Hepatobiliary cancers include a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma), gall bladder, and bile ducts (cholangiocarcinomas). Gallbladder cancer and cholangiocarcinomas are collectively known as biliary tract cancers. Gallbladder cancer is the most common and aggressive type of all the biliary tract cancers. Cholangiocarcinomas are diagnosed throughout the biliary tree and are typically classified as either intrahepatic or extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinomas are more common than intrahepatic cholangiocarcinomas. This manuscript focuses on the clinical management of patients with gallbladder cancer and cholangiocarcinomas (intrahepatic and extrahepatic).

Abstract

Hepatobiliary cancers include a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma), gall bladder, and bile ducts (cholangiocarcinomas). Gallbladder cancer and cholangiocarcinomas are collectively known as biliary tract cancers. Gallbladder cancer is the most common and aggressive type of all the biliary tract cancers. Cholangiocarcinomas are diagnosed throughout the biliary tree and are typically classified as either intrahepatic or extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinomas are more common than intrahepatic cholangiocarcinomas. This manuscript focuses on the clinical management of patients with gallbladder cancer and cholangiocarcinomas (intrahepatic and extrahepatic).

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview: Biliary Tract Cancers

Hepatobiliary cancers are highly lethal cancers including a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma [HCC]), gallbladder, and bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Gallbladder cancer and cholangiocarcinomas are collectively known as biliary tract cancers. In 2014, an estimated 33,190 people in the United States will be diagnosed with liver cancer and intrahepatic bile duct cancer and an additional 10,310 people will be diagnosed with gallbladder cancer or other biliary tract cancer. Approximately 23,000 deaths from liver or intrahepatic bile duct cancer will occur, and 3630 deaths will result from gallbladder cancer or other biliary tract cancer.1 The types of hepatobiliary cancers covered in these guidelines include HCC, gallbladder cancer, and intrahepatic and extrahepatic cholangiocarcinoma. This manuscript discusses the recommendations for the clinical management of patients with biliary tract cancers. For other topics related to hepatobiliary cancers, please refer to the full NCCN Guidelines for Hepatobiliary Cancers (available at NCCN.org).

Gallbladder Cancer

Gallbladder cancer is the most common and aggressive type of all the biliary tract cancers. Most gallbladder cancers are adenocarcinomas and their incidence steadily increases with age; women are more likely than men to be diagnosed with gallbladder cancer, and it is more common in white women.2,3 Gallbladder cancer is characterized by local and vascular invasion, extensive regional lymph node metastasis, and distant metastases. Gallbladder cancer is also associated with shorter median survival duration, a much shorter time to recurrence, and shorter survival duration after recurrence than hilar cholangiocarcinoma.4

Risk Factors

Cholelithiasis with the presence of chronic inflammation is the most prevalent risk factor for gallbladder cancer and the risk increases with the stone size.5,6 Calcification of the gallbladder (porcelain gallbladder), a result of chronic inflammation of the gallbladder, has also been regarded as a risk factor for gallbladder cancer.5 Recent reports, however, suggest that the risk of developing gallbladder cancer in patients with gallbladder calcification is much lower than anticipated (6% compared with 1% in patients without gallbladder calcifications).7,8 Other risk factors include anomalous pancreaticobiliary duct junctions, gallbladder polyps (solitary and symptomatic polyps >1 cm), chronic typhoid infection, adenomyomatosis of the gallbladder, and inflammatory bowel disease.6,9,10 Prophylactic cholecystectomy may be beneficial for patients who are at high risk of developing gallbladder cancer.5

F1NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 8; 10.6004/jnccn.2014.0112

F2NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 8; 10.6004/jnccn.2014.0112

F3NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 8; 10.6004/jnccn.2014.0112

F4NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 8; 10.6004/jnccn.2014.0112

F5NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 8; 10.6004/jnccn.2014.0112

Staging and Prognosis

In the AJCC staging system, gallbladder cancer is classified into 4 stages based on the depth of invasion into the gallbladder wall and the extent of spread to surrounding organs and lymph nodes. In the revised 2010 AJCC staging system, stage groupings have been changed to better correlate with the extent of cystic duct and lymph node involvement, resectability of the tumor, and patient outcome.11 Lymph node metastasis is now classified as stage IIIB (N1) or IVB (N2), and locally unresectable T4 tumors have been reclassified as stage IV. An analysis of 10,705 patients diagnosed with gallbladder cancer between 1989 and 1996 in the National Cancer Database showed that this revised staging system provided an improved prognostic discrimination of patients with stage III and IV disease.12

