Bile Duct Cancer (Cholangiocarcinoma) Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Bile Duct Cancer

Cancer of the bile duct (also called cholangiocarcinoma) is extremely rare. The true incidence of bile duct cancer is unknown, however, because establishing an accurate diagnosis is difficult.

Traditionally, bile duct tumors located within the liver have been classified with hepatocellular carcinoma as primary liver tumors.[1] In contrast, bile duct tumors located outside of the liver have been classified with gallbladder cancer as extrahepatic biliary tract tumors.[1] The classification of bile duct tumors has changed and now includes intrahepatic tumors of the bile ducts and perihilar and distal extrahepatic tumors of the bile ducts.

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

Many bile duct cancers are multifocal. In most patients, the tumor cannot be completely removed by surgery and is incurable. 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 and is classified by its anatomic location (Figure 1). Bile is produced by the liver and is important for fat digestion.

Intrahepatic bile duct

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

Figure 1. Anatomy of the intrahepatic bile duct.

Extrahepatic bile duct

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 the perihilar (hilum) region and distal region.

Figure 2. Anatomy of the extrahepatic bile duct.

• Perihilar (hilum) region. 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.
• Distal extrahepatic region. This region includes the common bile duct and inserts into the small intestine. Tumors of this region are also known as extrahepatic cholangiocarcinomas (Figure 2).

Risk Factors

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]

Clinical Features

Distal extrahepatic and perihilar bile duct cancers frequently cause biliary tract obstruction, leading to the following symptoms:

• Jaundice.
• Weight loss.
• Abdominal pain.
• Fever.
• Pruritus.

Intrahepatic bile duct cancer may be relatively indolent and difficult to clinically differentiate from metastatic adenocarcinoma deposits in the liver.

Diagnostic and Staging Evaluation

Clinical evaluation is dependent on laboratory and radiographic imaging tests that include the following:

• Liver function tests and other laboratory studies.
• Abdominal ultrasound.
• Computed tomography.
• Magnetic resonance imaging.
• Magnetic resonance cholangiopancreatography.

These tests demonstrate the extent of the primary tumor and help determine 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 done to establish definitive pathologic staging.

Prognosis

Prognosis depends in part on the tumor's anatomic location, which affects its resectability. Because of its nearness to major blood vessels and diffuse extension within the liver, a bile duct tumor can be difficult to resect. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct; the resectability rate is lower for lesions that occur in more proximal sites.[3]

Complete resection with negative surgical margins offers the only chance of cure for bile duct cancer. For localized, resectable extrahepatic and intrahepatic tumors, the presence of involved lymph nodes and perineural invasion are significant adverse prognostic factors.[4,5,6]

Additionally, the following have been associated with worse outcomes among patients with intrahepatic cholangiocarcinomas:[7,8,9]

• A personal history of primary sclerosing cholangitis.
• Elevated cancer antigen 19-9 level.
• Periductal infiltrating tumor growth pattern.
• Presence of hepatic venous invasion.

Related Summaries

Other PDQ summaries containing information related to bile duct cancer include the following:

• Adult Primary Liver Cancer Treatment

References:

1. Siegel R, Ma J, Zou Z, et al.: Cancer statistics, 2014. CA Cancer J Clin 64 (1): 9-29, 2014 Jan-Feb.
2. de Groen PC, Gores GJ, LaRusso NF, et al.: Biliary tract cancers. N Engl J Med 341 (18): 1368-78, 1999.
3. Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992.
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.
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.
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.
7. Rosen CB, Nagorney DM, Wiesner RH, et al.: Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 213 (1): 21-5, 1991.
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.
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.

Cellular Classification of Bile Duct Cancer

Intrahepatic Bile Duct Cancer

The most common histopathologic types of intrahepatic bile duct tumor include the following:[1]

• Intrahepatic cholangiocarcinoma.
  • Mass-forming tumor growth pattern.
  • Periductal-infiltrating tumor growth pattern.
  • Mixed mass-forming and periductal-infiltrating growth pattern.
• Mixed hepatocellular cholangiocarcinoma.

Perihilar Bile Duct Cancer

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

• Carcinoma in situ.
• Adenocarcinoma, 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.

Distal Extrahepatic Bile Duct Cancer

Adenocarcinomas are the most common type of distal extrahepatic bile duct tumor. The histologic types of distal extrahepatic bile duct cancer include the following:[3]

• Carcinoma in situ.
• Adenocarcinoma, 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.

