Bile Duct Cancers–for health professionals (PDQ®)

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General Information About Bile Duct Cancers

Cancers of the bile duct are extremely rare; however, the true incidence of bile duct cancers is unknown because establishing an accurate diagnosis is difficult. Traditionally, bile duct tumors located within the liver (intrahepatic cholangiocarcinomas) have been classified with hepatocellular carcinoma as primary liver tumors.[1] In contrast, bile duct tumors located outside of the liver (extrahepatic cholangiocarcinomas) have been classified with gallbladder cancer as extrahepatic biliary tract tumors.[1] The classification of bile duct tumors has changed, and the term now includes intrahepatic, perihilar, and distal extrahepatic tumors of the bile ducts.

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 liver fluke, Clonorchis sinensis.[2] The most common symptoms caused by bile duct cancer include the following:

  • Jaundice.
  • Pain.
  • Fever.
  • Pruritis.

In most patients, the tumor cannot be completely removed by surgery and is incurable. Many bile duct cancers are multifocal. Palliative measures, such as resection, radiation therapy (e.g., brachytherapy or external-beam radiation therapy) or stenting procedures, may maintain adequate biliary drainage and allow for improved quality of life.

Anatomy

The biliary system consists of a network of ducts that carry bile from the liver to the small bowel (Figure 1). Bile is produced by the liver and is important for fat digestion. The biliary system is classified by its anatomic location.

Enlarge Anatomy of the extrahepatic bile ducts; drawing shows the liver, right and left hepatic ducts, gallbladder, cystic duct, common hepatic duct (hilum region), common bile duct (distal region), extrahepatic bile duct, pancreas, and small intestine. An inset shows the liver, bile ducts, and gallbladder.
Figure 1. Bile duct, extrahepatic, anatomy.

The bile ducts located within the liver are called intrahepatic bile ducts. Tumors of the intrahepatic bile ducts, also known as intrahepatic cholangiocarcinomas, originate from small intrahepatic ductules or large intrahepatic ducts that are proximal to the bifurcation of the right and left hepatic ducts.

The bile ducts located outside of the liver are called extrahepatic bile ducts. They include part of the right and left hepatic ducts that are outside the liver, the common hepatic duct, and the common bile duct. The extrahepatic bile ducts can be further divided into perihilar region and distal bile ducts.

Perihilar bile ducts (hilum)

The hilum is the region where the right and left hepatic ducts exit the liver and join to form the common hepatic duct that is proximal to the origin of the cystic duct. Tumors of this region are also known as perihilar cholangiocarcinomas, or Klatskin tumors (Figure 2).

Enlarge Klatskin tumor; drawing shows cancer in the common hepatic duct, the area where the right and left hepatic duct meet. Also shown are the liver and gallbladder.
Figure 2. Klatskin tumor anatomy.

Distal extrahepatic bile ducts

This region includes the common bile duct and inserts into the small intestine. Tumors of this region are also known as extrahepatic cholangiocarcinomas.

Approximately 50% of cholangiocarcinomas arise in the perihilar region, 40% arise in the distal extrahepatic region, and 10% arise in the intrahepatic region.

Risk Factors and Clinical Presentation

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 liver fluke, Clonorchis sinensis.[2] Extrahepatic and perihilar bile duct cancers frequently cause biliary tract obstruction, leading to symptoms of jaundice, weight loss, abdominal pain, fever, and pruritus. Intrahepatic bile duct cancers may be relatively indolent and difficult to clinically differentiate from metastatic adenocarcinoma deposits to the liver.

Clinical Evaluation and Staging

Clinical staging is dependent on radiographic imaging, including computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography, which demonstrates the extent of the primary tumor and assesses for the presence or absence of distant metastases. If a patient is medically fit for surgery, and the tumor is amenable to surgical resection, surgical exploration is performed. Pathologic examination of the resected specimen is performed to establish definitive pathologic staging.