Tumor stage is the strongest prognostic factor for patients with gallbladder cancer.2,13 In an analysis of approximately 2500 patients with gallbladder cancer from hospital cancer registries throughout the United States, the 5-year survival rates were 60%, 39%, and 15% for patients with stage 0, I, and III disease, respectively, whereas the corresponding survival rates were only 5% and 1% for patients with stage III and IV disease, respectively.2 Results from a retrospective analysis of 435 patients treated at a single center showed a median overall survival (OS) of 10.3 months for the entire cohort of patients.13 The median survival was 12.9 and 5.8 months for those presenting with stage IA-III and stage IV disease, respectively. In a recent report of 122 patients with gallbladder cancer identified in a prospectively maintained database, liver involvement was associated with decreased relapse-free survival (RFS) and disease-specific survival for patients with T2 tumors (median RFS was 12 months vs not reached for patients without liver involvement, P=.004; median disease-specific survival was 25 months vs not reached for patients without liver involvement, P=.003) but not in patients with T1b tumors.14

Diagnosis

Gallbladder cancer is often diagnosed at an advanced stage because of the aggressive nature of the tumor, which can spread rapidly. Another factor contributing to late diagnosis of gallbladder cancer is a clinical presentation that mimics that of biliary colic or chronic cholecystitis. Hence, it is not uncommon for a diagnosis of gallbladder cancer to be an incidental finding at cholecystectomy for a benign gallbladder disease or, more frequently, on pathologic review following cholecystectomy for symptomatic cholelithiasis. In a retrospective review of 435 patients diagnosed and treated with curative resection at a single center during 1995 to 2005, 123 patients (47%) were diagnosed with gallbladder cancer as an incidental finding during laparoscopic cholecystectomy.13 Other possible clinical presentations of gallbladder cancer include a suspicious mass detected on ultrasound or biliary tract obstruction with jaundice. The presence of jaundice in patients with gallbladder cancer is usually associated with a poor prognosis; patients with jaundice are more likely to have advanced-stage disease (96% vs 60%; P<.001) and significantly lower disease-specific survival (6 vs 16 months; P<.0001) than those without jaundice.15

Workup

The initial workup of patients presenting with a gallbladder mass or disease suspicious for gallbladder cancer should include liver function tests and an assessment of hepatic reserve. High-quality cross-sectional imaging (ultrasound, CT, or MRI) of the chest, abdomen, and pelvis is recommended to evaluate tumor penetration within the wall of the gallbladder to determine the presence of nodal and distant metastases and to detect the extent of direct tumor invasion of other organs/biliary system or major vascular invasion.16 CT is more useful than ultrasound for the detection of lymph node involvement, adjacent organ invasion, and distant metastasis; MRI may be useful for distinguishing benign conditions from gallbladder cancer.3 Although the role of PET scan has not been established in the evaluation of patients with gallbladder cancer, emerging evidence indicates that it may be useful for detecting regional lymph node metastases and distant metastatic disease in patients with otherwise potentially resectable disease.17-19

For patients presenting with jaundice, additional workup should include cholangiography to evaluate for hepatic and biliary invasion of tumor. Noninvasive magnetic resonance cholangiography (MRCP) is preferred over endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC), unless a therapeutic intervention is planned.16

Carcinoembryonic antigen (CEA) and CA 19-9 testing could be considered as part of initial work-up (in conjunction with imaging studies). Elevated serum CEA levels (>4.0 ng/mL) or CA 19-9 levels (>20.0 units/mL) could be suggestive of gallbladder cancer.20 Although CA 19-9 had higher specificity than CEA (92.7% vs 79.2%), its sensitivity was lower (50.0% vs 79.4%). However, these markers are not specific for gallbladder cancer, and CA 19-9 could also be elevated in patients with jaundice from other benign causes.

Surgical Management

The surgical approach to the management of all patients with resectable gallbladder cancer is the same, except that in patients with an incidental finding of gallbladder cancer on pathologic review, the gallbladder has been removed. Complete resection with negative margins remains the only curative treatment for patients with gallbladder cancer.21 The optimal resection consists of cholecystectomy with a limited hepatic resection (segments IVB and V), and portal lymphadenectomy to encompass the tumor with negative margins.22 Lymphadenectomy should include lymph nodes in the porta hepatis, gastrohepatic ligament, and retroduodenal regions, without routine resection of the bile duct if possible. Extended hepatic resections (beyond segments IVB and V) and resection of the bile duct may be necessary in some patients to obtain negative margins, depending on the stage and location of the tumor, depth of tumor invasion, proximity to adjacent organs, and expertise of the surgeon.

