Medication Summary

Few patients are diagnosed with early-stage resectable tumors. Guidelines for unresectable or metastatic disease include various chemotherapy regimens. Targeted agents are available as second-line therapy for cholangiocarcinoma with specific driver mutations, including fibroblast growth factor receptor 2 (FGFR2)–selective tyrosine kinase inhibitors for advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement, and an isocitrate dehydrogenase 1 (IDH1) inhibitor for IDH1-mutated cholangiocarcinoma.

Class Summary

Inhibition of FGFR disrupts tumor cell proliferation, survival, migration, and angiogenesis.

Pemigatinib (Pemazyre)

View full drug information

Pemigatinib is a small molecule kinase inhibitor that targets FGFR1, 2, and 3 by inhibiting FGFR1-3 phosphorylation and signaling. Indicated for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

Infigratinib (Truseltiq)

View full drug information

Infigratinib is indicated for adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

Futibatinib (Lytgobi)

View full drug information

Indicated for previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma in adults harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.

Class Summary

Inhibitors of isocitrate dehydrogenase type 1 (IDH1) specifically inhibit a mutated form of IDH1 in the cytoplasm, which inhibits the formation of the oncometabolite, 2-hydroxyglutarate (2HG). This may lead to both an induction of cellular differentiation and an inhibition of cellular proliferation in IDH1-expressing tumor cells. IDH1, an enzyme in the citric acid cycle, is mutated in a variety of cancers; it initiates and drives cancer growth by both blocking cell differentiation and catalyzing the formation of 2HG.

Ivosidenib (Tibsovo)

View full drug information

Indicated for locally advanced or metastatic cholangiocarcinoma in previously treated adults with IDH1 mutation.

