Treatment options for locally advanced cholangiocarcinoma
- Christopher D Anderson, MD, FACS
Christopher D Anderson, MD, FACS
- James D. Hardy Professor and Chair, Department of Surgery
- Chief, Transplant and Hepatobiliary Surgery
- University of Mississippi Medical Center
- Keith E Stuart, MD
Keith E Stuart, MD
- Chairman, Department of Hematology and Oncology
- Lahey Hospital and Medical Center
- Manisha Palta, MD
Manisha Palta, MD
- Assistant Professor of Radiation Oncology
- Duke University
- Section Editors
- Richard M Goldberg, MD
Richard M Goldberg, MD
- Section Editor — Gastrointestinal Cancer
- Director of the West Virginia University Cancer Institute and the Mary Babb Randolph Cancer Center
- Professor of Medicine
- Laurence S. & Jean J. DeLynn Chair of Oncology
- Kenneth K Tanabe, MD
Kenneth K Tanabe, MD
- Section Editor — Gastrointestinal Malignancies
- Professor of Surgery
- Harvard Medical School
Cholangiocarcinomas are rare malignancies arising from the epithelial cells of the intrahepatic and extrahepatic bile ducts. Locally advanced, unresectable cholangiocarcinoma encompasses a heterogeneous mix of patients who fit the following categories:
●Macroscopic residual disease following resection
●Locally advanced, categorically unresectable disease at presentation (see "Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis", section on 'Preoperative assessment and criteria for resectability')
●Locally recurrent disease after potentially curative treatment
The prognosis for patients with either locally unresectable or locally recurrent disease is typically measured in months, and their lives are characterized by rapid decline with symptoms of progressive biliary obstruction. The goals of palliative therapy are relief of symptoms (pain, pruritus, jaundice) and improvement in quality of life. There is no role for surgical debulking in these cases.
- Matsuo K, Rocha FG, Ito K, et al. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am Coll Surg 2012; 215:343.
- Eckel F, Brunner T, Jelic S, ESMO Guidelines Working Group. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 Suppl 6:vi40.
- Kim YI, Park JW, Kim BH, et al. Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma. Radiat Oncol 2013; 8:292.
- Robertson JM, Lawrence TS, Andrews JC, et al. Long-term results of hepatic artery fluorodeoxyuridine and conformal radiation therapy for primary hepatobiliary cancers. Int J Radiat Oncol Biol Phys 1997; 37:325.
- Ben-Josef E, Normolle D, Ensminger WD, et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol 2005; 23:8739.
- Czito BG, Anscher MS, Willett CG. Radiation therapy in the treatment of cholangiocarcinoma. Oncology (Williston Park) 2006; 20:873.
- Tao R, Krishnan S, Bhosale PR, et al. Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis. J Clin Oncol 2016; 34:219.
- Kopek N, Holt MI, Hansen AT, Høyer M. Stereotactic body radiotherapy for unresectable cholangiocarcinoma. Radiother Oncol 2010; 94:47.
- Jung DH, Kim MS, Cho CK, et al. Outcomes of stereotactic body radiotherapy for unresectable primary or recurrent cholangiocarcinoma. Radiat Oncol J 2014; 32:163.
- Mahadevan A, Dagoglu N, Mancias J, et al. Stereotactic Body Radiotherapy (SBRT) for Intrahepatic and Hilar Cholangiocarcinoma. J Cancer 2015; 6:1099.
- Barney BM, Olivier KR, Macdonald OK, et al. Clinical outcomes and dosimetric considerations using stereotactic body radiotherapy for abdominopelvic tumors. Am J Clin Oncol 2012; 35:537.
- Polistina FA, Guglielmi R, Baiocchi C, et al. Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma. Results of a five year experience. Radiother Oncol 2011; 99:120.
- Hong TS, Wo JY, Yeap BY, et al. Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. J Clin Oncol 2016; 34:460.
- Tran TB, Bal CK, Schaberg K, et al. Locally Advanced Intrahepatic Cholangiocarcinoma: Complete Pathologic Response to Neoadjuvant Chemotherapy Followed by Left Hepatic Trisectionectomy and Caudate Lobectomy. Dig Dis Sci 2015; 60:3226.
- Hashimoto K, Tono T, Nishida K, et al. [A case of curatively resected advanced intrahepatic cholangiocellular carcinoma through effective response to neoadjuvant chemotherapy]. Gan To Kagaku Ryoho 2014; 41:2083.
- Kim JH, Yoon HK, Sung KB, et al. Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing outcomes. Cancer 2008; 113:1614.
- Boehm LM, Jayakrishnan TT, Miura JT, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol 2015; 111:213.
- Kiefer MV, Albert M, McNally M, et al. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer 2011; 117:1498.
- Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol 2013; 20:3779.
- Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer 2008; 113:2119.
- Rafi S, Piduru SM, El-Rayes B, et al. Yttrium-90 radioembolization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety study. Cardiovasc Intervent Radiol 2013; 36:440.