A simple cholecystectomy is an adequate treatment for patients with T1a tumors, with the long-term survival rates approaching 100%.23 Although cholecystectomy combined with hepatic resection and lymphadenectomy is associated with an improved survival for patients with T2 or higher tumors, no definite evidence exists regarding the benefit of radical resection over simple cholecystectomy for patients with T1b tumors.24-29 Some studies have demonstrated a significant improvement in cancer-specific survival among patients with T1b and T2 tumors, and no improvement in survival among patients with T3 tumors.25-27 Other reports suggest that a survival benefit associated with extended resection and lymphadenectomy is seen only in patients with T2 tumors and some with T3 tumors with localized hepatic invasion and limited regional node involvement.28,29 Major hepatic resection and bile duct resection have also been shown to increase morbidity without improvement in survival.22,30 A multivariate analysis of prospective data collected on 104 patients undergoing surgery for gallbladder cancer from 1990 to 2002 showed that higher T and N stage, poor differentiation, and common bile duct involvement were independent predictors of poor disease-specific survival.30 Major hepatectomy and common bile duct excision significantly increased overall perioperative morbidity (53%) and were not independently associated with long-term survival.30 Fuks et al22 from the AFS-GBC-2009 study group also reported that bile duct resection resulted in a postoperative morbidity rate of 60% in patients with an incidental finding of gallbladder cancer. However, for patients with incidental findings of gallbladder cancer, Pawlik et al31 reported that common duct resection should be performed at the time of re-resection for those with positive cystic duct margins, because of the presence of residual disease.

With these data in mind, the guidelines recommend that extended hepatic (beyond segments IVB and V) and bile duct resections should be performed only when necessary to obtain negative margins (R0 resection) in certain clinical situations, as discussed earlier.25,27-29

Among patients with an incidental finding of gallbladder cancer, some evidence shows that a delayed resection due to referral to a tertiary cancer center or a radical resection following an initial noncurative procedure is not associated with a survival deficit compared with immediate resection.32,33 However, these comparisons are difficult to interpret because of selection bias. Nevertheless, in all patients with convincing clinical evidence of gallbladder cancer, the guidelines recommend that surgery should be performed by an experienced surgeon who is prepared to perform a definitive resection of the tumor. If expertise is unavailable, patients should be referred to a center with available expertise. The panel is also of the opinion that surgery should not be performed in situations where the extent and resectability of the disease has not been established.

Management of Resectable Disease

All patients should undergo cross-sectional imaging (ultrasound, CT, or MRI) of the chest, abdomen, and pelvis before surgery to evaluate for the presence of distant metastases. Staging laparoscopy has been shown to identify radiographically occult disseminated disease in patients with primary gallbladder cancer.34 In a prospective study that evaluated the role of staging laparoscopy in 409 patients diagnosed with primary gallbladder cancer, Agarwal et al34 reported a significantly higher yield in locally advanced tumors compared with early-stage tumors (25.2% vs 10.7%; P=.02); the accuracy for detecting unresectable disease and a detectable lesion in locally advanced tumors (56.0% and 94.1%, respectively) was similar to that in early-stage tumors (54.6% and 100.0%, respectively). The use of staging laparoscopy obviated the need for laparotomy in 55.9% of patients with unresectable disease. Staging laparoscopy, however, is of relatively low yield in patients with an incidental finding of gallbladder cancer, because disseminated disease is relatively uncommon; higher yields may be obtained in patients who are at higher risk for disseminated metastases (those with poorly differentiated, T3 or higher tumors or margin-positive tumors at cholecystectomy).35 Because the risk of peritoneal metastases is high for patients with primary gallbladder cancer, staging laparoscopy should be considered for if no distant metastases are found on imaging or if any suspicion exists of metastatic disease on imaging that is not amenable to percutaneous biopsy.34 In patients with an incidental finding of gallbladder cancer, staging laparoscopy can be considered in those who are at high risk for disseminated metastases.35

Radical cholecystectomy (cholecystectomy plus en bloc hepatic resection and lymphadenectomy with or without bile duct excision) is the preferred primary treatment for patients with an incidental finding of gallbladder cancer at surgery. The guidelines also recommend intraoperative staging and procurement of frozen section of gallbladder for biopsy (in selected cases if the diagnosis is not clear) before definitive resection.

