder carcinomas. Bosn J Basic Med Sci. 2006;6(4):58–63.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wistuba II, Maitra A, Carrasco R, Tang M, Troncoso P, Minna JD, et al. High resolution chromosome 3p, 8p, 9q and 22q allelotyping analysis in the pathogenesis of gallbladder carcinoma. Br J Cancer. 2002;87(4):432–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yoshida H, Shimada K, Kosuge T, Hiraoka N. A significant subgroup of resectable gallbladder cancer patients has an her2 positive status. Virchows Arch. 2016;468(4):431–9.

    Article  CAS  PubMed  Google Scholar 

  34. Chang HJ, Kim SW, Kim YT, Kim WH. Loss of heterozygosity in dysplasia and carcinoma of the gallbladder. Mod Pathol. 1999;12(8):763–9.

    CAS  PubMed  Google Scholar 

  35. Wistuba II, Ashfaq R, Maitra A, Alvarez H, Riquelme E, Gazdar AF. Fragile histidine triad gene abnormalities in the pathogenesis of gallbladder carcinoma. Am J Pathol. 2002;160(6):2073–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Watanabe H, Date K, Itoi T, Matsubayashi H, Yokoyama N, Yamano M, et al. Histological and genetic changes in malignant transformation of gallbladder adenoma. Ann Oncol. 1999;10(Suppl 4):136–9.

    Article  PubMed  Google Scholar 

  37. Zhai G, Yan K, Ji X, Xu W, Yang J, Xiong F, et al. Laptm4b allele ∗2 is a marker of poor prognosis for gallbladder carcinoma. PLoS One. 2012;7(9):e45290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yuan LW, Liu DC, Yang ZL. Correlation of s1p1 and erp29 expression to progression, metastasis, and poor prognosis of gallbladder adenocarcinoma. Hepatobiliary Pancreat Dis Int. 2013;12(2):189–95.

    Article  CAS  PubMed  Google Scholar 

  39. Ghosh M, Sakhuja P, Singh S, Agarwal AK. P53 and beta-catenin expression in gallbladder tissues and correlation with tumor progression in gallbladder cancer. Saudi J Gastroenterol. 2013;19(1):34–9.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wang YF, Feng FL, Zhao XH, Ye ZX, Zeng HP, Li Z, et al. Combined detection tumor markers for diagnosis and prognosis of gallbladder cancer. World J Gastroenterol. 2014;20(14):4085–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Huang HL, Yao HS, Wang Y, Wang WJ, Hu ZQ, Jin KZ. Proteomic identification of tumor biomarkers associated with primary gallbladder cancer. World J Gastroenterol. 2014;20(18):5511–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. Microrna expression profiles classify human cancers. Nature. 2005;435(7043):834–8.

    Article  CAS  PubMed  Google Scholar 

  43. Jin K, Xiang Y, Tang J, Wu G, Li J, Xiao H, et al. Mir-34 is associated with poor prognosis of patients with gallbladder cancer through regulating telomere length in tumor stem cells. Tumour Biol. 2014;35(2):1503–10.

    Article  CAS  PubMed  Google Scholar 

  44. Ma MZ, Chu BF, Zhang Y, Weng MZ, Qin YY, Gong W, et al. Long non-coding rna ccat1 promotes gallbladder cancer development via negative modulation of mirna-218-5p. Cell Death Dis. 2015;6:e1583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Peng HH, Zhang YD, Gong LS, Liu WD, Zhang Y. Increased expression of microrna-335 predicts a favorable prognosis in primary gallbladder carcinoma. Onco Targets Ther. 2013;6:1625–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kitamura T, Connolly K, Ruffino L, Ajiki T, Lueckgen A, DiGiovanni J, et al. The therapeutic effect of histone deacetylase inhibitor pci-24781 on gallbladder carcinoma in bk5.Erbb2 mice. J Hepatol. 2012;57(1):84–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chang Y, Liu C, Yang J, Liu G, Feng F, Tang J, et al. Mir-20a triggers metastasis of gallbladder carcinoma. J Hepatol. 2013;59(3):518–27.

    Article  CAS  PubMed  Google Scholar 

  48. Kono H, Nakamura M, Ohtsuka T, Nagayoshi Y, Mori Y, Takahata S, et al. High expression of microrna-155 is associated with the aggressive malignant behavior of gallbladder carcinoma. Oncol Rep. 2013;30(1):17–24.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Qiu Y, Luo X, Kan T, Zhang Y, Yu W, Wei Y, et al. Tgf-beta upregulates mir-182 expression to promote gallbladder cancer metastasis by targeting cadm1. Mol BioSyst. 2014;10(3):679–85.

    Article  CAS  PubMed  Google Scholar 

  50. Glazer ES, Liu P, Abdalla EK, Vauthey JN, Curley SA. Neither neoadjuvant nor adjuvant therapy increases survival after biliary tract cancer resection with wide negative margins. J Gastrointest Surg. 2012;16(9):1666–71.

