Opinion statement
Biliary tract cancers (BTCs) are a diverse group of malignancies arising from the biliary tree, including cholangiocarcinoma and gallbladder carcinoma. Patients that are candidates for surgical resection should also have lymphadenectomy. Since recurrence rates are high, after surgical resection, patients should be considered for adjuvant therapy in a multidiscipline setting. The limited availability of randomized clinical trial data makes the optimal treatment option unclear; however, chemotherapy or chemoradiation has been shown to have benefits especially in patients with R1 or R2 resections or lymph node involvement. Patients with unresectable disease should be considered for neoadjuvant therapy with chemotherapy or chemoradiation. Patients that are unable to tolerate chemotherapy should also be considered for locoregional therapies. Clinical trial enrollment is strongly recommended for all patients. Trials involving targeted or immunotherapy are currently ongoing in patients with advanced disease.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
National Comprehensive Cancer Network (NCCN). NCCN hepatobiliary cancer guidelines. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed October 11, 2018.
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(5):755–62.
Rahman R, Simoes EJ, Schmaltz C, Jackson CS, Ibdah JA. Trend analysis and survival of primary gallbladder cancer in the United States: a 1973–2009 population-based study. Cancer Med. 2017;6(4):874–80. https://doi.org/10.1002/cam4.1044.
SEER Training Modules. Introduction to pancreatic & biliary tract cancers. Accessed 2018 October 11th. Available online: http://training.seer.cancer.gov/biliary/intro/
Margonis GA, Gani F, Buettner S, Amini N, Sasaki K, Andreatos N, et al. Rates and patterns of recurrence after curative intent resection for gallbladder cancer: a multi-institution analysis from the US extra-hepatic biliary malignancy consortium. HPB Oxford. 2016;18:872–8.
Kim WS, Choi DW, You DD, Ho CY, Heo JS, Choi SH. Risk factors influencing recurrence, patterns of recurrence, and the efficacy of adjuvant therapy after radical resection for gallbladder carcinoma. J Gastrointest Surg. 2010;14:679–87.
Altekruse SF, Petrick JL, Rolin AI, et al. Geographic variation of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and hepatocellular carcinoma in the United States. Lu S-N, ed. PLoS One. 2015;10(4):e0120574. https://doi.org/10.1371/journal.pone.0120574.
Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21(5):594–9. https://doi.org/10.1634/theoncologist.2015-0446.
Ercolani G, Vetrone G, Grazi GL, Aramaki O, Cescon M, Ravaioli M, et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg. 2010;252:107–14.
Saiura A, Yamamoto J, Kokudo N, Koga R, Seki M, Hiki N, et al. Intrahepatic cholangiocarcinoma: analysis of 44 consecutive resected cases including 5 cases with repeat resections. Am J Surg. 2011;201:203–8.
Groot Koerkamp B, Wiggers JK, Allen PJ, Besselink MG, Blumgart LH, Busch ORC, et al. Recurrence rates and patterns of perihilar cholangiocarcinoma after curative intent resection. J Am Coll Surg. 2015;221:1041–9.
Lidsky ME, Jarnagin WR. Surgical management of hilar cholangiocarcinoma at Memorial Sloan Kettering Cancer Center. Ann Gastroenterol Surg. 2018;2(4):304–12. https://doi.org/10.1002/ags3.12181.
Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol. 1999;10(Suppl 4):308–11.
Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare. Lu S-N, ed. PLoS One. 2017;12(10):e0186643. https://doi.org/10.1371/journal.pone.0186643.
Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011;54:173–84.
Welzel TM, Graubard BI, El-Serag HB, 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.
Huai JP, Ding J, Ye XH, Chen YP. Inflammatory bowel disease and risk of cholangiocarcinoma: evidence from a meta-analysis of population-based studies. Asian Pac J Cancer Prev. 2014;15:3477–82.
Shindoh J, de Aretxabala X, Aloia TA, Roa JC, Roa I, Zimmitti G, et al. Tumor location is a strong predictor of tumor progression and survival in T2 gallbladder cancer: an international multicenter study. Ann Surg. 2015;261:733–9.
