Cholangiocarcinoma is typically incurable at diagnosis which is why early detection is ideal.[9][1] In these cases palliative treatments may include surgical resection, chemotherapy, radiation therapy, and stenting procedures.[1] In about a third of cases involving the common bile duct and less commonly with other locations the tumor can be completely removed by surgery offering a chance of a cure.[1] Even when surgical removal is successful chemotherapy and radiation therapy are generally recommended.[1] In certain cases surgery may include a liver transplantation.[3] Even when surgery is successful the 5-year survival is typically less than 50%.[6]
Cholangiocarcinoma is rare in the Western world, with estimates of it occurring in 0.5–2 people per 100,000 per year.[1][6] Rates are higher in Southeast Asia where liver flukes are common.[5] Rates in parts of Thailand are 60 per 100,000 per year.[5] It typically occurs in people in their 70s; however, in those with primary sclerosing cholangitis it often occurs in the 40s.[3] Rates of cholangiocarcinoma within the liver in the Western world have increased.[6]
The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice (yellowing of the eyes and skin occurring when bile ducts are blocked by tumor), abdominal pain (30–50%), generalized itching (66%), weight loss (30–50%), fever (up to 20%), and changes in the color of stool or urine.[10] To some extent, the symptoms depend upon the location of the tumor: people with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the bile ducts within the liver more often have pain without jaundice.[11]
Although most people present without any known risk factors evident, a number of risk factors for the development of cholangiocarcinoma have been described. In the Western world, the most common of these is primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts which is closely associated with ulcerative colitis (UC).[13] Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is on the order of 10–15%,[14] although autopsy series have found rates as high as 30% in this population.[15] For inflammatory bowel disease patients with altered DNA repair functions, the progression from PSC to cholangiocarcinoma may be a consequence of DNA damage resulting from biliary inflammation and bile acids.[16]
Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukesOpisthorchis viverrini (found in Thailand, Laos PDR, and Vietnam)[17][18][19] or Clonorchis sinensis (found in China, Taiwan, eastern Russia, Korea, and Vietnam)[20][21] has been associated with the development of cholangiocarcinoma. Control programs (Integrated Opisthorchiasis Control Program) aimed at discouraging the consumption of raw and undercooked food have been successful at reducing the incidence of cholangiocarcinoma in some countries.[22] People with chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or hepatitis C),[23][24][25]alcoholic liver disease, or cirrhosis of the liver due to other causes, are at significantly increased risk of cholangiocarcinoma.[26][27]HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was unclear whether HIV itself or other correlated and confounding factors (e.g. hepatitis C infection) were responsible for the association.[26]
Congenital liver abnormalities, such as Caroli disease (a specific type of five recognized choledochal cysts), have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma.[29][30] The rare inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with cholangiocarcinoma.[31][32] The presence of gallstones (cholelithiasis) is not clearly associated with cholangiocarcinoma. However, intrahepatic stones (called hepatolithiasis), which are rare in the West but common in parts of Asia, have been strongly associated with cholangiocarcinoma.[33][34][35] Exposure to Thorotrast, a form of thorium dioxide which was used as a radiologic contrast medium, has been linked to the development of cholangiocarcinoma as late as 30–40 years after exposure; Thorotrast was banned in the United States in the 1950s due to its carcinogenicity.[36][37][38]
Pathophysiology
Digestive system diagram showing bile duct location.
Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. Tumors occurring in the bile ducts within the liver are referred to as intrahepatic, those occurring in the ducts outside the liver are extrahepatic, and tumors occurring at the site where the bile ducts exit the liver may be referred to as perihilar. A cholangiocarcinoma occurring at the junction where the left and right hepatic ducts meet to form the common hepatic duct may be referred to eponymously as a Klatskin tumor.[39]
Although cholangiocarcinoma is known to have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the actual cell of origin is unknown. Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise from a pluripotent hepatic stem cell.[40][41][42] Cholangiocarcinoma is thought to develop through a series of stages – from early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma – in a process similar to that seen in the development of colon cancer.[43]Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.[43][44][45]
Micrograph of an intrahepatic, i.e. in the liver, cholangiocarcinoma (right of image); benign hepatocytes are seen (left of image). Histologically, this is a cholangiocarcinoma as (1) atypical bile duct-like cells (left of image) extend from the tumor in an interlobular septum (the normal anatomical location of bile ducts), and (2) the tumor has the abundant desmoplastic stroma often seen in cholangiocarcinomas. A portal triad (upper-left of image) has a histologically normal bile duct. H&E stain.