- Mouli S, Memon K, Baker T, et al. Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis. J Vasc Interv Radiol 2013; 24:1227.
- 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; 35:105.
- Ohnishi H, Asada M, Shichijo Y, et al. External radiotherapy for biliary decompression of hilar cholangiocarcinoma. Hepatogastroenterology 1995; 42:265.
- Park JY, Park SW, Chung JB, et al. Concurrent chemoradiotherapy with doxifluridine and paclitaxel for extrahepatic bile duct cancer. Am J Clin Oncol 2006; 29:240.
- Crane CH, Macdonald KO, Vauthey JN, et al. Limitations of conventional doses of chemoradiation for unresectable biliary cancer. Int J Radiat Oncol Biol Phys 2002; 53:969.
- Alden ME, Mohiuddin M. The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys 1994; 28:945.
- Foo ML, Gunderson LL, Bender CE, Buskirk SJ. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 1997; 39:929.
- Gerhards MF, van Gulik TM, González González D, et al. Results of postoperative radiotherapy for resectable hilar cholangiocarcinoma. World J Surg 2003; 27:173.
- Vallis KA, Benjamin IS, Munro AJ, et al. External beam and intraluminal radiotherapy for locally advanced bile duct cancer: role and tolerability. Radiother Oncol 1996; 41:61.
- Minsky BD, Kemeny N, Armstrong JG, et al. Extrahepatic biliary system cancer: an update of a combined modality approach. Am J Clin Oncol 1991; 14:433.
- Robertson JM, Lawrence TS, Dworzanin LM, et al. Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy. J Clin Oncol 1993; 11:1286.
- Kamada T, Saitou H, Takamura A, et al. The role of radiotherapy in the management of extrahepatic bile duct cancer: an analysis of 145 consecutive patients treated with intraluminal and/or external beam radiotherapy. Int J Radiat Oncol Biol Phys 1996; 34:767.
- Kuvshinoff BW, Armstrong JG, Fong Y, et al. Palliation of irresectable hilar cholangiocarcinoma with biliary drainage and radiotherapy. Br J Surg 1995; 82:1522.
- Shin HS, Seong J, Kim WC, et al. Combination of external beam irradiation and high-dose-rate intraluminal brachytherapy for inoperable carcinoma of the extrahepatic bile ducts. Int J Radiat Oncol Biol Phys 2003; 57:105.
- Baisden JM, Kahaleh M, Weiss GR, et al. Multimodality Treatment With Helical Tomotherapy Intensity Modulated Radiotherapy, Capecitabine, and Photodynamic Therapy is Feasible and Well Tolerated in Patients With Hilar Cholangiocarcinoma. Gastrointest Cancer Res 2008; 2:219.
- Ben-David MA, Griffith KA, Abu-Isa E, et al. External-beam radiotherapy for localized extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 2006; 66:772.
- Grendar J, Grendarova P, Sinha R, Dixon E. Neoadjuvant therapy for downstaging of locally advanced hilar cholangiocarcinoma: a systematic review. HPB (Oxford) 2014; 16:297.
- Glazer ES, Liu P, Abdalla EK, et al. Neither neoadjuvant nor adjuvant therapy increases survival after biliary tract cancer resection with wide negative margins. J Gastrointest Surg 2012; 16:1666.
- Nelson JW, Ghafoori AP, Willett CG, et al. Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 2009; 73:148.
- Berr F, Wiedmann M, Tannapfel A, et al. Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. Hepatology 2000; 31:291.
- Witzigmann H, Berr F, Ringel U, et al. Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to r1/r2 resection. Ann Surg 2006; 244:230.
- Dumoulin FL, Gerhardt T, Fuchs S, et al. Phase II study of photodynamic therapy and metal stent as palliative treatment for nonresectable hilar cholangiocarcinoma. Gastrointest Endosc 2003; 57:860.
- Wiedmann M, Berr F, Schiefke I, et al. Photodynamic therapy in patients with non-resectable hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study. Gastrointest Endosc 2004; 60:68.
- Kahaleh M, Mishra R, Shami VM, et al. Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy. Clin Gastroenterol Hepatol 2008; 6:290.
- Zoepf T, Jakobs R, Arnold JC, et al. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol 2005; 100:2426.
- Gao F, Bai Y, Ma SR, et al. Systematic review: photodynamic therapy for unresectable cholangiocarcinoma. J Hepatobiliary Pancreat Sci 2010; 17:125.
- Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003; 125:1355.
- Prasad GA, Wang KK, Baron TH, et al. Factors associated with increased survival after photodynamic therapy for cholangiocarcinoma. Clin Gastroenterol Hepatol 2007; 5:743.
- Wentrup R, Winkelmann N, Mitroshkin A, et al. Photodynamic Therapy Plus Chemotherapy Compared with Photodynamic Therapy Alone in Hilar Nonresectable Cholangiocarcinoma. Gut Liver 2016; 10:470.