Lee H, Choi DW, Park JY, Youn S, Kwon W, Heo JS, et al. Surgical strategy for T2 gallbladder cancer according to tumor location. Ann Surg Oncol. 2015;22:2779–86.
de Jong MC, Hong S-M, Augustine MM, Goggins MG, Wolfgang CL, Hirose K, et al. Hilar cholangiocarcinoma: tumor depth as a predictor of outcome. Arch Surg. 2011;146:697–703.
Hong S-M, 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.
Chun YS, Pawlik TM, Vauthey JN. 8th edition of the AJCC cancer staging manual: pancreas and hepatobiliary cancers. Ann Surg Oncol. 2018;25:845. https://doi.org/10.1245/s10434-017-6025-x.
Nathan H, Aloia TA, Vauthey J-N, Abdalla EK, Zhu AX, Schulick RD, et al. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2009;16:14–22.
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.
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.
Amin MB, Edge SB, Greene FL, et al. AJCC cancer staging manual. 8th ed. New York: Springer; 2016.
Altman AM, Kizy S, Marmor S, Huang JL, Denbo JW, Jensen EH. Current survival and treatment trends for surgically resected intrahepatic cholangiocarcinoma in the United States. J Gastrointest Oncol. 2018;9(5):942–52.
Moon A, Choi DW, Choi SH, Heo JS, Jang KT. Validation of T stage according to depth of invasion and N stage subclassification based on number of metastatic lymph nodes for distal extrahepatic bile duct (EBD) carcinoma. Medicine (Baltimore). 2015;94:e2064.
Kiriyama M, Ebata T, Aoba T, Kaneoka Y, Arai T, Shimizu Y, et al. Prognostic impact of lymph node metastasis in distal cholangiocarcinoma. Br J Surg. 2015;102:399–406.
•• Primrose JN, Fox R, Palmer DH, Prasad R, Mirza D, Anthoney DA, et al. Adjuvant capecitabine for biliary tract cancer: the BILCAP randomized study. J Clin Oncol. 2017;35(suppl):4006 This trial was the first and as of now only phase III trial that showed benefit of adjuvant therapy for localized surgically resected BTC.
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. https://doi.org/10.1056/NEJMoa0908721.
• Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019–03;37:658–67 This randomized phase III clinical trial showed no survival benefit of adjuvant GEMOX in patients with GC and CCA, including those patients with LN involvement.
• Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018;105:192–202 This randomized phase III clinical trial showed no survival benefit of adjuvant gemcitabine in patients with CCA, including those patients with LN involvement.
Ben-Josef E, Guthrie KA, El-Khoueiry AB, 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. 2015;33(24):2617–22. https://doi.org/10.1200/JCO.2014.60.2219.
Kim YS, SY O, Go SI, et al. The role of adjuvant therapy after R0 resection for patients with intrahepatic and perihilar cholangiocarcinomas. Cancer Chemother Pharmacol. 2017;79(1):99–106.
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(16):1934–40. https://doi.org/10.1200/JCO.2011.40.5381.
Zhu GQ, Shi KQ, You J, Zou H, Lin YQ, Wang LR, et al. Systematic review with network meta-analysis: adjuvant therapy for resected biliary tract cancer. Aliment Pharmacol Ther. 2014;40(7):759–70. https://doi.org/10.1111/apt.12900.
Ma N, Cheng H, Qin B, Zhong R, Wang B. Adjuvant therapy in the treatment of gallbladder cancer: a meta-analysis. BMC Cancer. 2015;15:615.
Hyder O, Dodson RM, Sachs T, et al. Impact of adjuvant external beam radiotherapy on survival in surgically resected gallbladder adenocarcinoma: a propensity score-matched Surveillance, Epidemiology, and End Results analysis. Surgery. 2013;155(1):85–93.
Kim TH, Han SS, Park SJ, Lee WJ, Woo SM, Moon SH, et al. Role of adjuvant chemoradiotherapy for resected extrahepatic biliary tract cancer. Int J Radiat Oncol Biol Phys. 2011;81:e853–9.
Tran CH. The role of surgery and adjuvant therapy in lymph node-positive cancers of the gallbladder and intrahepatic bile ducts. Cancer. 2018–01;124:74–83.