    Article  PubMed  Google Scholar 

  51. 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  PubMed  Google Scholar 

  52. Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, et al. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(35):4627–32.

    Article  Google Scholar 

  53. Konishi M. Adjuvant chemotherapy for resectable biliary tract cancer: current status and future direction. Journal of Hepatobiliary Pancreat Sci. 2012;19(4):301–5.

    Article  Google Scholar 

  54. 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 Off J Am Soc Clin Oncol. 2012;30(16):1934–40.

    Article  Google Scholar 

  55. Ben-Josef E, Guthrie KA, El-Khoueiry AB, Corless CL, Zalupski MM, Lowy AM, et al. Swog s0809: a phase ii intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(24):2617–22.

    Article  CAS  Google Scholar 

  56. Benson AB 3rd, D’Angelica MI, Abbott D, Abrams TA, Alberts SR, Saenz DA, Are C, Brown D, Chang DT, Covey AM, Hawkins W, Iyer R, Jacob R, Karachristos A, Kelley RK, Kim R, Palta M, Park JO, Sahai V, Schefter T, Schmidt C, Sicklick JK, Singh G, Sohal D, Stein S, Tian GG, Vauthey J, Venook AP, Zhu AX. Hepatobiliary cancers, version 1.2017, NCCN clinical practice guidelines in oncology. Available through https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. 2017.

  57. Dingle BH, Rumble RB, Brouwers MC. Cancer Care Ontario’s Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site G. The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: a systematic review. Can J Gastroenterol. 2005;19(12):711–6.

    Article  PubMed  Google Scholar 

  58. 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 Off J Am Soc Clin Oncol. 2005;23(10):2332–8.

    Article  CAS  Google Scholar 

  59. 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  PubMed  Google Scholar 

  60. 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 

  61. 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  PubMed  Google Scholar 

  62. Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(30):4581–6.

    Article  CAS  Google Scholar 

  63. 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  PubMed  Google Scholar 

  64. Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, 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 

  65. Kipp BR, Voss JS, Kerr SE, Barr Fritcher EG, Graham RP, Zhang L, et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol. 2012;43(10):1552–8.

    Article  CAS  PubMed  Google Scholar 

  66. Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct idh-mutant molecular profiles. Cell Rep. 2017;18(11):2780–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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  CAS  PubMed  PubMed Central  Google Scholar 

  68. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7(Suppl 4):2–8.

    Article  CAS  PubMed  Google Scholar 

  69. Chang YT, Chang MC, Huang KW, Tung CC, Hsu C, Wong JM. Clinicopathological and prognostic significances of egfr, kras and braf mutations in biliary tract carcinomas in taiwan. J Gastroenterol Hepatol. 2014;29(5):1119–25.

    Article  CAS  PubMed  Google Scholar 

  70. Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase ii study of erlotinib in patients with advanced biliary cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(19):3069–74.

    Article  CAS  Google Scholar 

  71. 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. The Lancet Oncology. 2012;13(2):181–8.

    Article  CAS  PubMed  Google Scholar 

  72. Riley E, Carloss H. Dramatic response to panitumumab and bevacizumab in metastatic gallbladder carcinoma. Oncologist. 2011;16(5):e1–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D, Kaczirek K, 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 

  74. 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 randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hezel AF, Noel MS, Allen JN, Abrams TA, Yurgelun M, Faris JE, 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 

  76. Leone F, Marino D, Cereda S, Filippi R, Belli C, Spadi R, 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 

  77. Zaczek A, Brandt B, Bielawski KP. The diverse signaling network of egfr, her2, her3 and her4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol Histopathol. 2005;20(3):1005–15.

    CAS  PubMed  Google Scholar 

  78. 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  PubMed  Google Scholar 

  79. Papadopoulou E, Metaxa-Mariatou V, Tsaousis G, Tsoulos N, Tsirigoti A, Efstathiadou C, et al. Molecular predictive markers in tumors of the gastrointestinal tract. World J Gastrointest Oncol. 2016;8(11):772–85.

    Article  PubMed  PubMed Central  Google Scholar 

  80. 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  PubMed  Google Scholar 

  81. Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz HJ, Yen Y, 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 

  82. Javle M, Churi C, Kang HC, Shroff R, Janku F, Surapaneni R, et al. Her2/neu-directed therapy for biliary tract cancer. J Hematol Oncol. 2015;8:58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Peck J, Wei L, Zalupski M, O’Neil B, Villalona Calero M, Bekaii-Saab T. Her2/neu may not be an interesting target in biliary cancers: results of an early phase ii study with lapatinib. Oncology. 2012;82(3):175–9.

