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Cancer arising in the extrahepatic bile duct is an uncommon disease, and is curable by surgery in fewer than 10% of all cases. Prognosis depends in part on the tumor's anatomic location, which affects its resectability. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct, a resectability rate that is clearly better than for lesions that occur in more proximal sites.
Anatomy of the extrahepatic bile duct.
Bile duct cancer may occur more frequently in patients with a history of primary sclerosing cholangitis, chronic ulcerative colitis, choledochal cysts, or infections with the fluke, Clonorchis sinensis. The most common symptoms caused by bile duct cancer are jaundice, pain, fever, and pruritus.
In most patients, the tumor cannot be completely removed by surgery and is incurable. Palliative resections or other palliative measures such as radiation therapy (e.g., brachytherapy or external-beam radiation therapy) or stenting procedures may maintain adequate biliary drainage and allow for improved survival. Many bile duct cancers are multifocal. Perineural invasion has a negative impact on survival.
|1.||Henson DE, Albores-Saavedra J, Corle D: Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates. Cancer 70 (6): 1498-501, 1992.|
|2.||Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992.|
|3.||de Groen PC, Gores GJ, LaRusso NF, et al.: Biliary tract cancers. N Engl J Med 341 (18): 1368-78, 1999.|
|4.||Bhuiya MR, Nimura Y, Kamiya J, et al.: Clinicopathologic studies on perineural invasion of bile duct carcinoma. Ann Surg 215 (4): 344-9, 1992.|
The term, cholangiocarcinoma, is sometimes used to refer to any primary cancer of the biliary system; however, its use is often restricted to intrahepatic tumors and, therefore, it is not included in this summary. Adenocarcinomas are the most common type of extrahepatic bile duct cancers. The histologic types are listed below:
Malignant mesenchymal tumors, although rare, include the following:
|1.||Extrahepatic bile ducts. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 145-150.|
Note: The American Joint Committee on Cancer has recently published a new edition of the AJCC Cancer Staging Manual, which includes revisions to the staging for this disease. The PDQ Adult Treatment Editorial Board, which is responsible for maintaining this summary, is currently reviewing the new staging to determine the changes that need to be made in the summary. In addition to updating this Stage Information section, additional changes may need to be made to other parts of this summary to ensure that it is up-to-date. The changes will be made as soon as possible.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
From a clinical and practical point of view, extrahepatic bile duct cancers can be considered to be localized (resectable) or unresectable. This has obvious prognostic importance.
Localized extrahepatic bile duct cancer
Patients with localized extrahepatic bile duct cancer have cancer that can be completely removed by the surgeon. These patients represent a very small minority of cases of bile duct cancer and usually are those with a lesion of the distal common bile duct where 5-year survival rate of 25% may be achieved. Extended resections of hepatic duct bifurcation tumors (Klatskin tumors, also known as hilar tumors) to include adjacent liver, either by lobectomy or removal of portions of segments 4 and 5 of the liver, may be performed. There has been no randomized trial of adjuvant therapy for patients with localized disease. Radiation therapy (external-beam radiation with or without brachytherapy), however, has been reported to improve local control.[1,2][Level of evidence: 3iiiDiii]
Unresectable extrahepatic bile duct cancer
Patients with unresectable extrahepatic bile duct cancer have cancer that cannot be completely removed by the surgeon. These patients represent the majority of patients with bile duct cancer. Often the cancer invades directly into the portal vein, the adjacent liver or along the common bile duct, and to adjacent lymph nodes. Spread to distant parts of the body is uncommon but intra-abdominal metastases, particularly peritoneal metastases, do occur. At this stage patient management is directed at palliation.
The TNM staging system should be used when staging the disease of a patient with extrahepatic bile duct cancer. Most cancers are staged following surgery and pathologic examination of the resected specimen. Evaluation of the extent of disease at laparotomy is most important for staging.
Staging depends on imaging, which often defines the limits of the tumor, and surgical exploration with pathologic examination of the resected specimen. In many cases, it may be difficult to completely resect the primary tumor.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification  Stages defined by TNM classification apply to all primary carcinomas arising in the extrahepatic bile duct or in the cystic duct and do not apply to intrahepatic cholangiocarcinomas, sarcomas, or carcinoid tumors.
