• Disease Overview
  • Synonyms
  • Subdivisions
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Cholangiocarcinoma

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Last updated: 3/14/2024
Years published: 2014, 2017, 2020, 2024


Acknowledgment

NORD gratefully acknowledges Layal Al Mahmasani, MD and Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, Internal Medicine, Medical Oncology, for the preparation of this report.


Disease Overview

Cholangiocarcinomas are cancers that arise from the cells lining the bile duct. They originally were grouped according to the location from which they arise as intrahepatic (arising from the bile ducts inside the liver), perihilar (arising from the bile ducts where they exit the liver), or distal (arising from the bile ducts outside the liver). Gallbladder cancers are also biliary tract cancers but arise from the cells lining the inside of the gallbladder.

Another way of grouping depends on genetic testing using next generation sequencing, a technology that is used to look for gene variants that may be present in some patients and may offer several new applicable therapies. More than 95% of tumors arising from the biliary tract are a type of cancer called adenocarcinoma. Most patients with bile duct cancer are diagnosed when the cancer is far too advanced to be removed by surgery. In some patients, even if the cancer cannot be removed by surgery, an operation may be needed to relieve jaundice or blockage of the stomach outlet. If the cancer is diagnosed at an early stage where surgery is possible, complex operating techniques are often required and surgery should be performed by a specialist surgeon with expertise and experience in dealing with patients with bile duct cancers.

 

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Synonyms

  • bile duct adenocarcinoma
  • biliary tract cancer
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Subdivisions

  • distal cholangiocarcinoma
  • gallbladder adenocarcinoma (biliary tract cancer, not cholangiocarcinoma)
  • intrahepatic cholangiocarcinoma
  • perihilar cholangiocarcinoma
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Signs & Symptoms

Most patients have no symptoms, particularly when the cancer is at an early stage. Occasionally biliary tract cancers are diagnosed incidentally when a CT or MRI scan is done for another reason, or when the gallbladder is removed due to symptomatic gallstones. Patients may have non-specific symptoms including weight loss, abdominal pain, fevers, night sweats and fatigue. Distal and perihilar cholangiocarcinoma or gallbladder cancers more frequently cause patients to develop jaundice due to tumor or lymph nodes blocking a major bile duct.

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Causes

Most cases of biliary tract cancer are sporadic, with no identifiable predisposing factors. There are several known risk factors for development of cholangiocarcinoma, however, including liver cirrhosis, hepatitis B and C, biliary tract stones, liver fluke infections, a congenital anatomical abnormality called a choledochal cyst and the chronic condition of inflamed bile ducts also called primary sclerosing cholangitis. Exposure to some industrial chemicals such as nitrosamines, dioxin, asbestos and polychlorinated biphenyls are also thought to increase the risk of developing cholangiocarcinoma. In the U.S., gallbladder cancer is commonly associated with the presence of long-standing gallstones resulting in calcification of the gallbladder wall or “porcelain gallbladder”. Gallbladder polyps are also associated with increased risk of gallbladder cancer. The incidence of bile duct cancers differs worldwide, likely reflecting both differing genetic predisposition and variable exposure to known risk factors.

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Affected populations

Approximately 20,000 new cases of bile duct cancers are diagnosed in the U.S. each year, of which over 12,000 are gallbladder cancers and distal/perihilar cholangiocarcinoma and 6,000 are intrahepatic cholangiocarcinoma. The incidence of intrahepatic cholangiocarcinoma in the U.S. is approximately 1.49 per 100,000 people.  Recently, the incidence of bile duct cancers has been increasing. This trend may be explained by the improved diagnostic techniques including imaging, increased disease awareness among physicians and wider acceptance of liver biopsy by patients.  Unlike intrahepatic and extrahepatic bile duct cancer, gallbladder cancer is more common in females than males, and in some countries the rates are three times higher for females. Certain geographic areas have a high incidence of gallbladder cancer, including Chile, Bolivia and India. A high incidence also has been reported in North American Native Americans and Mexican Americans.

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Diagnosis

A diagnosis of cholangiocarcinoma or gallbladder cancer is based on identification of characteristic symptoms (if present), a detailed patient history, clinical examination and several specialized tests including blood tests, imaging tests and endoscopic procedures. Either CT or MRI scans may be used to assess the tumor size and to look for blockage of the bile ducts and sites of spread. Endoscopic retrograde cholangiopancreatography (ERCP) may be used to insert a stent into a blocked bile duct to relieve jaundice. A biopsy is usually required to confirm the pathologic diagnosis and may be obtained by a CT or endoscopic ultrasound (EUS) guided biopsy. It is critical that genetic testing using next generation sequencing be performed on the biopsy sample. Some patients with gallbladder cancer are incidentally diagnosed following elective removal of their gallbladder due to gallstones, where the cancer is only detected on pathologic examination.

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Standard Therapies

Treatment
Optimal treatment of biliary tract cancers requires coordinated care of a team of medical professionals, usually including a medical oncologist, surgical oncologist, radiation oncologist, gastroenterologist and pathologist.