Prognosis

Complete surgical resection with negative surgical margins offers the only chance of cure for a diagnosis of bile duct cancer. Prognosis depends in part on the tumor’s anatomic location, which affects its resectability. Because of their close proximity to major blood vessels and diffuse extension within the liver, bile duct tumors can be difficult to resect. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct, which is better than the resectability rate for lesions that occur in more proximal sites.[3]

Achievement of a negative surgical margin at the time of resection may be difficult but is associated with improved patient outcomes. For local, resectable tumors, a negative surgical margin, presence of involved lymph nodes, and presence of perineural invasion are significant prognostic factors.[4-6]

Additionally, an underlying risk factor of primary sclerosing cholangitis, elevated CA 19-9, periductal infiltrating tumor growth pattern, and the presence of hepatic venous invasion have been associated with worse outcomes among patients with intrahepatic cholangiocarcinomas.[7-9]

References
  1. Siegel R, Ma J, Zou Z, et al.: Cancer statistics, 2014. CA Cancer J Clin 64 (1): 9-29, 2014 Jan-Feb. [PUBMED Abstract]
  2. de Groen PC, Gores GJ, LaRusso NF, et al.: Biliary tract cancers. N Engl J Med 341 (18): 1368-78, 1999. [PUBMED Abstract]
  3. Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992. [PUBMED Abstract]
  4. Wakai T, Shirai Y, Moroda T, et al.: Impact of ductal resection margin status on long-term survival in patients undergoing resection for extrahepatic cholangiocarcinoma. Cancer 103 (6): 1210-6, 2005. [PUBMED Abstract]
  5. Klempnauer J, Ridder GJ, von Wasielewski R, et al.: Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 15 (3): 947-54, 1997. [PUBMED Abstract]
  6. Bhuiya MR, Nimura Y, Kamiya J, et al.: Clinicopathologic studies on perineural invasion of bile duct carcinoma. Ann Surg 215 (4): 344-9, 1992. [PUBMED Abstract]
  7. Rosen CB, Nagorney DM, Wiesner RH, et al.: Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 213 (1): 21-5, 1991. [PUBMED Abstract]
  8. Shirabe K, Mano Y, Taketomi A, et al.: Clinicopathological prognostic factors after hepatectomy for patients with mass-forming type intrahepatic cholangiocarcinoma: relevance of the lymphatic invasion index. Ann Surg Oncol 17 (7): 1816-22, 2010. [PUBMED Abstract]
  9. Isa T, Kusano T, Shimoji H, et al.: Predictive factors for long-term survival in patients with intrahepatic cholangiocarcinoma. Am J Surg 181 (6): 507-11, 2001. [PUBMED Abstract]

Cellular Classification of Bile Duct Cancers

Extrahepatic Bile Duct Cancers

Adenocarcinomas are the most common type of extrahepatic bile duct tumors. The histologic types include the following:[1]

  • Carcinoma in situ.
  • Adenocarcinoma, not otherwise specified (NOS).
  • Adenocarcinoma, intestinal type.
  • Mucinous adenocarcinoma.
  • Clear cell adenocarcinoma.
  • Signet-ring cell carcinoma.
  • Adenosquamous carcinoma.
  • Squamous cell carcinoma.
  • Small cell (oat cell) carcinoma.
  • Undifferentiated carcinoma.
    • Spindle and giant cell types.
    • Small cell types.
  • Papillomatosis.
  • Papillary carcinoma, noninvasive.
  • Papillary carcinoma, invasive.
  • Carcinoma, NOS.