References:

1. 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.
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. 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.

Stage Information for Bile Duct Cancer

Staging for Bile Duct Cancer

Bile duct cancer is classified as resectable (localized) or unresectable, with obvious prognostic importance. The TNM (tumor, node, metastasis) staging system is used for staging bile duct cancer, commonly after surgery and pathologic examination of the resected specimen. Evaluation of the extent of disease at laparotomy is an important component of staging.

AJCC Staging System for Bile Duct Cancer

AJCC staging system for intrahepatic bile duct cancer

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define intrahepatic bile duct cancer.[1]

Tables 1, 2, 3, 4, 5, and 6 pertain to the intrahepatic bile duct cancer stages.

AJCC staging system for perihilar bile duct cancer

The AJCC has designated staging by TNM classification to define perihilar bile duct cancer.[2]

Tables 7, 8, 9, 10, 11, 12, and 13 pertain to the perihilar bile duct cancer stages.

AJCC staging system for distal extrahepatic bile duct cancer

The AJCC has designated staging by TNM classification to define distal extrahepatic bile duct cancer.[3] 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 14, 15, 16, 17, 18, 19, and 20 pertain to the distal extrahepatic bile duct cancer stages.

References:

1. 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.
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. 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.

Treatment Option Overview for Bile Duct Cancer

The treatment of bile duct cancer depends primarily on whether the cancer can be completely removed by surgery.

Resectable (Localized) Bile Duct Cancer

Localized intrahepatic and extrahepatic bile duct cancer may be removed completely by the surgeon. These tumors represent a very small number of cases that are usually in the distal common bile duct. Among patients treated with surgical resection, long-term prognosis varies depending on primary tumor extent, margin status, lymph node involvement, and additional pathologic features.[1,2]

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 are determined.

Unresectable Bile Duct Cancer

Most cases of intrahepatic, extrahepatic, and perihilar bile duct cancer are unresectable and cannot be completely removed by the surgeon. Often the cancer invades directly into the portal vein, the adjacent liver, along the common bile duct, and to adjacent lymph nodes. Portal hypertension may result from invasion of the portal vein. Spread to distant parts of the body is uncommon, but intra-abdominal metastases, particularly peritoneal metastases, do occur. Transperitoneal and hematogenous hepatic metastases also occur with bile duct cancer of all sites. Moreover, most patients who undergo resection will develop recurrent disease within the hepatobiliary system or, less frequently, at distant sites.

For patients with unresectable bile duct cancer, management is directed at palliation.

Treatment options for bile duct cancer are described in Table 21.

References:

1. Nagorney DM, Donohue JH, Farnell MB, et al.: Outcomes after curative resections of cholangiocarcinoma. Arch Surg 128 (8): 871-7; discussion 877-9, 1993.
2. Washburn WK, Lewis WD, Jenkins RL: Aggressive surgical resection for cholangiocarcinoma. Arch Surg 130 (3): 270-6, 1995.

Intrahepatic Bile Duct Cancer Treatment

Resectable Intrahepatic Bile Duct Cancer

Standard treatment options for resectable intrahepatic bile duct cancer include the following:

1. Surgery.

Surgery

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.

Partial liver resection or partial hepatectomy to achieve negative margins is the mainstay of cure for patients with intrahepatic cholangiocarcinoma.[1] 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.

Other treatment options

Other treatment options may include the following:

1. Chemotherapy. Numerous retrospective series have suggested that adjuvant chemotherapy may be beneficial after complete surgical resection.[2,3][Level of evidence: 3iiiDiii]
   1. A multi-institutional Japanese study compared surgery alone with mitomycin-C and infusional 5-fluorouracil (5-FU) followed by 5-FU until disease progression.[4][Level of evidence: 1iiA]
      • Among the subset of patients with bile duct cancers (n = 139), no survival benefit was seen.
2. External-beam radiation therapy (EBRT). There is little published literature evaluating the role of EBRT after resection for intrahepatic cholangiocarcinoma.
3. Clinical trials. All patients are encouraged to enroll in clinical trials for adjuvant therapies. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

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

Unresectable, Recurrent, or Metastatic Intrahepatic Bile Duct Cancer

Standard treatment options for unresectable, recurrent, or metastatic intrahepatic bile duct cancer include the following:

1. Palliative therapy.
2. Systemic chemotherapy.

Palliative therapy

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.[5,6]

Palliative 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.[7,8] Limited but emerging data are available regarding the potential role for alternative liver-directed therapies, including stereotactic body radiation therapy [9] and intra-arterial embolization.[10]

Systemic chemotherapy

Systemic chemotherapy is appropriate for selected patients with adequate performance status and intact organ function. The following agents have been reported to produce transient partial remissions in a minority of patients:

• Fluoropyrimidines.
• Gemcitabine.
• Platinum agents.
• Docetaxel.