Blood tests
There are no specific blood tests that can diagnose cholangiocarcinoma by themselves. Serum levels of carcinoembryonic antigen (CEA) and CA19-9 are often elevated, but are not sensitive or specific enough to be used as a general screening tool. However, they may be useful in conjunction with imaging methods in supporting a suspected diagnosis of cholangiocarcinoma.[48]
Ultrasound of the liver and biliary tree is often used as the initial imaging modality in people with suspected obstructive jaundice.[49][50] Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma.[51]Computed tomography (CT) scanning may also play an important role in the diagnosis of cholangiocarcinoma.[52][53][54]
Imaging of the biliary tree
ERCP image of cholangiocarcinoma, showing common bile duct stricture and dilation of the proximal common bile duct
While abdominal imaging can be useful in the diagnosis of cholangiocarcinoma, direct imaging of the bile ducts is often necessary. Endoscopic retrograde cholangiopancreatography (ERCP), an endoscopic procedure performed by a gastroenterologist or specially trained surgeon, has been widely used for this purpose. Although ERCP is an invasive procedure with attendant risks, its advantages include the ability to obtain biopsies and to place stents or perform other interventions to relieve biliary obstruction.[12]Endoscopic ultrasound can also be performed at the time of ERCP and may increase the accuracy of the biopsy and yield information on lymph node invasion and operability.[55] As an alternative to ERCP, percutaneous transhepatic cholangiography (PTC) may be utilized. Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive alternative to ERCP.[56][57][58] Some authors have suggested that MRCP should supplant ERCP in the diagnosis of biliary cancers, as it may more accurately define the tumor and avoids the risks of ERCP.[59][60][61]
Surgery
Photograph of cholangiocarcinoma in human liver.
Surgical exploration may be necessary to obtain a suitable biopsy and to accurately stage a person with cholangiocarcinoma. Laparoscopy can be used for staging purposes and may avoid the need for a more invasive surgical procedure, such as laparotomy, in some people.[62][63]
Histologically, cholangiocarcinomas are classically well to moderately differentiated adenocarcinomas. Immunohistochemistry is useful in the diagnosis and may be used to help differentiate a cholangiocarcinoma from hepatocellular carcinoma and metastasis of other gastrointestinal tumors.[65]Cytological scrapings are often nondiagnostic,[66] as these tumors typically have a desmoplastic stroma and, therefore, do not release diagnostic tumor cells with scrapings.