Among patients with an incidental finding of gallbladder cancer on pathologic review, those with T1a lesions may be observed if the tumor margins are negative, because these tumors have not penetrated the muscle layer and long-term survival approaches 100% with simple cholecystectomy.23 Extended hepatic resection and lymphadenectomy with or without bile duct excision is recommended for patients with T1b or greater lesions.25,27,28 Aggressive re-resection to achieve negative margins is often performed for patients with an incidental finding of T1b, T2, or T3 gallbladder cancer, because a significant percentage of these patients have been found to harbor residual disease within the liver and common bile duct.13,31 Port site resection was not associated with improved survival or disease recurrence in patients with incidental findings of gallbladder cancer and should not be considered during definitive resection.36,37

For patients with a suspicious mass detected on imaging or in patients presenting with jaundice, the guidelines recommend cholecystectomy plus en bloc hepatic resection and lymphadenectomy with or without bile duct excision. A biopsy is not necessary and a diagnostic laparoscopy is recommended before definitive resection.34 In selected patients where the diagnosis is not clear it may be reasonable to perform a cholecystectomy (including intraoperative frozen section) followed by the definitive resection during the same setting if pathology confirms cancer. However, jaundice in patients with gallbladder cancer is considered a relative contraindication to surgery and outcomes are generally poor in these patients; only a portion of those with node-negative disease potentially benefit from complete resection.15,38 In patients with jaundice, if gallbladder cancer is suspected, surgery should only be performed with a curative intent. These patients should be carefully evaluated before surgery and referral to an experienced center should be considered.

The optimal adjuvant treatment strategy for patients with resected gallbladder cancer has not been determined and limited clinical trial data support a standard regimen for adjuvant treatment. A multivariate Cox proportional hazards model developed to make individualized predictions of survival from the addition of radiotherapy following gallbladder cancer resection showed that the greatest benefit of radiotherapy was seen in patients with T2 or higher-stage tumors and node-positive disease.39,40 Results of these studies support omitting adjuvant chemoradiation in the postsurgical treatment of patients with gallbladder cancer characterized as T1b, N0.

The guidelines have included consideration of fluoropyrimidine chemoradiation (except T1a or T1b,N0) and fluoropyrimidine or gemcitabine chemotherapy as options for adjuvant treatment. See “Adjuvant Chemotherapy and Chemoradiation for Biliary Tract Cancers,” page 1172.

Management of Unresectable or Metastatic Disease

Preoperative evaluation and a biopsy to confirm the diagnosis is recommended for patients with unresectable (includes tumors with distant lymph node metastases in the celiac axis or aortocaval groove) or metastatic disease (includes distant metastases, nodal metastases beyond the porta hepatis, and extensive involvement of the porta hepatis causing jaundice or vascular encasement). Primary options for these patients include (1) a clinical trial; (2) fluoropyrimidine-based or gemcitabine-based chemotherapy; or (3) best supportive care. In addition, fluoropyrimidine chemoradiation is included as an option for patients with unresectable disease. See “Chemotherapy and Chemoradiation for Advanced Biliary Tract Cancers,” page 1174.

In patients with unresectable or metastatic gallbladder cancer and jaundice, biliary drainage is an appropriate palliative procedure and should be performed before instituting chemotherapy if technically feasible.38 Biliary drainage followed by chemotherapy can result in improved quality of life. CA 19-9 testing can be considered after biliary decompression.

Surveillance

No data support aggressive surveillance following resection of gallbladder cancer; determination of appropriate follow-up schedule/imaging should include a careful patient/physician discussion. It is recommended that follow-up of patients undergoing an extended cholecystectomy for gallbladder cancer should include consideration of imaging studies every 6 months for 2 years. Re-evaluation according to the initial workup should be considered in the event of disease relapse or progression.

Cholangiocarcinomas

Cholangiocarcinomas encompass all tumors originating in the epithelium of the bile duct. More than 90% of cholangiocarcinomas are adenocarcinomas and are broadly divided into 3 histologic types based on their growth patterns: mass-forming, periductal-infiltrating, and intraductal-growing.41 Cholangiocarcinomas are diagnosed throughout the biliary tree and are typically classified as either intrahepatic or extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinomas are more common than intrahepatic cholangiocarcinomas.