Primary tumor (T)
Regional lymph nodes (N)
Distant metastasis (M)
AJCC Stage Groupings
|1.||Kopelson G, Galdabini J, Warshaw AL, et al.: Patterns of failure after curative surgery for extra-hepatic biliary tract carcinoma: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 7 (3): 413-7, 1981.|
|2.||Minsky BD, Wesson MF, Armstrong JG, et al.: Combined modality therapy of extrahepatic biliary system cancer. Int J Radiat Oncol Biol Phys 18 (5): 1157-63, 1990.|
|3.||Extrahepatic bile ducts. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 145-150.|
In a minority of cases, proximal bile duct cancer can be completely resected. Cures are not often achieved in these patients, in contrast to patients with tumors arising in the distal bile duct, for whom a 5-year survival may be achieved in as many as 25% of patients.
Standard treatment options:
|1.||Surgery. The optimum surgical procedure for carcinoma of the extrahepatic bile duct will vary according to its location along the biliary tree, the extent of hepatic parenchymal involvement, and the proximity of the tumor to major blood vessels in this region. It is important to assess the state of the regional lymph nodes at the time of surgery because proven nodal involvement may preclude potentially curative resection. It should be fully recognized that operations for bile duct cancer are usually extensive and have a high operative mortality (5%–10%) and low curability. Cases with cancer of the lower end of the duct and regional lymph node involvement may warrant an extensive resection (Whipple procedure), but bypass operations or endoluminal stents are alternatives if lymph nodes are clinically involved by the cancer.
In jaundiced patients, percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction should be considered before surgery, particularly if jaundice is severe or an element of azotemia is present. An understanding of both the normal and varied vascular and ductal anatomy of the porta hepatis has increased the number of hepatic duct bifurcation tumors (Klatskin tumors) that can be resected.[1,2,3]
|2.||External-beam radiation (EBRT). EBRT has been used in conjunction with surgical resection.|
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with localized extrahepatic bile duct cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
|1.||Shutze WP, Sack J, Aldrete JS: Long-term follow-up of 24 patients undergoing radical resection for ampullary carcinoma, 1953 to 1988. Cancer 66 (8): 1717-20, 1990.|
|2.||Bismuth H, Nakache R, Diamond T: Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 215 (1): 31-8, 1992.|
|3.||Pinson CW, Rossi RL: Extended right hepatic lobectomy, left hepatic lobectomy, and skeletonization resection for proximal bile duct cancer. World J Surg 12 (1): 52-9, 1988.|
|4.||Cameron JL, Pitt HA, Zinner MJ, et al.: Management of proximal cholangiocarcinomas by surgical resection and radiotherapy. Am J Surg 159 (1): 91-7; discussion 97-8, 1990.|
Patients with unresectable extrahepatic bile duct cancer have cancer that cannot be completely removed by the surgeon. These patients represent the majority of cases of bile duct cancer. Often a proximal bile duct cancer invades directly into the adjacent liver or into the hepatic artery or portal vein. Portal hypertension may result. Spread to distant parts of the body is uncommon, though transperitoneal and hematogenous hepatic metastases do occur with bile duct cancers of all sites. Invasion along the biliary tree and into the liver is common. Moreover, the majority of patients who undergo resection will develop recurrent disease within the hepatobiliary system or less frequently at distant sites.
Patients with unresectable, recurrent, or metastatic extrahepatic bile duct cancer should be considered for inclusion in clinical trials whenever possible. Information about ongoing clinical trials is available from the NCI Web site.
|1.||Relief of biliary obstruction is warranted when symptoms such as pruritus and hepatic dysfunction outweigh other symptoms from the cancer. When possible, such palliation can be achieved by anastomosis of the bile duct to the bowel or by the placement of bile duct stents by operative, endoscopic, or percutaneous techniques.[1,2]
Palliative radiation therapy after biliary bypass or intubation may be beneficial, and patients may be candidates for inclusion in clinical trials that explore ways to improve the effects of radiation therapy with various radiation sensitizers, such as hyperthermia, radiosensitizer drugs, or cytotoxic chemotherapeutic agents. If a percutaneous catheter has been placed, it can be used as a conduit for placement of sources for brachytherapy.[3,4] Information about ongoing clinical trials is available from the NCI Web site.
|2.||Systemic chemotherapy is appropriate for selected patients with adequate performance status and intact organ function. Fluoropyrimidines, gemcitabine, platinum agents, and docetaxel have been reported to produce transient partial remissions in a minority of patients.