Resectable Disease

Surgery: Some patients with localized disease may be treated with surgery. The surgical approach differs depending on the location of the primary tumor. Intrahepatic cholangiocarcinoma is usually managed with a liver resection, while distal cholangiocarcinoma requires a Whipple procedure (pancreaticoduodenectomy) similar to pancreatic cancer, with resection of part of the stomach, pancreas and bile duct. Perihilar cholangiocarcinoma is located where the main bile ducts and blood vessels enter and exit the liver and may require a complex surgical procedure involving both liver and bile duct resection. Surgery for gallbladder cancer requires resection of the gallbladder and surrounding liver, and removal of several adjacent lymph nodes. Surgeons should ensure genetic sequencing is performed on tissue from the resected cancer.

Chemotherapy and Radiation Therapy

After surgical resection, the available treatments include chemotherapy and radiotherapy, or a combination of the two. The role of chemotherapy remains poorly defined, but data from a large study in the UK showed positive results using the oral chemotherapy capecitabine in some patients. Currently, adjuvant capecitabine can be considered for patients who have surgical resection of the tumor as preventative therapy.

As for radiation therapy, a recent study showed promising efficacy for post-operative chemotherapy followed by chemotherapy and radiation therapy for patients with gallbladder or extrahepatic cholangiocarcinoma who have surgery and have larger tumors, resection margin involved by disease, or several lymph nodes involved by disease. Further studies exploring these treatment options and others are under investigation or planned. Also, the role of neo-adjuvant therapy, which is defined as treatments given before surgical interventions, is being explored. Peri-adjuvant therapy, which includes treatment before surgery, followed by resection, followed by adjuvant treatment with the aim of controlling the disease early on and decreasing risk of recurrence at later stage, is currently being studied in clinical trials.

Unresectable Disease

Most patients with biliary tract cancer are diagnosed when the cancer is far too advanced to be removed by surgery. Chemotherapy has been the mainstay of treatment for decades. However, recent studies showed a positive role for combination of chemotherapy with immune checkpoint inhibitors, which are treatments that help the body recognize and attack cancer cells. While treatment in this setting is not a cure, it can control and contain the cancer, help patients live longer and delay or prevent the development of cancer related symptoms. The decision to treat is based on the patient’s level of well-being and presence of other medical conditions. In patients who are well enough, combining two chemotherapy drugs called gemcitabine and cisplatin along with immune checkpoint inhibitors (durvalumab or pembrolizumab) is considered a standard of care.

Later, when the disease progresses clinically or radiologically, other treatment options are available. Genetic sequencing should be done as early as possible since it will help determine therapy. If the patient continues to be well enough and the tumor has a gene variant that can be targeted by certain drugs, then treatment is based on the gene variant. These drugs include pemigatinib and futibatinib which are inhibitors of single or multiple FGFR receptors, ivosedinib which is an inhibitor of IDH1 gene variants, and dabrafenib/trametinib which targets the BRAF V600E gene variant. These drugs are called targeted therapy and work through blocking certain pathways in cancer cell development, hence preventing the tumor from growing and spreading. It is estimated that up to 30-40% of individuals with biliary tract cancers have at least one actionable or potentially actionable gene variant.

If the patient continues to be well enough, and the tumor has no targetable genomic alterations or variants, then chemotherapy remains an option. 5-fluorouracil-based regimen is the choice of treatment at this stage. Continuing immune checkpoint inhibitors in combination with a different chemotherapy regimen is under investigation.

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Clinical Trials and Studies

Several other targeted drug therapies are being investigated for the treatment of inoperable biliary tract cancers. These include inhibitors for Her-2, NTRK, RET and others. In addition, combination therapies are being investigated such as combination ivosedinib with immune checkpoint inhibitors and combination of trastuzumab with tucatinib.

Multiple other pathways and targets are currently being studied including the activating variants for genes for RAS and MDM2 proteins. These drugs are still investigations and under clinical development. The role of cellular therapies such as chimeric antigen receptor (CAR) T-cell therapy and cancer vaccine are also being studied.

Clinical trials investigating direct delivery of chemotherapy to the liver via a surgically implantable abdominal pump are underway. The role of liver transplant for intrahepatic cholangiocarcinoma has had limited study and remains controversial. Definitive evidence to support the role of transplant remains unclear.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Bekaii-Saab TS, et al. Adagrasib in advanced solid tumors harboring a KRAS(G12C) mutation. J Clin Oncol. Sep 1 2023;41(25):4097-4106.

Goyal L, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. New England Journal of Medicine. 2023;388(3):228-239.

Goyal L, et al. A phase IIa/IIb, open-label trial of BI 907828, an MDM2–p53 antagonist, in patients with locally advanced/metastatic biliary tract carcinoma or pancreatic ductal adenocarcinoma: Brightline-2. Journal of Clinical Oncology. 2023;41(16_suppl):TPS4179-TPS4179.