    Article  CAS  PubMed  Google Scholar 

  84. McMahon G. Vegf receptor signaling in tumor angiogenesis. Oncologist. 2000;5(Suppl 1):3–10.

    Article  CAS  PubMed  Google Scholar 

  85. Nakashima T, Kondoh S, Kitoh H, Ozawa H, Okita S, Harada T, et al. Vascular endothelial growth factor-c expression in human gallbladder cancer and its relationship to lymph node metastasis. Int J Mol Med. 2003;11(1):33–9.

    CAS  PubMed  Google Scholar 

  86. Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, 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 

  87. Iyer RV, Pokuri VK, Groman A, Ma WW, Malhotra U, Iancu DM, 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 

  88. 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 Off J Am Soc Clin Oncol. 2010;28(21):3491–7.

    Article  CAS  Google Scholar 

  89. Bengala C, Bertolini F, Malavasi N, Boni C, Aitini E, Dealis C, 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 

  90. Lee JK, Capanu M, O’Reilly EM, Ma J, Chou JF, Shia J, 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 

  91. LoConte NK, Holen KD, Schelman WR, Mulkerin DL, Deming DA, Hernan HR, et al. A phase i study of sorafenib, oxaliplatin and 2 days of high dose capecitabine in advanced pancreatic and biliary tract cancer: a wisconsin oncology network study. Investig New Drugs. 2013;31(4):943–8.

    Article  CAS  Google Scholar 

  92. Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT, Salgia R. Role of the hepatocyte growth factor receptor, c-met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev. 2002;13(1):41–59.

    Article  CAS  PubMed  Google Scholar 

  93. Yang L, Guo T, Jiang S, Yang Z. Expression of ezrin, hgf and c-met and its clinicopathological significance in the benign and malignant lesions of the gallbladder. Hepato-Gastroenterology. 2012;59(118):1769–75.

    PubMed  Google Scholar 

  94. Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005;16(2):159–78.

    Article  CAS  PubMed  Google Scholar 

  95. 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  PubMed  PubMed Central  Google Scholar 

  96. Pharmaceuticals N. A phase ii, single arm study of bgj398 in patients with advanced cholangiocarcinoma. Available through https://clinicaltrials.gov/ct2/show/NCT02150967?term=NCT02150967&rank=1.

  97. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, et al. Roles of the raf/mek/erk pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773(8):1263–84.

    Article  CAS  PubMed  Google Scholar 

  98. Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JS, et al. Multi-institutional phase ii study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(17):2357–63.

    Article  CAS  Google Scholar 

  99. Bridgewater J, Lopes A, Beare S, Duggan M, Lee D, Ricamara M, 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  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science (New York, NY). 1998;282(5392):1318–21.

    Article  CAS  Google Scholar 

  101. Hansel DE, Rahman A, Hidalgo M, Thuluvath PJ, Lillemoe KD, Schulick R, et al. Identification of novel cellular targets in biliary tract cancers using global gene expression technology. Am J Pathol. 2003;163(1):217–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Thant AA, Nawa A, Kikkawa F, Ichigotani Y, Zhang Y, Sein TT, et al. Fibronectin activates matrix metalloproteinase-9 secretion via the mek1-mapk and the pi3k-akt pathways in ovarian cancer cells. Clin Exp Metastasis. 2000;18(5):423–8.

    Article  CAS  PubMed  Google Scholar 

  103. Zoncu R, Efeyan A, Sabatini DM. Mtor: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21–35.

    Article  CAS  PubMed  Google Scholar 

  104. Herberger B, Puhalla H, Lehnert M, Wrba F, Novak S, Brandstetter A, et al. Activated mammalian target of rapamycin is an adverse prognostic factor in patients with biliary tract adenocarcinoma. Clin Cancer Res. 2007;13(16):4795–9.

    Article  CAS  PubMed  Google Scholar 

  105. Costello BA, Borad MJ, Qi Y, Kim GP, Northfelt DW, Erlichman C, et al. Phase i trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. Investig New Drugs. 2014;32(4):710–6.

    Article  CAS  Google Scholar 

  106. Li Q, Mou LJ, Tao L, Chen W, Sun XT, Xia XF, et al. Inhibition of mtor suppresses human gallbladder carcinoma cell proliferation and enhances the cytotoxicity of 5-fluorouracil by downregulating mdr1 expression. Eur Rev Med Pharmacol Sci. 2016;20(9):1699–706.

    CAS  PubMed  Google Scholar 

  107. Mohri D, Ijichi H, Miyabayashi K, Takahashi R, Kudo Y, Sasaki T, et al. A potent therapeutics for gallbladder cancer by combinatorial inhibition of the mapk and mtor signaling networks. J Gastroenterol. 2016;51(7):711–21.

    Article  CAS  PubMed  Google Scholar 

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Diab, M., Philip, P.A. (2019). Gallbladder Cancer: Current and Emerging Therapies. In: Yalcin, S., Philip, P. (eds) Textbook of Gastrointestinal Oncology. Springer, Cham. https://doi.org/10.1007/978-3-030-18890-0_12

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