Perihilar Bile Duct Cancers

Adenocarcinomas are the most common type of perihilar bile duct tumors. The histologic types include the following:[2]

  • Carcinoma in situ.
  • Adenocarcinoma, not otherwise specified (NOS).
  • Adenocarcinoma, intestinal type.
  • Mucinous adenocarcinoma.
  • Clear cell adenocarcinoma.
  • Signet-ring cell carcinoma.
  • Adenosquamous carcinoma.
  • Squamous cell carcinoma.
  • Small cell (oat cell) carcinoma.
  • Undifferentiated carcinoma
    • Spindle and giant cell types.
    • Small cell types.
  • Papillomatosis.
  • Papillary carcinoma, noninvasive.
  • Papillary carcinoma, invasive.
  • Carcinoma, NOS

Intrahepatic Bile Duct Cancers

The most common histologic types of intrahepatic bile duct tumors include the following:[3]

  • Intrahepatic cholangiocarcinoma.
    • Mass-forming tumor growth pattern.
    • Periductal-infiltrating tumor growth pattern.
    • Mixed mass-forming and periductal-infiltrating growth pattern.
  • Mixed hepatocellular.
References
  1. Distal bile duct. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 227-33.
  2. Perihilar bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 219-22.
  3. Intrahepatic bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 201-9.

Stage Information for Bile Duct Cancers

Staging for Bile Duct Cancers

Extrahepatic bile duct cancers are localized (resectable) or unresectable, with obvious prognostic importance. The TNM staging system is used for staging bile duct cancer, commonly following surgery and pathologic examination of the resected specimen. Evaluation of the extent of disease at laparotomy is most important for staging.

Localized bile duct cancers

Localized bile duct cancers may be removed completely by the surgeon. These tumors represent a very small minority of cases and usually are distal common bile duct lesions. Patients undergoing surgery for these cancers have a 5-year survival rate of 25%. 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. If major hepatic resection is necessary to achieve a complete resection, postoperative hepatic reserve should be evaluated. For patients with underlying cirrhosis, the Child-Pugh class and the Model for End-Stage Liver Disease score should be determined.

Unresectable bile duct cancers

Unresectable bile duct cancers represent the majority of bile duct tumors. Often the cancer invades directly into the portal vein, the adjacent liver, 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. For patients with unresectable bile duct cancer, management is directed at palliation.

Definitions of TNM for Bile Duct Cancers

Definitions of TNM for extrahepatic bile duct cancers

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define extrahepatic bile duct cancers.[1] Stages defined by TNM classification apply to all primary carcinomas arising in the distal extrahepatic bile duct or in the cystic duct; these stages do not apply to perihilar or intrahepatic cholangiocarcinomas, sarcomas, or carcinoid tumors.

Tables 1, 2, 3, and 4 pertain to the distal bile duct group.

Table 1. Primary Tumor (T)a
aReprinted with permission from AJCC: Distal bile duct. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 227-33.
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
Tis Carcinoma in situ.
T1 Tumor confined to the bile duct histologically.
T2 Tumor invades beyond the wall of the bile duct.
T3 Tumor invades the gallbladder, pancreas, duodenum, or other adjacent organs without involvement of the celiac axis or the superior mesenteric artery.
T4 Tumor involves the celiac axis or the superior mesenteric artery.
Table 2. Regional Lymph Nodes (N)a
aReprinted with permission from AJCC: Distal bile duct. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 227-33.
NX Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Regional lymph node metastasis.
Table 3. Distant Metastasis (M)a
aReprinted with permission from AJCC: Distal bile duct. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 227-33.
M0 No distant metastasis.
M1 Distant metastasis.
Table 4. Anatomic Stage/Prognostic Groupsa
Stage T N M
aReprinted with permission from AJCC: Distal bile duct. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 227-33.
0 Tis N0 M0
IA T1 N0 M0
IB T2 N0 M0
IIA T3 N0 M0
IIB T1 N1 M0
T2 N1 M0
T3 N1 M0
III T4 Any N M0
IV Any T Any N M1

Definitions of TNM for perihilar bile duct cancers

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define perihilar bile duct cancers.[2]

Tables 5, 6, 7, and 8 pertain to the perihilar bile duct group.