Harding JJ, Khalil DN, Fabris L, Abou-Alfa GK. Rational development of combination therapies for biliary tract cancers. Journal of Hepatology. 2023;78(1):217-228.

Kelley RK, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2023;401(10391):1853-1865.

Bekaii-Saab T, et al. P-74 SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: Biliary tract cancer cohort (trial in progress). Annals of Oncology. 2022;33:S273-S274.

Elvevi A, Laffusa A, Scaravaglio M, et al. Clinical treatment of cholangiocarcinoma: an updated comprehensive review. Ann Hepatol. 2022;27(5):100737. doi:10.1016/j.aohep.2022.100737

Feng Q, et al. Advances in CAR T-cell therapy in bile duct, pancreatic, and gastric cancers. Front Immunol. 2022;13:1025608.

Fransenn S, et al. Comparison of Hepatic Arterial Infusion Pump Chemotherapy vs Resection for Patients With Multifocal Intrahepatic Cholangiocarcinoma. JAMA Surg. 2022;157(7):590-596.

Lamarca A, et al. How I treat biliary tract cancer. ESMO Open. 2022.Volume 7, Issue 1.

Oh D-Y, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM evidence. 2022;1(8):EVIDoa2200015.

Ellington TD, et al. Incidence and mortality of cancers of thebBiliary tract, gallbladder, and liver by sex, age, race/ethnicity, and stage at diagnosis: United States, 2013 to 2017. Cancer Epidemiol Biomarkers Prev. 2021 Sep;30(9):1607-1614.

Lamarca A, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. The Lancet Oncology. 2021;22(5):690-701.

Yoo C, et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. The Lancet Oncology. 2021;22(11):1560-1572.

Abou-Alfa GK, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. The Lancet Oncology. 2020/05/01/ 2020;21(5):671-684.

Abou-Alfa GK, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. The Lancet Oncology. 2020;21(6):796-807.

Banales JM, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nature Reviews Gastroenterology and Hepatology 2020; 17:557–88.

Han S, et al. A perspective on cell therapy and cancer vaccine in biliary tract cancers (BTCs). Cancers (Basel). Nov 17 2020;12(11).

Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, et al. Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019 May;20(5):663-673.

Salama AKS, et al. Dabrafenib and trametinib in patients with tumors with BRAF V600E/K mutations: Results from the molecular analysis for therapy choice (MATCH) Arm H. Journal of Clinical Oncology. 2019;37(15_suppl):3002-3002.

Lowery MA, Ptashkin R, Jordan E, Berger MF, Zehir A, Capanu M, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res. 2018 Sep 1;24(17):4154-4161. https://pubmed.ncbi.nlm.nih.gov/29848569/

Ben-Josef E, 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. Journal of Clinical Oncology. 2015;33(24):2617.

American Society for Gastrointestinal Endoscopy (ASGE) Standards of Practice Committee, Anderson MA, Appalaneni V, et al. The role of endoscopy in the evaluation and treatment of patients with biliary neoplasia. Gastrointest Endosc. 2013;77(2):167-174. doi:10.1016/j.gie.2012.09.029

Castro FA. Biliary tract cancer incidence in the United States-Demographic and temporal variations by anatomic site. International Journal of Cancer. 2013;133(7):1664-71.

Lee SY. Operative management of cholangiocarcinoma. Seminars in Liver Disease. 2013;33(3):248-61.

Hyodo T, CT and MR. Cholangiography: advantages and pitfalls in perioperative evaluation of biliary tree. British Journal of Radiology. 2012;85(1015):887-96.

Marsh RdW. Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. Part I: diagnosis-clinical staging and pathology. Journal of Surgical Oncology. 2012;106(3):332-8.

Ruys AT. Radiological staging in patients with hilar cholangiocarcinoma: a systematic review and meta-analysis. British Journal of Radiology. 2012;85(1017):1255-62.

Charbel H. Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Current Gastroenterology Reports. 2011;13(2):182-7.

Yeh MM. Pathology of combined hepatocellular-cholangiocarcinoma. Journal of Gastroenterology and Hepatology. 2010;25(9):1485-92.

Reid KM. Diagnosis and surgical management of gallbladder cancer: a review. Journal of Gastrointestinal Surgery. 2007;11(5):671-81.

Leonard GD. Biliary tract cancers: current concepts and controversies. Expert Opinion on Pharmacotherapy. 2005; 6(2):211-23.

Clary B. Hilar cholangiocarcinoma. Journal of Gastrointestinal Surgery. 2004; 8(3):298-302.

de Groen PC. Biliary tract cancers. The New England Journal of Medicine. 1999; 341(18):1368-78.

INTERNET

Key Statistics for Bile Duct Cancer. American Cancer Society. Jan 12, 2023. https://www.cancer.org/cancer/types/bile-duct-cancer/about/key-statistics.html Accessed March 4, 2024.

NCCN Guidelines on Management of Biliary Tract Cancers. V. 3 2023. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517 Accessed March 4, 2024.

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