NORD gratefully acknowledges Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, Internal Medicine, Medical Oncology, for the preparation of this report.
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. A new way of grouping depends on genetic testing using next generation sequencing that offers several new applicable therapies. More than 95% of tumors arising from the biliary tract are a type of cancer called adenocarcinoma . The majority of patients with bile duct cancers 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 . In patients in whom 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 .
Patients may 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 cholangiocarcinomas or gallbladder cancers more frequently cause patients to develop jaundice due to tumor or lymph nodes blocking a major bile duct .
Most cases of biliary tract cancer are sporadic, with no identifiable predisposing patient 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 an individual’s risk of developing cholangiocarcinoma. In the USA, 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 .
Approximately 12,000 new affected individuals of bile duct cancers are diagnosed in the USA each year, of which over 9,000 are gallbladder cancers and distal/perihilar cholangiocarcinomas and 3,000 are intrahepatic cholangiocarcinomas . The overall incidence of perihilar cholangiocarcinoma in the United States is 1 person per 100,000 per year. The incidence of intrahepatic cholangiocarcinoma in the United States is approximately 0.7 per 100,000. During the last 30 years, it appears that the incidence of biliary tract cancers in the United States is increasing . This increase may be due in part to increased recognition of the diagnosis of biliary cancer, cases which may previously have been classified as cancer of unknown origin. Gallbladder cancer is more common in women than in men, and in some countries the rates are three times higher for women. Certain geographic areas are characterized by a high incidence of gallbladder cancer, including Chile, Bolivia and India. A high incidence also has been documented in North American Native Americans and Mexican Americans .
A diagnosis of cholangiocarcinoma or gallbladder cancer is made based on identification of characteristic symptoms (if present), a detailed patient history, clinical examination and several specialized tests including blood test, 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 [9, 10]. 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 obtained biopsy . 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.
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 .
Surgery: Selected patients with localized disease may be candidates for surgical resection. The surgical approach differs depending on the location of the primary tumor. Intrahepatic cholangiocarcinoma is usually managed with a liver resection, while distal cholangiocarcinomas require a Whipple procedure (pancreaticoduodenectomy) similar to pancreatic cancer, with resection of part of the stomach, pancreas and bile duct. Perihilar cholangiocarcinomas are located where the main bile ducts and blood vessels enter and exit the liver, and so 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 next generation sequencing is performed on obtained resected cancer .
Chemotherapy: Patients who undergo surgical resection of the tumor may be candidates for post-operative preventative chemotherapy. Due to the relative rarity of gallbladder cancer and cholangiocarcinoma, there is limited data available from clinical trials to guide the use of preventative treatment for these cancers. The benefit of post-operative chemotherapy for cholangiocarcinoma remains a subject under investigation. Nonetheless a large study performed in the UK evaluated the use of Xeloda (capecitabine), an oral chemotherapy agent, as preventative therapy in patients who have undergone surgical resection for cholangiocarcinoma / gallbladder cancer, did not meet its primary endpoint of improving overall survival. .
The majority of patients with biliary tract cancer are diagnosed when the cancer is far too advanced to be removed by surgery. In these cases, chemotherapy is the mainstay of treatment. While chemotherapy in this setting is not curative, it can control and contain the cancer, help patients to live longer and delay or prevent the development of cancer related symptoms. 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 Gemzar and Platinol (cisplatin) is considered a standard of care .
Beside chemotherapy, next generation sequencing is critical to be obtained as early as possible. In May 2020, the U.S. Food and Drug Administration (FDA) approved Pemazyre (pemigatinib) as the first treatment for adults with certain types of previously treated, advanced cholangiocarcinoma. Pemazyre works by blocking altered FGFR2 in tumor cells to prevent them from growing and spreading. FGFR2 alterations including fusions have been found in the tumors of approximately 9-14% of cholangiocarcinoma patients .
Several other targeted drug therapies have been investigated for the treatment of inoperable biliary tract cancers. These include ivosidenib targeting mutated IDH1, Her-2, and V600E [18,19,20]. Genetic testing of cholangiocarcinoma or gallbladder tumor biopsies or resection specimens can identify which patients are most likely to benefit from these targeted therapies. Clinical trials are also evaluating the activity of drugs which prevent cancer cells from suppressing the immune system and help immune cells to infiltrate tumors. More information is needed from ongoing clinical trials to assess if these treatments will be of benefit to patients with gallbladder cancer and/or cholangiocarcinoma in the future.
Clinical trials investigating direct delivery of chemotherapy to the liver via a surgically implantable abdominal pump are underway .
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
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Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
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/
1. de Groen PC. Biliary tract cancers. The New England Journal of Medicine. 1999; 341(18):1368-78.
2. Leonard GD. Biliary tract cancers: current concepts and controversies. Expert Opinion on Pharmacotherapy. 2005; 6(2):211-23.
3. Clary B. Hilar cholangiocarcinoma. Journal of Gastrointestinal Surgery. 2004; 8(3):298-302.
4. 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.
5. Charbel H. Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Current Gastroenterology Reports. 2011;13(2):182-7.
6. Siegel R. Cancer statistics, 2013. CA: A Cancer Journal for Clinicians. 2013;63(1):11-30.
7. 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.
8. Yeh MM. Pathology of combined hepatocellular-cholangiocarcinoma. Journal of Gastroenterology and Hepatology. 2010;25(9):1485-92.
9. Hyodo T, CT and MR. Cholangiography: advantages and pitfalls in perioperative evaluation of biliary tree. British Journal of Radiology. 2012;85(1015):887-96.
10. Ruys AT. Radiological staging in patients with hilar cholangiocarcinoma: a systematic review and meta-analysis. British Journal of Radiology. 2012;85(1017):1255-62.
11. American Society for Gastrointestinal Endoscopy Standards of Practice Committee, M.A. The role of endoscopy in the evaluation and treatment of patients with biliary neoplasia. Gastrointestinal Endoscopy. 2013;77(2):167-74.
12. 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/
13. Marsh RdW. Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. Part II: multidisciplinary management. Journal of Surgical Oncology. 2012; 106(3):339-45.
14. Lee SY. Operative management of cholangiocarcinoma. Seminars in Liver Disease. 2013;33(3):248-61.
15. Reid KM. Diagnosis and surgical management of gallbladder cancer: a review. Journal of Gastrointestinal Surgery. 2007;11(5):671-81.
16. 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.
17. Valle J, Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. The New England Journal of Medicine. 2010;362(14):1273-81.
18. 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 May;21(5):671-684.
18. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Jun;21(6):796-807.
19. Mondaca S, Razavi P, Xu C, Offin M, Myers M, Scaltriti M, et al. Genomic characterization of ERBB2-driven biliary cancer and a case of response to ado-trastuzumab emtansine. JCO Precision Oncology. 2019 Oct 17;3:PO.19.00223.
doi: 10.1200/PO.19.00223. eCollection 2019.
20. Subbiah V, Lassen U, Élez E, Italiano A, Curigliano G, Javle M, et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020 Sep;21(9):1234-1243.
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