Table 5. Primary Tumor (T)a
aReprinted with permission from AJCC: Perihilar bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 219-25.
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
Tis Carcinoma in situ.
T1 Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue.
T2a Tumor invades beyond the wall of the bile duct to surrounding adipose tissue.
T2b Tumor invades adjacent hepatic parenchyma.
T3 Tumor invades unilateral branches of the portal vein or hepatic artery.
T4 Tumor invades main portal vein or its branches bilaterally; or the common hepatic artery; or the second-order biliary radicals bilaterally; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement.
Table 6. Regional Lymph Nodes (N)a
aReprinted with permission from AJCC: Perihilar bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 219-25.
NX Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Regional lymph node metastases (including nodes along the cystic duct, common bile duct, hepatic artery, and portal vein).
N2 Metastases to periaortic, pericaval, superior mesenteric artery, and celiac artery lymph nodes.
Table 7. Distant Metastasis (M)a
aReprinted with permission from AJCC: Perihilar bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 219-25.
M0 No distant metastasis.
M1 Distant metastasis.
Table 8. Anatomic Stage/Prognostic Groupsa
Stage T N M
aReprinted with permission from AJCC: Perihilar bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 219-25.
0 Tis N0 M0
I T1 N0 M0
II T2a–b N0 M0
IIIA T3 N0 M0
IIIB T1–3 N1 M0
IVA T4 N0–1 M0
IVB Any T N2 M0
Any T Any N M1

Definitions of TNM for intrahepatic bile duct cancers

The AJCC has designated staging by TNM classification to define intrahepatic bile duct cancers.[3]

Tables 9, 10, 11, and 12 pertain to intrahepatic bile duct cancers.

Table 9. Primary Tumor (T)a
aReprinted with permission from AJCC: Intrahepatic bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 201-9.
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
Tis Carcinoma in situ (intraductal tumor).
T1 Solitary tumor without vascular invasion.
T2a Solitary tumor with vascular invasion.
T2b Multiple tumors, with or without vascular invasion.
T3 Tumor perforating the visceral peritoneum or involving the local extrahepatic structures by direct invasion.
T4 Tumor with periductal invasion.
Table 10. Regional Lymph Nodes (N)a
aReprinted with permission from AJCC: Intrahepatic bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 201-9.
NX Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Regional lymph node metastasis present.
Table 11. Distant Metastasis (M)a
aReprinted with permission from AJCC: Intrahepatic bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 201-9.
M0 No distant metastasis.
M1 Distant metastasis present.
Table 12. Anatomic Stage/Prognostic Groupsa
Stage T N M
aReprinted with permission from AJCC: Intrahepatic bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 201-9.
0 Tis N0 M0
I T1 N0 M0
II T2 N0 M0
III T3 N0 M0
IVA T4 N0 M0
Any T N1 M0
IVB Any T Any N M1
References
  1. Distal bile duct. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 227-33.
  2. Perihilar bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 219-22.
  3. Intrahepatic bile ducts. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 201-9.

Localized Bile Duct Cancers

Localized Extrahepatic Bile Duct Cancers

Complete surgical resection with negative surgical margins offers the only chance of cure for extrahepatic bile duct cancers. Because of the close proximity to major blood vessels and diffuse infiltration of adjacent bile ducts, bile duct tumors can be difficult to resect. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct, which is better than the resectability rate for lesions that occur in more proximal sites.[1]

No randomized trial data of adjuvant therapy for patients with localized disease are currently available. However, radiation therapy (external-beam radiation therapy [EBRT] with or without brachytherapy) has been reported to improve local control.[2,3][Level of evidence: 3iiiDiii]

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. The state of the regional lymph nodes are assessed at the time of surgery because they have prognostic significance. Surgery for bile duct cancer is usually extensive and has 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 intraoperatively the tumor is found to be unresectable.

    In jaundiced patients, percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction is considered before surgery, particularly if jaundice is severe, or an element of azotemia is present.

    Adjuvant treatment options:

    1. EBRT.Numerous retrospective studies have suggested a benefit of adding of EBRT after complete surgical resection.[2,3][Level of evidence: 1iiA] However, no prospective randomized trials have demonstrated an overall survival (OS) benefit.