A phase III study (NCT00262769) randomly assigned 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma to receive cisplatin followed by gemcitabine or to receive gemcitabine alone for up to 6 months and observed the following:[11]

• Median OS improved among patients treated with cisplatin and gemcitabine therapy (11.7 months) versus patients treated with gemcitabine alone (8.1 months) (hazard ratio, 0.64; 95% confidence interval, 0.52-0.80; P < .001).[11][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.
• Grades 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.

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

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. Dodson RM, Weiss MJ, Cosgrove D, et al.: Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 217 (4): 736-750.e4, 2013.
2. Todoroki T: Chemotherapy for bile duct carcinoma in the light of adjuvant chemotherapy to surgery. Hepatogastroenterology 47 (33): 644-9, 2000 May-Jun.
3. 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.
4. 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.
5. Nordback IH, Pitt HA, Coleman J, et al.: Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 115 (5): 597-603, 1994.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.

Perihilar Bile Duct Cancer Treatment

Resectable Perihilar Bile Duct Cancer

Standard treatment options for resectable perihilar bile duct cancer include the following:

1. Surgery.

Surgery

For perihilar cholangiocarcinomas (Klatskin tumors), 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 partial hepatectomy that includes the caudate lobe has improved long-term outcomes but may be associated with increased postoperative complications.[1] With this aggressive surgical approach, 5-year survival rates of 20% to 50% have been reported.[2] 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 that can be resected.

The primary site of relapse after surgical resection is local; however, distant recurrence has been frequently reported.[3] There has been no randomized trial of adjuvant therapy for patients with localized disease. However, radiation therapy (external-beam radiation therapy [EBRT] with or without brachytherapy) has been reported to improve local control.[4,5][Level of evidence: 3iiiDiii]

The optimal surgical procedure for carcinoma of the perihilar bile duct varies according to the location of the tumor 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 is 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 (approximately 10%) and low curability.[6]

In jaundiced patients, the role of percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction is controversial because of inconsistent findings of significant clinical benefit and concerns of increased risk of postoperative complications.[7] However, percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction may be considered before surgery, particularly if jaundice is severe or an element of azotemia is present.[8,9]

Other treatment options

Other treatment options may include the following:

1. EBRT. Numerous retrospective studies have suggested that adding EBRT after complete surgical resection may be beneficial.[4,5][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 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.[10][Level of evidence: 3iiiDiv]

   A phase II cooperative group trial, SWOG S0809 (NCT00789958), evaluated adjuvant capecitabine and gemcitabine followed by chemoradiation therapy for resected extrahepatic cholangiocarcinoma and gallbladder cancer. In total, 79 eligible patients with pT2 to pT4 disease, node-positive disease, or positive-margin resection were enrolled (extrahepatic bile duct cancer, n = 54; gallbladder cancer, n = 25).[11][Level of evidence: 2A]

   • The 2-year survival rate of 65% was significantly higher than expected, based on historical controls.[11][Level of evidence: 2A]
   • Grade 3 toxicity was observed in 52% of patients, and grade 4 toxicity was observed in 11% of patients.
   • On the basis of these results, this regimen was observed to be well tolerated with promising efficacy.
2. Chemotherapy. Numerous retrospective series have suggested that adjuvant chemotherapy after complete surgical resection may be beneficial.[12,13][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.
   1. A multi-institutional Japanese study compared surgery alone with mitomycin-C and infusional 5-fluorouracil (5-FU) followed by 5-FU until disease progression.[14][Level of evidence: 1iiA]
      • Among the subset of patients with bile duct cancer (n = 139), no survival benefit was seen.
3. Clinical trials. All patients are encouraged to enroll in clinical trials for adjuvant therapies. Information about ongoing clinical trials is available from the NCI website.

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.