Staging
Although there are at least three staging systems for cholangiocarcinoma (e.g. those of Bismuth, Blumgart, and the American Joint Committee on Cancer), none have been shown to be useful in predicting survival.[67] The most important staging issue is whether the tumor can be surgically removed, or whether it is too advanced for surgical treatment to be successful. Often, this determination can only be made at the time of surgery.[12]
General guidelines for operability include:[68][69]
Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be fully resected (cut out surgically). Since the operability of the tumor can only be assessed during surgery in most cases,[70] a majority of people undergo exploratory surgery unless there is already a clear indication that the tumor is inoperable.[12] However, the Mayo Clinic has reported significant success treating early bile duct cancer with liver transplantation using a protocolized approach and strict selection criteria.[71]
Adjuvant therapy followed by liver transplantation may have a role in treatment of certain unresectable cases.[72] Locoregional therapies including transarterial chemoembolization (TACE), transarterial radioembolization (TARE) and ablation therapies have a role in intrahepatic variants of cholangiocarcinoma to provide palliation or potential cure in people who are not surgical candidates.[73]
Adjuvant chemotherapy and radiation therapy
If the tumor can be removed surgically, people may receive adjuvantchemotherapy or radiation therapy after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has been totally excised), adjuvant therapy is of uncertain benefit. Both positive[74][75] and negative[11][76][77] results have been reported with adjuvant radiation therapy in this setting, and no prospective randomized controlled trials have been conducted as of March 2007. Adjuvant chemotherapy appears to be ineffective in people with completely resected tumors.[78][79] The role of combined chemoradiotherapy in this setting is unclear. However, if the tumor tissue margins are positive, indicating that the tumor was not completely removed via surgery, then adjuvant therapy with radiation and possibly chemotherapy is generally recommended based on the available data.[80][81]
Treatment of advanced disease
The majority of cases of cholangiocarcinoma present as inoperable (unresectable) disease[82] in which case people are generally treated with palliativechemotherapy, with or without radiotherapy. Chemotherapy has been shown in a randomized controlled trial to improve quality of life and extend survival in people with inoperable cholangiocarcinoma.[83] There is no single chemotherapy regimen which is universally used, and enrollment in clinical trials is often recommended when possible.[81] Chemotherapy agents used to treat cholangiocarcinoma include 5-fluorouracil with leucovorin,[84]gemcitabine as a single agent,[85] or gemcitabine plus cisplatin,[86]irinotecan,[87] or capecitabine.[88] A small pilot study suggested possible benefit from the tyrosine kinase inhibitor erlotinib in people with advanced cholangiocarcinoma.[89]
Radiation therapy appears to prolong survival in people with resected extrahepatic cholangiocarcinoma,[90] and the few reports of its use in unresectable cholangiocarcinoma appear to show improved survival, but numbers are small.[6]
Pemigatinib (Pemazyre) is a kinase inhibitor of fibroblast growth factor receptor 2 (FGFR2) that was approved for medical use in the United States in April 2020.[92] It is indicated for the treatment of adults with 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.
Ivodesinib (Tibsovo) is a small molecule inhibitor of isocitrate dehydrogenase 1. The FDA approved ivosidenib in August 2021 for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.[93]
Durvalumab, (Imfinzi) is an immune checkpoint inhibitor that blocks the PD-L1 protein on the surface of immune cells, thereby allowing the immune system to recognize and attack tumor cells. In Phase III clinical trials, durvalumab, in combination with standard-of-care chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in overall survival and progression-free survival versus chemotherapy alone as a 1st-line treatment for patients with advanced biliary tract cancer.[94]
Futibatinib (Lytgobi) was approved for medical use in the United States in September 2022.[95]
Prognosis
Surgical resection offers the only potential chance of cure in cholangiocarcinoma. For non-resectable cases, the five-year survival rate is 0% where the disease is inoperable because distal lymph nodes show metastases,[96] and less than 5% in general.[97] Overall mean duration of survival is less than 6 months in people with metastatic disease.[98]