      One small randomized trial of 207 patients with pancreatic and periampullary cancers demonstrated no survival benefit of administering chemoradiation therapy after surgery. This study is limited, however, in that only a few patients had a diagnosis of bile duct cancer, and 20% of the patients randomly assigned to receive chemoradiation therapy did not receive treatment.[4][Level of evidence: 3iiiDiv]

    2. Chemotherapy. Numerous retrospective series have similarly suggested a benefit of adding chemotherapy after complete surgical resection.[5,6][Level of evidence: 3iiiDiii] However, no prospective randomized trials have demonstrated an OS benefit. Two randomized trials of pancreaticobiliary tumors, which included distal bile duct cancers, have attempted to address the potential benefit of additional chemotherapy.

      A multi-institutional Japanese study compared surgery alone with mitomycin-C and infusional 5-fluorouracil (5-FU) followed by 5-FU until progression.[7] Among the subset of patients with bile duct cancers (n = 139), no survival benefit was seen.

      The ESPAC-3 (NCT00058201) study randomly assigned 428 patients with periampullary cancer, which included 96 bile duct cancers, to one of three arms: observation, 6 months of 5-FU/leukovorin, or 6 months of gemcitabine. [8][Level of evidence: 1iiA] In a preplanned subgroup analysis of the 96 patients with bile duct cancer, no benefit was seen among patients treated with chemotherapy. The median survivals were 27 months for the observation-alone group, 18 months for the 5-FU-leucovorin group, and 20 months for the gemcitabine-alone group.

    3. Clinical Trials. All patients are encouraged to enroll in clinical trials for adjuvant therapies.

Current Clinical Trials

Check the list of NCI-supported 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 website.

Localized Perihilar Bile Duct Cancers

For perihilar cholangiocarcinomas, bile duct resection alone leads to high local recurrence rates resulting from the early confluence of the hepatic ducts and the caudate lobe. The addition of routine partial hepatectomy including the caudate lobe has improved long-term outcomes but may also be associated with increased postoperative complications.[9] With this aggressive surgical approach, 5-year survival rates of 20% to 50% have been reported.[10] 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.

The primary site of relapse after surgical resection is local; however, distant recurrence has also been frequently reported.[11] There has been no randomized trial of adjuvant therapy for patients with localized disease. Radiation therapy (EBRT with or without brachytherapy), however, has been reported to improve local control.[2,3][Level of evidence: 3iiiDiii]

Standard treatment options:

  1. Surgery.The optimal surgical procedure for carcinoma of the perihilar 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. The state of the regional lymph nodes should be assessed at the time of surgery because of their prognostic significance. Operations for bile duct cancer are usually extensive and have a high operative mortality rate (5%–10%) and low curability.

    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.

Adjuvant treatment options:

  1. EBRT. Numerous retrospective studies have suggested a benefit of adding EBRT after complete surgical resection.[2,3][Level of evidence: 1iiA] However, no prospective randomized trials have demonstrated an OS benefit.

    One small randomized trial of 207 patients with pancreatic and periampullary cancers demonstrated no survival benefit of adding chemoradiation therapy after surgery. This study is limited, however, because only a few patients had a diagnosis of bile duct cancer, and 20% of the patients randomly assigned to receive chemoradiation therapy did not receive treatment.[4][Level of evidence: 3iiiDiv]

  2. Chemotherapy. Numerous retrospective series have similarly suggested a benefit of adding chemotherapy after complete surgical resection.[5,6][Level of evidence: 3iiiDiii] However, no prospective randomized trials have demonstrated an OS benefit.

    One randomized trial of pancreaticobiliary tumors, which included bile duct cancers, attempted to address the potential benefit of additional chemotherapy. In a multi-institutional Japanese study that compared surgery alone with mitomycin-C and infusional 5-FU followed by 5-FU until progression, among the subset of patients with bile duct cancers (n = 139), there was no survival benefit.[7][Level of evidence: 1iiA]

  3. Clinical Trials. All patients are encouraged to enroll in clinical trials for adjuvant therapies.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I perihilar bile duct cancer and stage II perihilar 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 website.