Unresectable, Recurrent, or Metastatic Perihilar Bile Duct Cancer

Standard treatment options for unresectable, recurrent, or metastatic perihilar bile duct cancer include the following:

1. Palliative therapy.
2. Systemic chemotherapy.

Palliative therapy

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.[15,16]

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.[17,18]

Systemic chemotherapy

Systemic chemotherapy is appropriate for selected patients with adequate performance status and intact organ function. The following agents have been reported to produce transient partial remissions in a minority of patients:

• Fluoropyrimidines.
• Gemcitabine.
• Platinum agents.
• Docetaxel.

A phase III study (NCT00262769) randomly assigned 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma to receive cisplatin followed by gemcitabine or to receive gemcitabine alone for up to 6 months, and observed the following:[19]

• Median OS improved among patients treated with cisplatin and gemcitabine therapy (11.7 months) versus patients treated with gemcitabine alone (8.1 months) (hazard ratio, 0.64; 95% confidence interval, 0.52-0.80; P < .001).[19][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.

Neoadjuvant chemoradiation and orthotopic liver transplantation have been evaluated in carefully selected patients with locally unresectable perihilar bile duct cancer.[20][Level of evidence: 3iiiD] This approach is not regarded as standard care and should be considered only in the context of a clinical trial in specialized transplant centers.

Other drugs and drug combinations await evaluation in randomized trials.

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

Current Clinical Trials

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

References:

1. 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.
2. Nakeeb A, Tran KQ, Black MJ, et al.: Improved survival in resected biliary malignancies. Surgery 132 (4): 555-63; discussion 563-4, 2002.
3. 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.
4. 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.
5. 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.
6. Loehrer AP, House MG, Nakeeb A, et al.: Cholangiocarcinoma: are North American surgical outcomes optimal? J Am Coll Surg 216 (2): 192-200, 2013.
7. Liu F, Li Y, Wei Y, et al.: Preoperative biliary drainage before resection for hilar cholangiocarcinoma: whether or not? A systematic review. Dig Dis Sci 56 (3): 663-72, 2011.
8. Nimura Y: Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB (Oxford) 10 (2): 130-3, 2008.
9. Laurent A, Tayar C, Cherqui D: Cholangiocarcinoma: preoperative biliary drainage (Con). HPB (Oxford) 10 (2): 126-9, 2008.
10. 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.
11. Ben-Josef E, Guthrie KA, El-Khoueiry AB, 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. J Clin Oncol 33 (24): 2617-22, 2015.
12. Todoroki T: Chemotherapy for bile duct carcinoma in the light of adjuvant chemotherapy to surgery. Hepatogastroenterology 47 (33): 644-9, 2000 May-Jun.
13. 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.
14. 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.
15. Nordback IH, Pitt HA, Coleman J, et al.: Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 115 (5): 597-603, 1994.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.

Distal Extrahepatic Bile Duct Cancer Treatment

Resectable Distal Extrahepatic Bile Duct Cancer

Standard treatment options for resectable distal extrahepatic bile duct cancer include the following:

1. Surgery.

Surgery

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

The optimum surgical procedure for carcinoma of the distal extrahepatic bile duct will vary according to the location of the tumor along the biliary tree, the extent of hepatic parenchymal involvement, and the proximity of the tumor to major blood vessels in this region. The regional lymph nodes are assessed at the time of surgery because they have prognostic significance. Patients with cancer of the lower end of the duct and regional lymph node involvement may warrant an extensive resection (Whipple procedure). The 5-year outcomes range between 20% and 50%.[2,3] Bypass operations or endoluminal stents are alternatives if intraoperatively the tumor is found to be unresectable.[2,3]

In jaundiced patients, the role of percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction is controversial, but may be considered before surgery, particularly if jaundice is severe or an element of azotemia is present.[4,5]

Other treatment options

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.[6,7][Level of evidence: 3iiiDiii]

Other treatment options may include the following:

1. EBRT. Numerous retrospective studies have suggested that adding EBRT after complete surgical resection may be beneficial.[6,7][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 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.[8][Level of evidence: 3iiiDiv]

   A phase II cooperative group trial, SWOG S0809 (NCT00789958), evaluated adjuvant capecitabine and gemcitabine followed by chemoradiation therapy for resected extrahepatic cholangiocarcinoma and gallbladder cancer. In total, 79 eligible patients with pT2 to pT4 disease or node-positive disease, or positive margin resection were enrolled (extrahepatic bile duct cancer, n = 54; gallbladder cancer, n = 25).[9][Level of evidence: 2A]