For surgical cases, the odds of cure vary depending on the tumor location and whether the tumor can be completely, or only partially, removed. Distal cholangiocarcinomas (those arising from the common bile duct) are generally treated surgically with a Whipple procedure; long-term survival rates range from 15 to 25%, although one series reported a five-year survival of 54% for people with no involvement of the lymph nodes.[99] Intrahepatic cholangiocarcinomas (those arising from the bile ducts within the liver) are usually treated with partial hepatectomy. Various series have reported survival estimates after surgery ranging from 22 to 66%; the outcome may depend on involvement of lymph nodes and completeness of the surgery.[100] Perihilar cholangiocarcinomas (those occurring near where the bile ducts exit the liver) are least likely to be operable. When surgery is possible, they are generally treated with an aggressive approach often including removal of the gallbladder and potentially part of the liver. In patients with operable perihilar tumors, reported 5-year survival rates range from 20 to 50%.[101]
The prognosis may be worse for people with primary sclerosing cholangitis who develop cholangiocarcinoma, likely because the cancer is not detected until it is advanced.[15][102] Some evidence suggests that outcomes may be improving with more aggressive surgical approaches and adjuvant therapy.[103]
Cholangiocarcinoma is a relatively rare form of cancer; each year, approximately 2,000 to 3,000 new cases are diagnosed in the United States, translating into an annual incidence of 1–2 cases per 100,000 people.[105]Autopsy series have reported a prevalence of 0.01% to 0.46%.[82][106] There is a higher prevalence of cholangiocarcinoma in Asia, which has been attributed to endemic chronic parasitic infestation. The incidence of cholangiocarcinoma increases with age, and the disease is slightly more common in men than in women (possibly due to the higher rate of primary sclerosing cholangitis, a major risk factor, in men).[47] The prevalence of cholangiocarcinoma in people with primary sclerosing cholangitis may be as high as 30%, based on autopsy studies.[15]
Multiple studies have documented a steady increase in the incidence of intrahepatic cholangiocarcinoma; increases have been seen in North America, Europe, Asia, and Australia.[107] The reasons for the increasing occurrence of cholangiocarcinoma are unclear; improved diagnostic methods may be partially responsible, but the prevalence of potential risk factors for cholangiocarcinoma, such as HIV infection, has also been increasing during this time frame.[26]
Liver tumor types by relative incidence in adults in the United States, with cholangiocarcinoma at top right.[108]
^ abcBosman, Frank T. (2014). "Chapter 5.6: Liver cancer". In Stewart, Bernard W.; Wild, Christopher P (eds.). World Cancer Report(PDF). the International Agency for Research on Cancer, World Health Organization. pp. 403–12. ISBN978-92-832-0443-5.
^Epidemiologic studies which have addressed the incidence of cholangiocarcinoma in people with primary sclerosing cholangitis include the following:
Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Lööf L, Danielsson A, et al. (March 2002). "Hepatic and extrahepatic malignancies in primary sclerosing cholangitis". Journal of Hepatology. 36 (3): 321–7. doi:10.1016/S0168-8278(01)00288-4. PMID11867174.
^Rustagi T, Dasanu CA (June 2012). "Risk factors for gallbladder cancer and cholangiocarcinoma: similarities, differences and updates". Journal of Gastrointestinal Cancer. 43 (2): 137–47. doi:10.1007/s12029-011-9284-y. PMID21597894. S2CID31590872.
^Lu H, Ye MQ, Thung SN, Dash S, Gerber MA (December 2000). "Detection of hepatitis C virus RNA sequences in cholangiocarcinomas in Chinese and American patients". Chinese Medical Journal. 113 (12): 1138–41. PMID11776153.
^ abcShaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA (March 2005). "Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study". Gastroenterology. 128 (3): 620–6. doi:10.1053/j.gastro.2004.12.048. PMID15765398.
^Sorensen HT, Friis S, Olsen JH, Thulstrup AM, Mellemkjaer L, Linet M, et al. (October 1998). "Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark". Hepatology. 28 (4): 921–5. doi:10.1002/hep.510280404. PMID9755226. S2CID72842845.
^Dayton MT, Longmire WP, Tompkins RK (January 1983). "Caroli's Disease: a premalignant condition?". American Journal of Surgery. 145 (1): 41–8. doi:10.1016/0002-9610(83)90164-2. PMID6295196.
^Mecklin JP, Järvinen HJ, Virolainen M (March 1992). "The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma". Cancer. 69 (5): 1112–4. doi:10.1002/cncr.2820690508. PMID1310886. S2CID23468163.
^Lee CC, Wu CY, Chen GH (September 2002). "What is the impact of coexistence of hepatolithiasis on cholangiocarcinoma?". Journal of Gastroenterology and Hepatology. 17 (9): 1015–20. doi:10.1046/j.1440-1746.2002.02779.x. PMID12167124. S2CID25753564.
^Donato F, Gelatti U, Tagger A, Favret M, Ribero ML, Callea F, et al. (December 2001). "Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy". Cancer Causes & Control. 12 (10): 959–64. doi:10.1023/A:1013747228572. PMID11808716. S2CID12117363.
^Zhu AX, Lauwers GY, Tanabe KK (2004). "Cholangiocarcinoma in association with Thorotrast exposure". Journal of Hepato-Biliary-Pancreatic Surgery. 11 (6): 430–3. doi:10.1007/s00534-004-0924-5. PMID15619021.