- Park DH, Lee SS, Park SE, et al. Randomised phase II trial of photodynamic therapy plus oral fluoropyrimidine, S-1, versus photodynamic therapy alone for unresectable hilar cholangiocarcinoma. Eur J Cancer 2014; 50:1259.
- Knüppel M, Kubicka S, Vogel A, et al. Combination of conservative and interventional therapy strategies for intra- and extrahepatic cholangiocellular carcinoma: a retrospective survival analysis. Gastroenterol Res Pract 2012; 2012:190708.
- Fuks D, Bartoli E, Delcenserie R, et al. Biliary drainage, photodynamic therapy and chemotherapy for unresectable cholangiocarcinoma with jaundice. J Gastroenterol Hepatol 2009; 24:1745.
- Hong MJ, Cheon YK, Lee EJ, et al. Long-term outcome of photodynamic therapy with systemic chemotherapy compared to photodynamic therapy alone in patients with advanced hilar cholangiocarcinoma. Gut Liver 2014; 8:318.
- Wagner A, Wiedmann M, Tannapfel A, et al. Neoadjuvant Down-Sizing of Hilar Cholangiocarcinoma with Photodynamic Therapy--Long-Term Outcome of a Phase II Pilot Study. Int J Mol Sci 2015; 16:26619.
- 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; 33:2617.
- Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005; 242:451.
- 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.
- Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for cholangiocarcinoma. Arch Surg 1995; 130:270.
- Pichlmayr R, Weimann A, Klempnauer J, et al. Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg 1996; 224:628.
- Benjamin IS. Surgical possibilities for bile duct cancer: standard surgical treatment. Ann Oncol 1999; 10 Suppl 4:239.
- Smith AC, Dowsett JF, Russell RC, et al. Randomised trial of endoscopic stenting versus surgical bypass in malignant low bileduct obstruction. Lancet 1994; 344:1655.
- Shepherd HA, Royle G, Ross AP, et al. Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg 1988; 75:1166.
- Lai EC, Chu KM, Lo CY, et al. Choice of palliation for malignant hilar biliary obstruction. Am J Surg 1992; 163:208.
- Andersen JR, Sørensen SM, Kruse A, et al. Randomised trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut 1989; 30:1132.
- Prat F, Chapat O, Ducot B, et al. Predictive factors for survival of patients with inoperable malignant distal biliary strictures: a practical management guideline. Gut 1998; 42:76.
- Saluja SS, Gulati M, Garg PK, et al. Endoscopic or percutaneous biliary drainage for gallbladder cancer: a randomized trial and quality of life assessment. Clin Gastroenterol Hepatol 2008; 6:944.
- Piñol V, Castells A, Bordas JM, et al. Percutaneous self-expanding metal stents versus endoscopic polyethylene endoprostheses for treating malignant biliary obstruction: randomized clinical trial. Radiology 2002; 225:27.
- Paik WH, Park YS, Hwang JH, et al. Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach. Gastrointest Endosc 2009; 69:55.
- Speer AG, Cotton PB, Russell RC, et al. Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet 1987; 2:57.
- Dowsett JF, Vaira D, Hatfield AR, et al. Endoscopic biliary therapy using the combined percutaneous and endoscopic technique. Gastroenterology 1989; 96:1180.
- Levy MJ, Baron TH, Gostout CJ, et al. Palliation of malignant extrahepatic biliary obstruction with plastic versus expandable metal stents: An evidence-based approach. Clin Gastroenterol Hepatol 2004; 2:273.
- Chan G, Barkun J, Barkun AN, et al. The role of ciprofloxacin in prolonging polyethylene biliary stent patency: a multicenter, double-blinded effectiveness study. J Gastrointest Surg 2005; 9:481.
- OVERVIEW OF THE THERAPEUTIC APPROACH
- ANTINEOPLASTIC THERAPY
- Intrahepatic cholangiocarcinoma
- - Radiotherapy and chemoradiotherapy
- Microscopically positive margins
- Locally unresectable and recurrent disease
- - Neoadjuvant approaches
- - Local ablation and embolization
- Extrahepatic cholangiocarcinoma
- - Radiotherapy and chemoradiotherapy
- Microscopically positive margins
- Locally unresectable and recurrent
- - Neoadjuvant approaches
- - Photodynamic therapy
- Systemic chemotherapy
- Role of orthotopic liver transplantation
- Guidelines from expert groups
- - NCCN
- Intrahepatic cholangiocarcinoma
- Extrahepatic cholangiocarcinoma
- - ESMO
- PALLIATION OF OBSTRUCTIVE JAUNDICE
- Surgical bypass
- - Percutaneous versus endoscopic approach
- - Unilateral versus bilateral stents
- - Plastic versus metal stents
- - Covered versus uncovered stents
- - Prophylactic antibiotics
- SUMMARY AND RECOMMENDATIONS