   • The 2-year survival rate of 65% was significantly higher than expected, based on historical controls.[9][Level of evidence: 2A]
   • Grade 3 toxicity was observed in 52% of patients, and grade 4 toxicity was observed in 11% of patients.
   • On the basis of these results, this regimen was observed to be well tolerated with promising efficacy.
2. Chemotherapy. Numerous retrospective series have suggested that adjuvant chemotherapy after complete surgical resection is beneficial.[10,11][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 cancer, addressed the potential benefit of additional chemotherapy.
   1. A multi-institutional Japanese study compared surgery alone with mitomycin-C and infusional 5-fluorouracil (5-FU) followed by 5-FU until disease progression.[12]
      • Among the subset of patients with bile duct cancers (n = 139), no survival benefit was seen.
3. 1. The European Study Group for Pancreatic Cancer (ESPAC-3 [NCT00058201]) trial randomly assigned 428 patients with periampullary cancer, which included 96 patients with bile duct cancers, to observation, 6 months of 5-FU/leucovorin, or 6 months of gemcitabine.[13][Level of evidence: 1iiA]
      • Among all patients, adjuvant chemotherapy, compared with observation, was not associated with significant OS benefit. However, after adjusting for prognostic variables by multivariable analysis, a statistically significant OS benefit was associated with adjuvant chemotherapy (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.57-0.98; P = .03).
      • In a preplanned subgroup analysis of the 96 patients with bile duct cancer, no benefit was seen among patients treated with chemotherapy. Limitations of this subgroup analysis include limited statistical power and difficulty in differentiating ampullary versus distal common bile duct tumors as pathologic site of origin.
      • 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.[13][Level of evidence: 1iiA]
4. Clinical trials. All patients are encouraged to enroll in clinical trials for adjuvant therapies. Information about ongoing clinical trials is available from the NCI website.

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.

Unresectable, Recurrent, or Metastatic Distal Extrahepatic Bile Duct Cancer

Standard treatment options for unresectable, recurrent, or metastatic distal extrahepatic bile duct cancer include the following:

1. Palliative Therapy.
2. Systemic Chemotherapy.

Palliative therapy

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.[14,15]

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.[16,17]

Systemic chemotherapy

Systemic chemotherapy. Systemic chemotherapy is appropriate for selected patients with adequate performance status and intact organ function. The following agents have been reported to produce transient partial remissions in a minority of patients:

• Fluoropyrimidines.
• Gemcitabine.
• Platinum agents.
• Docetaxel.

A phase III study (NCT00262769) randomly assigned 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma to receive cisplatin followed by gemcitabine or to receive gemcitabine alone for up to 6 months, and observed the following:[18]

• Median OS improved among patients treated with cisplatin and gemcitabine therapy (11.7 months) versus patients treated with gemcitabine alone (8.1 months) (HR, 0.64; 95% CI, 0.52-0.80; P < .001).[18][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.
• Grades 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.

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

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.

References:

1. Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992.
2. Fong Y, Blumgart LH, Lin E, et al.: Outcome of treatment for distal bile duct cancer. Br J Surg 83 (12): 1712-5, 1996.
3. Bortolasi L, Burgart LJ, Tsiotos GG, et al.: Adenocarcinoma of the distal bile duct. A clinicopathologic outcome analysis after curative resection. Dig Surg 17 (1): 36-41, 2000.
4. Nimura Y: Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB (Oxford) 10 (2): 130-3, 2008.
5. Laurent A, Tayar C, Cherqui D: Cholangiocarcinoma: preoperative biliary drainage (Con). HPB (Oxford) 10 (2): 126-9, 2008.
6. 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.
7. 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.
8. 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.
9. Ben-Josef E, Guthrie KA, El-Khoueiry AB, 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. J Clin Oncol 33 (24): 2617-22, 2015.
10. Todoroki T: Chemotherapy for bile duct carcinoma in the light of adjuvant chemotherapy to surgery. Hepatogastroenterology 47 (33): 644-9, 2000 May-Jun.
11. 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.
12. 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.
13. 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.
14. Nordback IH, Pitt HA, Coleman J, et al.: Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 115 (5): 597-603, 1994.
15. 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.
16. 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.
17. 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.
18. 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.

Changes to This Summary (02 / 09 / 2017)

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.

Editorial changes were made to this 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 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:

• 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 reviewer for Bile Duct Cancer (Cholangiocarcinoma) Treatment is:

• 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.

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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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Bile Duct Cancer (Cholangiocarcinoma) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/liver/hp/bile-duct-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389308]

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Last Revised: 2017-02-09