^Lipshutz GS, Brennan TV, Warren RS (November 2002). "Thorotrast-induced liver neoplasia: a collective review". Journal of the American College of Surgeons. 195 (5): 713–8. doi:10.1016/S1072-7515(02)01287-5. PMID12437262.
^Klatskin G (February 1965). "Adenocarcinoma of the Hepatic Duct at Its Bifurcation Within The Porta Hepatis. An Unusual Tumor With Distinctive Clinical And Pathological Features". American Journal of Medicine. 38 (2): 241–56. doi:10.1016/0002-9343(65)90178-6. PMID14256720.
^Studies of the performance of serum markers for cholangiocarcinoma (such as carcinoembryonic antigen and CA19-9) in patients with and without primary sclerosing cholangitis include the following:
Siqueira E, Schoen RE, Silverman W, Martin J, Rabinovitz M, Weissfeld JL, et al. (July 2002). "Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis". Gastrointestinal Endoscopy. 56 (1): 40–7. doi:10.1067/mge.2002.125105. PMID12085033.
Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD (September 2005). "The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis". Digestive Diseases and Sciences. 50 (9): 1734–40. doi:10.1007/s10620-005-2927-8. PMID16133981. S2CID24744509.
Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ (January 2000). "The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis". American Journal of Gastroenterology. 95 (1): 204–7. doi:10.1111/j.1572-0241.2000.01685.x. PMID10638584. S2CID11325616.
^Sharma MP, Ahuja V (1999). "Aetiological spectrum of obstructive jaundice and diagnostic ability of ultrasonography: a clinician's perspective". Tropical Gastroenterology. 20 (4): 167–9. PMID10769604.
^Valls C, Gumà A, Puig I, Sanchez A, Andía E, Serrano T, et al. (2000). "Intrahepatic peripheral cholangiocarcinoma: CT evaluation". Abdominal Imaging. 25 (5): 490–6. doi:10.1007/s002610000079. PMID10931983. S2CID12010522.
^Tillich M, Mischinger HJ, Preisegger KH, Rabl H, Szolar DH (September 1998). "Multiphasic helical CT in diagnosis and staging of hilar cholangiocarcinoma". AJR. American Journal of Roentgenology. 171 (3): 651–8. doi:10.2214/ajr.171.3.9725291. PMID9725291.
^Zhang Y, Uchida M, Abe T, Nishimura H, Hayabuchi N, Nakashima Y (1999). "Intrahepatic peripheral cholangiocarcinoma: comparison of dynamic CT and dynamic MRI". Journal of Computer Assisted Tomography. 23 (5): 670–7. doi:10.1097/00004728-199909000-00004. PMID10524843.
^Sugiyama M, Hagi H, Atomi Y, Saito M (1997). "Diagnosis of portal venous invasion by pancreatobiliary carcinoma: value of endoscopic ultrasonography". Abdominal Imaging. 22 (4): 434–8. doi:10.1007/s002619900227. PMID9157867. S2CID19988847.
^Lee MG, Park KB, Shin YM, Yoon HK, Sung KB, Kim MH, et al. (March 2003). "Preoperative evaluation of hilar cholangiocarcinoma with contrast-enhanced three-dimensional fast imaging with steady-state precession magnetic resonance angiography: comparison with intraarterial digital subtraction angiography". World Journal of Surgery. 27 (3): 278–83. doi:10.1007/s00268-002-6701-1. PMID12607051. S2CID25092608.
^Yeh TS, Jan YY, Tseng JH, Chiu CT, Chen TC, Hwang TL, et al. (February 2000). "Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings". American Journal of Gastroenterology. 95 (2): 432–40. doi:10.1111/j.1572-0241.2000.01763.x. PMID10685746. S2CID25350361.
^Freeman ML, Sielaff TD (2003). "A modern approach to malignant hilar biliary obstruction". Reviews in Gastroenterological Disorders. 3 (4): 187–201. PMID14668691.