A randomized phase III study of up to 6 months of gemcitabine versus gemcitabine and cisplatin in 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma demonstrated an improvement in median overall survival (OS) among patients treated with combination therapy (11.7 months vs. 8.1 months; HR = 0.64; (95% confidence interval, 0.52–0.80); P < .001.[Level of evidence: 1iiA] A similar median OS benefit was demonstrated in all subgroups, including 73 patients with extrahepatic bile duct cancer and 57 patients with hilar tumors. Grade 3 and 4 toxicities occurred with similar frequency in both study arms, with the exception of increased hematologic toxicity in patients randomly assigned to gemcitabine-cisplatin and increased hepatotoxicity in patients randomly assigned to single-agent gemcitabine.
Other drugs and drug combinations await evaluation in randomized trials.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with unresectable extrahepatic bile duct cancer, recurrent extrahepatic bile duct cancer and metastatic extrahepatic bile duct cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
|1.||Nordback IH, Pitt HA, Coleman J, et al.: Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 115 (5): 597-603, 1994.|
|2.||Levy MJ, Baron TH, Gostout CJ, et al.: Palliation of malignant extrahepatic biliary obstruction with plastic versus expandable metal stents: An evidence-based approach. Clin Gastroenterol Hepatol 2 (4): 273-85, 2004.|
|3.||Fritz P, Brambs HJ, Schraube P, et al.: Combined external beam radiotherapy and intraluminal high dose rate brachytherapy on bile duct carcinomas. Int J Radiat Oncol Biol Phys 29 (4): 855-61, 1994.|
|4.||Shin HS, Seong J, Kim WC, et al.: Combination of external beam irradiation and high-dose-rate intraluminal brachytherapy for inoperable carcinoma of the extrahepatic bile ducts. Int J Radiat Oncol Biol Phys 57 (1): 105-12, 2003.|
|5.||Valle J, Wasan H, Palmer DH, et al.: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362 (14): 1273-81, 2010.|
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Extrahepatic Bile Duct Cancer
Added image to include the extrahepatic bile duct anatomy.
Unresectable, Recurrent, or Metastatic Extrahepatic Bile Duct Cancer
Revised section title to include "Recurrent, or Metastatic."
Added text to state that the majority of patients who undergo resection will develop recurrent disease within the hepatobiliary system or less frequently at distant sites.
Added text to state that patients may be candidates for inclusion in clinical trials that explore ways to improve the effects of radiation therapy with various radiation sensitizers, such as hyperthermia, radiosensitizer drugs, or cytotoxic chemotherapeutic agents.
Added text about the use of systemic chemotherapy as a treatment option that is appropriate for selected patients with adequate performance status and intact organ function, and that fluoropyrimidines, gemcitabine, platinum agents, and docetaxel have been reported to produce transient partial remissions in a minority of patients.
Added text to state that a randomized phase III study of up to 6 months of gemcitabine versus gemcitabine and cisplatin in 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma demonstrated an improvement in median overall survival (OS) among patients treated with combination therapy (cited Valle et al. as reference 5 and level of evidence 1iiA). Also added that a similar median OS benefit was demonstrated in all subgroups and grade 3 and 4 toxicities occurred with similar frequency in both study arms, with the exception of increased hematologic toxicity in patients randomly assigned to gemcitabine-cisplatin and increased hepatotoxicity in patients randomly assigned to single-agent gemcitabine; concluded that other drugs and drug combinations await evaluation in randomized trials.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of extrahepatic bile duct cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Extrahepatic Bile Duct Cancer Treatment are:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Extrahepatic Bile Duct Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/bileduct/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2011-08-19
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