Follow-up

Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018 Feb. 15 (2):95-111. [QxMD MEDLINE Link]. [Full Text].
Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014 Jun 21. 383 (9935):2168-79. [QxMD MEDLINE Link]. [Full Text].
Blechacz B, Gores GJ. Tumors of the Bile Ducts, Gallbladder, and Ampulla. In: Fledman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 10th ed. Philadelphia, PA: Elsevier Saunders; 2015. 1171-83.
Patel T, Borad MJ. Cancer of the Biliary Tree. DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. 10th. Philadelphia, Pa: Wolters Kluwer Health; 2015. 715-33.
Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016 May. 13 (5):261-80. [QxMD MEDLINE Link].
Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis. An unusual tumor with distinctive clinical and pathological features. Am J Med. 1965 Feb. 38:241-56. [QxMD MEDLINE Link].
Clary B, Jarnigan W, Pitt H, et al. Hilar cholangiocarcinoma. J Gastrointest Surg. 2004 Mar-Apr. 8(3):298-302. [QxMD MEDLINE Link].
Doherty B, Nambudiri VE, Palmer WC. Update on the Diagnosis and Treatment of Cholangiocarcinoma. Curr Gastroenterol Rep. 2017 Jan. 19 (1):2. [QxMD MEDLINE Link].
Singal AK, Vauthey JN, Grady JJ, Stroehlein JR. Intra-hepatic cholangiocarcinoma--frequency and demographic patterns: thirty-year data from the M.D. Anderson Cancer Center. J Cancer Res Clin Oncol. 2011 Jul. 137(7):1071-8. [QxMD MEDLINE Link].
Sarcognato S, Sacchi D, Fassan M, Fabris L, Cadamuro M, Zanus G, et al. Cholangiocarcinoma. Pathologica. 2021 Jun. 113 (3):158-169. [QxMD MEDLINE Link].
Mimaki S, Totsuka Y, Suzuki Y, Nakai C, Goto M, Kojima M, et al. Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes. Carcinogenesis. 2016 Aug. 37 (8):817-26. [QxMD MEDLINE Link].
Kim TS, Pak JH, Kim JB, Bahk YY. Clonorchis sinensis, an Oriental Liver Fluke, as a Human Biological Agent (Carcinogen) of Cholangiocarcinoma: A Brief Review. BMB Rep. 2016 Jul 7. [QxMD MEDLINE Link].
Cancer Facts & Figures 2022. American Cancer Society. Available at https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html. Accessed: Janauary 12, 2022.
McGee EE, Castro FA, Engels EA, Freedman ND, Pfeiffer RM, Nogueira L, et al. Associations between autoimmune conditions and hepatobiliary cancer risk among elderly US adults. Int J Cancer. 2018 Aug 28. [QxMD MEDLINE Link].
Koshiol J, Ferreccio C, Devesa SS, Roa JC, Fraumeni JF Jr. Biliary Tract Cancer. Thun MJ, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D, eds. Cancer. Epidemiology and Prevention. 4th Edition. New York, NY: Oxford University Press; 2018. 661-671.
Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology. 2000 Jan. 31(1):7-11. [QxMD MEDLINE Link].
Travis LB, Hauptmann M, Gaul LK, Storm HH, Goldman MB, Nyberg U, et al. Site-specific cancer incidence and mortality after cerebral angiography with radioactive thorotrast. Radiat Res. 2003 Dec. 160(6):691-706. [QxMD MEDLINE Link].
Li JS, Han TJ, Jing N, Li L, Zhang XH, Ma FZ, et al. Obesity and the risk of cholangiocarcinoma: a meta-analysis. Tumour Biol. 2014 Apr 13. [QxMD MEDLINE Link].
Ramage JK, Donaghy A, Farrant JM, Iorns R, Williams R. Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology. 1995 Mar. 108 (3):865-9. [QxMD MEDLINE Link]. [Full Text].
Bergquist JR, Ivanics T, Storlie CB, Groeschl RT, Tee MC, Habermann EB, et al. Implications of CA19-9 elevation for survival, staging, and treatment sequencing in intrahepatic cholangiocarcinoma: A national cohort analysis. J Surg Oncol. 2016 Jul 20. [QxMD MEDLINE Link].
Li CX, Zhang H, Wang K, Wang X, Li XC. Preoperative Bilirubin Level Predicts Overall Survival and Tumor Recurrence After Resection for Perihilar Cholangiocarcinoma Patients. Cancer Manag Res. 2019. 11:10157-10165. [QxMD MEDLINE Link]. [Full Text].
Esnaola NF, Meyer JE, Karachristos A, Maranki JL, Camp ER, Denlinger CS. Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma. Cancer. 2016 May 1. 122 (9):1349-69. [QxMD MEDLINE Link]. [Full Text].
Fritscher-Ravens A, Broering DC, Knoefel WT, et al. EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology. Am J Gastroenterol. 2004 Jan. 99(1):45-51. [QxMD MEDLINE Link].
Uchida M, Ishibashi M, Tomita N, et al. Hilar and suprapancreatic cholangiocarcinoma: value of 3D angiography and multiphase fusion images using MDCT. AJR Am J Roentgenol. 2005 May. 184(5):1572-7. [QxMD MEDLINE Link].
[Guideline] Chapman MH, Thorburn D, Hirschfield GM, Webster GGJ, Rushbrook SM, Alexander G, et al. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019 Aug. 68 (8):1356-1378. [QxMD MEDLINE Link]. [Full Text].
Petrowsky H, Wildbrett P, Husarik DB. Impact of Integrated PET and CT on staging and management of glabladder cancer and cholangiocarcinoma. J Hepatol. 2006. Epub Apr 19:
American Joint Committee on Cancer. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, et al, eds. AJCC Cancer Staging Manual. 8th Edition. New York: Springer; 2017.
Simmons DT, Baron TH, Peterson BT. A Novel Endoscopic Approach to Brachytherapy in the Management of Hilar Cholangiocarcinoma. Am J Gastroenterol. 2006. Epub ahead of print:
Butros SR, Shenoy-Bhangle A, Mueller PR, Arellano RS. Radiofrequency ablation of intrahepatic cholangiocarcinoma: feasability, local tumor control, and long-term outcome. Clin Imaging. 2014 Feb 7. [QxMD MEDLINE Link].
Braunwarth E, Schullian P, Kummann M, Reider S, Putzer D, Primavesi F, et al. Aggressive local treatment for recurrent intrahepatic cholangiocarcinoma-Stereotactic radiofrequency ablation as a valuable addition to hepatic resection. PLoS One. 2022. 17 (1):e0261136. [QxMD MEDLINE Link].
Kida M, Miyazawa S, Iwai T, et al. Endoscopic management of malignant biliary obstruction by means of covered metallic stents: primary stent placement vs. re-intervention. Endoscopy. 2011 Dec. 43(12):1039-44. [QxMD MEDLINE Link].
Ortner MA, Liebetruth J, Schreiber S, et al. Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology. 1998 Mar. 114(3):536-42. [QxMD MEDLINE Link].
Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 2003 Nov. 125(5):1355-63. [QxMD MEDLINE Link].
Smart AC, Goyal L, Horick N, Petkovska N, Zhu AX, Ferrone CR, et al. Hypofractionated Radiation Therapy for Unresectable/Locally Recurrent Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2019 Dec 23. [QxMD MEDLINE Link].
Jackson MW, Amini A, Jones BL, Rusthoven CG, Schefter TE, Goodman KA. Treatment Selection and Survival Outcomes With and Without Radiation for Unresectable, Localized Intrahepatic Cholangiocarcinoma. Cancer J. 2016 Jul-Aug. 22 (4):237-42. [QxMD MEDLINE Link].
Mosconi C, Gramenzi A, Ascanio S, Cappelli A, Renzulli M, Pettinato C, et al. Yttrium-90 radioembolization for unresectable/recurrent intrahepatic cholangiocarcinoma: a survival, efficacy and safety study. Br J Cancer. 2016 Jul 26. 115 (3):297-302. [QxMD MEDLINE Link].
Thongprasert S, Napapan S, Charoentum C, Moonprakan S. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol. 2005 Feb. 16(2):279-81. [QxMD MEDLINE Link].
Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann Oncol. 2005. 16 Suppl 2:ii93-6. [QxMD MEDLINE Link].
Rangarajan K, Simmons G, Manas D, Malik H, Hamady ZZ. Systemic adjuvant chemotherapy for cholangiocarcinoma surgery: A systematic review and meta-analysis. Eur J Surg Oncol. 2019 Nov 15. [QxMD MEDLINE Link].
[Guideline] NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Version 2.2022 — July 15, 2022; Accessed: October 11, 2022.
Goyal L, Meric-Bernstam F, Hollebecque A, Morizane C, Valle JW, Karasic TB, et al. Updated results of the FOENIX-CCA2 trial: Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements (abstract 4009). Presented at the 2022 ASCO Annual Meeting. J Clin Oncol. 2022 June 01;40(16 suppl). [Full Text].
Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020 Mar 20. [QxMD MEDLINE Link].
Javie MM, Roychowdhury S, Kelley RK, Sadeghi S, Mararulla T, Waldschmidt DT, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement (abstract). Presented at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. J Clin Oncol. 2021 Jan 20. 39(3 suppl):265-265. [Full Text].
FDA Approves Ivosidenib for Bile Duct Cancer. U.S. Food & Drug Administration. Available at https://www.medscape.com/viewarticle/957291. August 26, 2021; Accessed: August 26, 2021.
Heimbach JK, Haddock MG, Alberts SR, et al. Transplantation for hilar cholangiocarcinoma. Liver Transpl. 2004 Oct. 10(10 Suppl 2):S65-8. [QxMD MEDLINE Link].
Shen WF, Zhong W, Liu Q, Sui CJ, Huang YQ, Yang JM. Adjuvant Transcatheter Arterial Chemoembolization for Intrahepatic Cholangiocarcinoma after Curative Surgery: Retrospective Control Study. World J Surg. 2011 Jun 23. [QxMD MEDLINE Link].
Seshadri RA, Majhi U. Endobiliary metastasis from rectal cancer mimicking intrahepatic cholangiocarcinoma: a case report and review of literature. J Gastrointest Cancer. 2009. 40 (3-4):123-7. [QxMD MEDLINE Link].
Anderson MA, Appalaneni V, Ben-Menachem T, Decker GA, Early DS, Evans JA, et al. The role of endoscopy in the evaluation and treatment of patients with biliary neoplasia. Gastrointest Endosc. 2013 Feb. 77 (2):167-74. [QxMD MEDLINE Link].
[Guideline] Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T, Arnold D, et al. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep. 27 (suppl 5):v28-v37. [QxMD MEDLINE Link]. [Full Text].
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 May. 99(2):120-3. [QxMD MEDLINE Link].
Atanasov G, Schierle K, Hau HM, Dietel C, Krenzien F, Brandl A, et al. Prognostic Significance of Tumor Necrosis in Hilar Cholangiocarcinoma. Ann Surg Oncol. 2016 Aug 1. [QxMD MEDLINE Link].
Ghafoori AP, Nelson JW, Willett CG, et al. Radiotherapy in the treatment of patients with unresectable extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2011 Nov 1. 81(3):654-9. [QxMD MEDLINE Link].
McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013 Aug. 39 (5):534-40. [QxMD MEDLINE Link].
Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014 Jun. 106 (6):dju124. [QxMD MEDLINE Link]. [Full Text].
Okuno M, Ebata T, Yokoyama Y, Igami T, Sugawara G, Mizuno T, et al. Appraisal of inflammation-based prognostic scores in patients with unresectable perihilar cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2016 Jul 30. [QxMD MEDLINE Link].