Le Roy B, Gelli M, Pittau G, et al. Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. Br J Surg. 2018;105:839–47.
Lunsford KE, Javle M, Gaber AO, Vauthey JN, Ghobrial RM. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma. Lancet Gastroenterol Hepatol. 2018;3(8):529–30.
Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242:451–8.
Loveday BPT, Knox JJ, Dawson LA, Metser U, Brade A, Horgan AM, et al. Neoadjuvant hyperfractionated chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma in Canada. J Surg Oncol. 2018;117:213–9.
Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012;143:88–98 e3; quiz e14.
Sirohi B, Mitra A, Jagannath P, Singh A, Ramadvar M, Kulkarni S, et al. Neoadjuvant chemotherapy in patients with locally advanced gallbladder cancer. Future Oncol. 2015;11:1501–9. https://doi.org/10.2217/fon.14.308.
Engineer R, Goel M, Chopra S, Patil P, Purandare N, Rangarajan V, et al. Neoadjuvant chemoradiation followed by surgery for locally advanced gallbladder cancers: a new paradigm. Ann Surg Oncol. 2016;23(9):3009–15.
Kim JH, Won HJ, Shin YM, Kim KA, Kim PN. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Roentgenol. 2011;196:W205–9.
Smith I, Kahaleh M. Biliary tumor ablation with photodynamic therapy and radiofrequency ablation. Gastrointest Endosc Clin N Am. 2015;25(4):793–804.
Yang J, Wang J, Zhou H, et al. Efficacy and safety of endoscopic radiofrequency ablation for unresectable extrahepatic cholangiocarcinoma: a randomized trial. Endoscopy. 2018;50(8):751–760. https://doi.org/10.1055/s-0043-124870.
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.
Aliberti C, Carandina R, Sarti D, Mulazzani L, Catalano V, Felicioli A, et al. Hepatic arterial infusion of polyethylene glycol drug-eluting beads for primary and metastatic liver cancer therapy. Anticancer Res. 2016;36:3515–21.
Zhao Q, Qian S, Zhu L, Qu XD, Zhang W, Yan ZP, et al. Transcatheter arterial chemoembolization with gemcitabine and oxaliplatin for the treatment of advanced biliary tract cancer. Oncol Targets Ther. 2015;8:595–600.
Vente MAD, Hobbelink MGG, Van het Schip AD, Zonnenberg BA, Nijsen JFW. Radionuclide liver cancer therapies: from concept to current clinical status. Anti Cancer Agents Med Chem. 2007;7(4):441–59.
Hoffmann RT, Paprottka PM, Schön A, et al. Transarterial hepatic Yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol. 2012;35(1):105–16.
Gangi A, Shah J, et al. Intrahepatic cholangiocarcinoma treated with transarterial Yttrium-90 glass microsphere radioembolization: results of a single institution retrospective study. J Vasc Interv Radiol. 2018;29:1101–8.
Shaker TM, Chung C, Varma MK, et al. Is there a role for Ytrrium-90 in the treatment of unresectable and metastatic intrahepatic cholangiocarcinoma? Am J Surg. 2018;215:467e470.
Rayar M, Sulpice L, Edeline J, et al. The combination of intra-arterial yttrium-90 radioembolization with systemic chemotherapy is a promising method for the downstaging to surgery of initially unresectable huge intrahepatic cholangiocarcinoma. Ann Surg Oncol, Springer Verlag. 2015;22(9):3102–8.
Graham RP, Barr Fritcher EG, Pestova E, Schulz J, Sitailo LA, Vasmatzis G, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014;45:1630–8.
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;17:72–9.
Javle M, Churi C, Kang HC, et al. HER2/neu-directed therapy for biliary tract cancer. J Hematol Oncol. 2015;8:58.
Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10 37.
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Nadia Ashai, Preethi Prasad, and Lakshmi Rajdev declare they have no conflict of interest.
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Ashai, N., Prasad, P. & Rajdev, L. Multimodality Management of Localized Biliary Cancer. Curr. Treat. Options in Oncol. 20, 58 (2019). https://doi.org/10.1007/s11864-019-0655-0
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DOI: https://doi.org/10.1007/s11864-019-0655-0