Author Information: Maeve A. Lowerey, MD, Ghassan K. Abou-Alfa, MD Affiliation of Authors: Maeve A. Lowery, Memorial Sloan Kettering Cancer Center, Internal Medicine, Medical Oncology (Ireland and Europe); Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, Internal Medicine, Medical Oncology. NORD gratefully thanks the authors Maeve A Lowery MD, and Ghassan Abou-Alfa MD for providing the research article.
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 . 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 .
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 is not yet well established. A large study performed in France did not show a benefit to the addition of post-operative chemotherapy using chemotherapy with the combination of two drugs Gemzar (gemcitabine) and Eloxatin (oxaliplatin) . An ongoing study in the UK is evaluating the use of Gemzar in combination with with an oral chemotherapy agent, Xeloda (capecitabine), as preventative therapy in patients who have undergone surgical resection for cholangiocarcinoma / gallbladder cancer; results of this study are awaited. In selected cases of perihilar/distal cholangiocarcinoma, preventative radiation therapy may be considered in addition to chemotherapy .
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 .
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 FGFR2 in tumor cells to prevent them from growing and spreading. FGFR2 fusions have been found in the tumors of approximately 9% to 14% of cholangiocarcinoma patients.
Several targeted drug therapies are under investigation for treatment of inoperable biliary tract cancers, including inhibitors of IDH1 and FGFR2 [18, 19]. Genetic testing of cholangiocarcinoma or gallbladder tumor biopsies or resection specimens can identify which patients are most likely to benefit 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:
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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/
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