Media Gallery

Bismuth classification for perihilar cholangiocarcinoma. Shaded areas represent tumor location.
Tight stricture of a common hepatic duct in a patient presenting with jaundice. Cytologic studies confirmed cholangiocarcinoma.
Three-dimensional treatment planning uses CT scan slices to reconstruct the patient as a volume. Shown here is the display for planning external-beam radiotherapy to the cholangiocarcinoma (green structure). A biliary catheter (red tube) runs through the tumor volume and was used to deliver brachytherapy, which was given in addition to external-beam radiotherapy. Such technology has assisted greatly in the delivery of high doses to the tumor, while sparing vital normal structures, such as the kidney and spinal cord.

of 3

Table 1. TNM staging for intrahepatic bile duct tumors

T - Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ (intraductal tumor)
T1	Solitary tumor without vascular invasion, ≤5 cm or > 5 cm
	T1a		Solitary tumor ≤5 cm without vascular invasion
	T1b	Solitary tumor > 5 cm without vascular invasion
T2	Solitary tumor with intrahepatic vascular invasion, or multiple tumors with or without vascular invasion
T3	Tumor perforating the visceral peritoneum
T4	Tumor involving local extrahepatic structures by direct invasion
N – Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis present
M – Distant metastasis
M0	No distant metastasis
M1	Distant metastasis present

Table 2. TNM staging for perihilar bile duct tumors.

T - Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ – high-grade dysplasia
T1	Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue
T2	Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma
	T2a		Tumor invades beyond the wall of the bile duct to surrounding adipose tissue
	T2b	Tumor invades adjacent hepatic parenchyma
T3	Tumor invades unilateral branches of the portal vein or hepatic artery
T4	Tumor invades main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals bilaterally with contralateral portal vein or hepatic artery involvement
N – Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes
N2	Four or more positive lymph nodes from the sites described for N1
M – Distant metastasis
M0	No distant metastasis
M1	Distant metastasis

Table 3. TNM staging for distal bile duct tumors.

T - Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ – high-grade dysplasia
T1	Tumor invades the bile duct wall with a depth less than 5 m
T2	Tumor invades the bile duct wall with a depth of 5–12 m
T3	Tumor invades the bile duct wall with a depth greater than 12 mm
T4	Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery
N – Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in 1-3 regional lymph nodes
N2	Metastasis in ≥4 regional lymph nodes
M – Distant metastasis
M0	No distant metastasis
M1	Distant metastasis