^Szklaruk J, Tamm E, Charnsangavej C (October 2002). "Preoperative imaging of biliary tract cancers". Surgical Oncology Clinics of North America. 11 (4): 865–76. doi:10.1016/S1055-3207(02)00032-7. PMID12607576.
^Callery MP, Strasberg SM, Doherty GM, Soper NJ, Norton JA (July 1997). "Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy". Journal of the American College of Surgeons. 185 (1): 33–9. doi:10.1016/s1072-7515(97)00003-3. PMID9208958.
^Image by
Mikael Häggström, MD. Source for caption: - Nat Pernick, M.D. "Cytokeratin 19 (CK19, K19)". Pathology Outlines. Last author update: 1 October 2013
^Länger F, von Wasielewski R, Kreipe HH (July 2006). "[The importance of immunohistochemistry for the diagnosis of cholangiocarcinomas]". Der Pathologe (in German). 27 (4): 244–50. doi:10.1007/s00292-006-0836-z. PMID16758167. S2CID7571236.
^Zervos EE, Osborne D, Goldin SB, Villadolid DV, Thometz DP, Durkin A, et al. (November 2005). "Stage does not predict survival after resection of hilar cholangiocarcinomas promoting an aggressive operative approach". American Journal of Surgery. 190 (5): 810–5. doi:10.1016/j.amjsurg.2005.07.025. PMID16226963.
^Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H, et al. (February 2000). "Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma". International Journal of Radiation Oncology, Biology, Physics. 46 (3): 581–7. doi:10.1016/S0360-3016(99)00472-1. PMID10701737.
^Alden ME, Mohiuddin M (March 1994). "The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer". International Journal of Radiation Oncology, Biology, Physics. 28 (4): 945–51. doi:10.1016/0360-3016(94)90115-5. PMID8138448.
^González González D, Gouma DJ, Rauws EA, van Gulik TM, Bosma A, Koedooder C (1999). "Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma". Annals of Oncology. 10 (Suppl 4): 215–20. doi:10.1023/A:1008339709327. PMID10436826.
^Choi CW, Choi IK, Seo JH, Kim BS, Kim JS, Kim CD, et al. (August 2000). "Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas". American Journal of Clinical Oncology. 23 (4): 425–8. doi:10.1097/00000421-200008000-00023. PMID10955877.
^Bhargava P, Jani CR, Savarese DM, O'Donnell JL, Stuart KE, Rocha Lima CM (September 2003). "Gemcitabine and irinotecan in locally advanced or metastatic biliary cancer: preliminary report". Oncology. 17 (9 Suppl 8): 23–6. PMID14569844.
^Knox JJ, Hedley D, Oza A, Feld R, Siu LL, Chen E, et al. (April 2005). "Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial". Journal of Clinical Oncology. 23 (10): 2332–8. doi:10.1200/JCO.2005.51.008. PMID15800324.
^Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. (July 2006). "Phase II study of erlotinib in patients with advanced biliary cancer". Journal of Clinical Oncology. 24 (19): 3069–74. doi:10.1200/JCO.2005.05.3579. PMID16809731.
^Bonet Beltrán M, Allal AS, Gich I, et al. (2012). "Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies". Cancer Treat Rev. 38 (2): 111–119. doi:10.1016/j.ctrv.2011.05.003. PMID21652148.
^Farley DR, Weaver AL, Nagorney DM (May 1995). "'Natural history' of unresected cholangiocarcinoma: patient outcome after noncurative intervention". Mayo Clinic Proceedings. 70 (5): 425–9. doi:10.4065/70.5.425. PMID7537346.
^Grove MK, Hermann RE, Vogt DP, Broughan TA (April 1991). "Role of radiation after operative palliation in cancer of the proximal bile ducts". American Journal of Surgery. 161 (4): 454–8. doi:10.1016/0002-9610(91)91111-U. PMID1709795.
^Studies of surgical outcomes in distal cholangiocarcinoma include:
Bortolasi L, Burgart LJ, Tsiotos GG, Luque-De León E, Sarr MG (2000). "Adenocarcinoma of the distal bile duct. A clinicopathologic outcome analysis after curative resection". Digestive Surgery. 17 (1): 36–41. doi:10.1159/000018798. PMID10720830. S2CID23190342.