Localized Intrahepatic Bile Duct Cancers

For intrahepatic bile duct cancers, hepatic resection to achieve negative margins is the curative procedure. If a major liver resection is necessary to achieve negative surgical margins, preoperative portal vein embolization may be considered to increase the volume of the remnant liver.

Standard treatment options:

  1. Surgery. Partial liver resection or partial hepatectomy to acheive negative margins resection is the mainstay of cure for patients with intrahepatic cholangiocarcinoma. The extent of liver resection necessary is dependent on the extent of hepatic parenchymal involvement and the proximity of the tumor to major blood vessels in this region. The role of routine portal lymphadenectomy has not been well established because of the risk of common bile duct devascularization.

Adjuvant treatment options:

  1. EBRT. There is little published literature evaluating the role of EBRT after resection for intrahepatic cholangiocarcinoma.
  2. Chemotherapy. Numerous retrospective series have similarly suggested a benefit to the addition of chemotherapy after complete surgical resection.[5,6][Level of evidence: 3iiiDiii] However, to date, no prospective randomized trials have demonstrated an OS benefit.

    One randomized trial of pancreaticobiliary tumors, which included bile duct cancers, has attempted to address the potential benefit of additional chemotherapy. In a multi-institutional Japanese study which compared surgery alone with mitomycin-C and infusional 5-FU followed by 5-FU until progression, among the subset of patients with bile duct cancers (n = 139) , no survival benefit was seen.[7][Level of evidence: 1iiA]

  3. Clinical Trials. All patients are encouraged to enroll in clinical trials for adjuvant therapies.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with intrahepatic 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 website.

References
  1. Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992. [PUBMED Abstract]
  2. Kim TH, Han SS, Park SJ, et al.: Role of adjuvant chemoradiotherapy for resected extrahepatic biliary tract cancer. Int J Radiat Oncol Biol Phys 81 (5): e853-9, 2011. [PUBMED Abstract]
  3. Hughes MA, Frassica DA, Yeo CJ, et al.: Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct. Int J Radiat Oncol Biol Phys 68 (1): 178-82, 2007. [PUBMED Abstract]
  4. Klinkenbijl JH, Jeekel J, Sahmoud T, et al.: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 230 (6): 776-82; discussion 782-4, 1999. [PUBMED Abstract]
  5. Todoroki T: Chemotherapy for bile duct carcinoma in the light of adjuvant chemotherapy to surgery. Hepatogastroenterology 47 (33): 644-9, 2000 May-Jun. [PUBMED Abstract]
  6. Murakami Y, Uemura K, Sudo T, et al.: Adjuvant gemcitabine plus S-1 chemotherapy improves survival after aggressive surgical resection for advanced biliary carcinoma. Ann Surg 250 (6): 950-6, 2009. [PUBMED Abstract]
  7. Takada T, Amano H, Yasuda H, et al.: Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 95 (8): 1685-95, 2002. [PUBMED Abstract]
  8. Neoptolemos JP, Moore MJ, Cox TF, et al.: Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 308 (2): 147-56, 2012. [PUBMED Abstract]
  9. Burke EC, Jarnagin WR, Hochwald SN, et al.: Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 228 (3): 385-94, 1998. [PUBMED Abstract]
  10. Nakeeb A, Tran KQ, Black MJ, et al.: Improved survival in resected biliary malignancies. Surgery 132 (4): 555-63; discission 563-4, 2002. [PUBMED Abstract]
  11. Hasegawa S, Ikai I, Fujii H, et al.: Surgical resection of hilar cholangiocarcinoma: analysis of survival and postoperative complications. World J Surg 31 (6): 1256-63, 2007. [PUBMED Abstract]

Unresectable, Recurrent, or Metastatic Bile Duct Cancers

Patients with unresectable bile duct cancers 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 bile duct cancers should be considered for inclusion in clinical trials whenever possible. Information about ongoing clinical trials is available from the NCI website.