Fong Y, Blumgart LH, Lin E, Fortner JG, Brennan MF (December 1996). "Outcome of treatment for distal bile duct cancer". British Journal of Surgery. 83 (12): 1712–5. doi:10.1002/bjs.1800831217. PMID9038548. S2CID30172073.
^Studies of outcome in intrahepatic cholangiocarcinoma include:
Lieser MJ, Barry MK, Rowland C, Ilstrup DM, Nagorney DM (1998). "Surgical management of intrahepatic cholangiocarcinoma: a 31-year experience". Journal of Hepato-Biliary-Pancreatic Surgery. 5 (1): 41–7. doi:10.1007/PL00009949. PMID9683753.
Valverde A, Bonhomme N, Farges O, Sauvanet A, Flejou JF, Belghiti J (1999). "Resection of intrahepatic cholangiocarcinoma: a Western experience". Journal of Hepato-Biliary-Pancreatic Surgery. 6 (2): 122–7. doi:10.1007/s005340050094. PMID10398898.
Nakagohri T, Asano T, Kinoshita H, Kenmochi T, Urashima T, Miura F, et al. (March 2003). "Aggressive surgical resection for hilar-invasive and peripheral intrahepatic cholangiocarcinoma". World Journal of Surgery. 27 (3): 289–93. doi:10.1007/s00268-002-6696-7. PMID12607053. S2CID25358444.
Weber SM, Jarnagin WR, Klimstra D, DeMatteo RP, Fong Y, Blumgart LH (October 2001). "Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes". Journal of the American College of Surgeons. 193 (4): 384–91. doi:10.1016/S1072-7515(01)01016-X. PMID11584966.
^Estimates of survival after surgery for perihilar cholangiocarcinoma include:
Nagino M, Nimura Y, Kamiya J, Kanai M, Uesaka K, Hayakawa N, et al. (1998). "Segmental liver resections for hilar cholangiocarcinoma". Hepato-Gastroenterology. 45 (19): 7–13. PMID9496478.
Launois B, Reding R, Lebeau G, Buard JL (2000). "Surgery for hilar cholangiocarcinoma: French experience in a collective survey of 552 extrahepatic bile duct cancers". Journal of Hepato-Biliary-Pancreatic Surgery. 7 (2): 128–34. doi:10.1007/s005340050166. PMID10982604.
^Kaya M, de Groen PC, Angulo P, Nagorney DM, Gunderson LL, Gores GJ, et al. (April 2001). "Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience". American Journal of Gastroenterology. 96 (4): 1164–9. doi:10.1111/j.1572-0241.2001.03696.x. PMID11316165. S2CID295347.
^Nakeeb A, Tran KQ, Black MJ, Erickson BA, Ritch PS, Quebbeman EJ, et al. (October 2002). "Improved survival in resected biliary malignancies". Surgery. 132 (4): 555–63, discission 563–4. doi:10.1067/msy.2002.127555. PMID12407338.
^Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC (December 2002). "Changing international trends in mortality rates for liver, biliary and pancreatic tumours". Journal of Hepatology. 37 (6): 806–13. doi:10.1016/S0168-8278(02)00297-0. PMID12445422.
^Multiple independent studies have documented a steady increase in the worldwide incidence of cholangiocarcinoma. Some relevant journal articles include:
Patel T (June 2001). "Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States". Hepatology. 33 (6): 1353–7. doi:10.1053/jhep.2001.25087. PMID11391522. S2CID23115927.
Shaib YH, Davila JA, McGlynn K, El-Serag HB (March 2004). "Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?". Journal of Hepatology. 40 (3): 472–7. doi:10.1016/j.jhep.2003.11.030. PMID15123362.
Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC (December 2002). "Changing international trends in mortality rates for liver, biliary and pancreatic tumours". Journal of Hepatology. 37 (6): 806–13. doi:10.1016/S0168-8278(02)00297-0. PMID12445422.