Unresectable, Recurrent, or Metastatic Extrahepatic Bile Duct Cancers

Standard treatment options:

  1. Palliative therapy. Relief of biliary obstruction is warranted when symptoms such as pruritus and hepatic dysfunction outweigh other symptoms of 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 brachytherapy sources.[3,4] Information about ongoing clinical trials is available from the NCI website.

  2. Systemic chemotherapy. 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 (NCT00262769) 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; hazard ratio [HR], 0.64; (95% confidence interval [CI], 0.52–0.80); P < .001.[5][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 the gemcitabine-cisplatin arm and increased hepatic toxicity in patients randomly assigned to the single-agent gemcitabine arm.

Other drugs and drug combinations await evaluation in randomized trials.

Current Clinical Trials

Check the list of NCI-supported 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 website.

Unresectable, Recurrent, or Metastatic Perihilar Bile Duct Cancers

Standard treatment options:

  1. Palliative therapy. 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]

  2. Systemic chemotherapy. 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 (NCT00262769) 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 OS among patients treated with combination therapy (11.7 months vs. 8.1 months; HR, 0.64; (95% CI, 0.52–0.80); P < .001.[5][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 the gemcitabine-cisplatin arm and increased hepatic toxicity in patients randomly assigned to the single-agent gemcitabine arm.

  3. Neoadjuvant chemoradiation and orthotopic liver transplantation. Neoadjuvant chemoradiation and orthotopic liver transplantation have been evaluated in carefully selected patients with locally unresectable perihilar bile duct cancers.[6][Level of evidence: 3iiiD] This approach is not considered standard of care and should only be performed in the context of a clinical trial in specialized transplant centers.

Other drugs and drug combinations await evaluation in randomized trials.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage III perihilar bile duct cancer and stage IV perihilar 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 website.

Unresectable, Recurrent, or Metastatic Intrahepatic Bile Duct Cancers

Standard treatment options:

  1. Palliative therapy. Relief of biliary obstruction is warranted when symptoms such as pruritus and hepatic dysfunction outweigh other symptoms of the cancer. When possible, such palliation can be achieved with the placement of bile duct stents by operative, endoscopic, or percutaneous techniques.[1,2]

    Radiation therapy 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 brachytherapy sources.[3,4] Limited but emerging data are available regarding the potential role for alternative liver-directed therapies, including stereotactic body radiation therapy [7] and intra-arterial embolization.[8]

  2. Systemic chemotherapy. 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 (NCT00262769) 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 OS among patients treated with combination therapy (11.7 months vs. 8.1 months; HR, 0.64; (95% CI, 0.52–0.80); P < .001.[5][Level of evidence: 3iii] 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 the gemcitabine-cisplatin arm and increased hepatic toxicity in patients randomly assigned to the single-agent gemcitabine arm.

Other drugs and drug combinations await evaluation in randomized trials.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage III intrahepatic bile duct cancer, stage IV intrahepatic bile duct cancer and recurrent intrahepatic 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 website.

References
  1. Nordback IH, Pitt HA, Coleman J, et al.: Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 115 (5): 597-603, 1994. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  6. Rea DJ, Heimbach JK, Rosen CB, et al.: Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 242 (3): 451-8; discussion 458-61, 2005. [PUBMED Abstract]
  7. Barney BM, Olivier KR, Miller RC, et al.: Clinical outcomes and toxicity using stereotactic body radiotherapy (SBRT) for advanced cholangiocarcinoma. Radiat Oncol 7: 67, 2012. [PUBMED Abstract]
  8. Hyder O, Marsh JW, Salem R, et al.: Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol 20 (12): 3779-86, 2013. [PUBMED Abstract]

Changes to This Summary (07/29/2015)

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.

This is a new summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of bile duct cancers. 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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

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 Bile Duct Cancers are:

  • Jason E. Faris, MD (Massachusetts General Hospital)
  • Jennifer Wo, MD (Massachusetts General Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Bile Duct Cancers. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/liver/hp/bile-duct-treatment-pdq. Accessed <MM/DD/YYYY>.

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