Intrahepatic cholangiocarcinomas (also known as peripheral cholangiocarcinomas) are located within the hepatic parenchyma and have also been called peripheral cholangiocarcinomas (see Figure 1, available online, in these guidelines, at NCCN.org). Extrahepatic cholangiocarcinomas occur anywhere within the common hepatic duct, at or near the junction of the right and left hepatic ducts, or the common bile duct, including the intrapancreatic portion, and are further classified into hilar or distal tumors (see Figure 1). Hilar cholangiocarcinomas (also called Klatskin tumors) occur at or near the junction of the right and left hepatic ducts; distal cholangiocarcinomas are extrahepatic lesions arising in the extrahepatic bile ducts above the ampulla of Vater.42 Hilar cholangiocarcinomas are the most common type of extrahepatic cholangiocarcinomas.

These NCCN Guidelines discuss the clinical management of patients with intrahepatic and extrahepatic cholangiocarcinomas, including the hilar cholangiocarcinomas and the distal bile duct tumors. Tumors of the ampulla of Vater are not included.

Risk Factors

No predisposing factors have been identified in most patients diagnosed with cholangiocarcinoma,43 although evidence shows that particular risk factors may be associated with the disease in some patients. These risk factors, like those for gallbladder cancer, are associated with the presence of chronic inflammation. Primary sclerosing cholangitis, chronic calculi of the bile duct (hepatolithiasis), choledochal cysts, and liver fluke infections are well-established risk factors for cholangiocarcinoma. Unlike gallbladder cancer, however, cholelithiasis is not thought to be closely linked with cholangiocarcinoma.44 Other potential but less-established risk factors include inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol, and tobacco. Recently, several case-controlled studies from Asian and Western countries have reported hepatitis C viral infection as a significant risk factor for intrahepatic cholangiocarcinoma.45-48 This may be responsible for the increased incidence of intrahepatic cholangiocarcinoma recently observed at some centers, although future studies are needed to further explore this putative association.49

Staging and Prognosis

Intrahepatic Cholangiocarcinoma: In the 6th edition of the AJCC staging system, intrahepatic cholangiocarcinoma was staged identically to HCC. However, this staging system did not include predictive clinicopathologic features (multiple hepatic tumors, regional nodal involvement, and large tumor size) that are specific to intrahepatic cholangiocarcinoma.50 In more recent reports, tumor size had no effect on survival in patients undergoing surgery.51,52 In a SEER database analysis of 598 patients with intrahepatic cholangiocarcinoma who had undergone surgery, Nathan et al51 first reported that multiple lesions and vascular invasion predicted an adverse prognosis following resection, and lymph node status was of prognostic significance among patients without distant metastases. In this study, tumor size had no independent effect on survival. These findings were confirmed in a subsequent multi-institutional international study of 449 patients undergoing surgery for intrahepatic cholangiocarcinoma.52 The 5-year survival rate was higher for patients who lacked all 3 risk factors (multiple tumors, vascular invasion, and N1 disease) than for those with one or more risk factors (38.3%, 27.3%, and 18.1%, respectively), and, more importantly, tumor number and vascular invasion were of prognostic significance only in patients with N0 disease. Although tumor size was associated with survival in the univariate analysis, it was not of prognostic significance in the multivariate analysis.

In the revised 7th edition of the AJCC staging system, intrahepatic cholangiocarcinoma has a new staging classification that is independent of the staging classification used for HCC.11 The new classification focuses on multiple tumors, vascular invasion, and lymph node metastasis. Farges et al53 from the AFC-IHCC study group validated the new staging classification in 163 patients with resectable intrahepatic cholangiocarcinoma. The revised classification was useful in predicting survival according to the TNM staging. With a median follow-up of 34 months, the median survival was not reached for patients with stage I disease, was 53 months for those with stage II disease (P=.01), and was 16 months for those with stage III disease (P<.0001).

Extrahepatic Cholangiocarcinoma: In the previous AJCC classification, extrahepatic cholangiocarcinomas (hilar, middle, and distal tumors) were grouped together as a single entity. The 7th edition of AJCC staging system includes a separate TNM classification for hilar and distal bile duct tumors based on the extent of liver involvement and distant metastatic disease.11 Although the depth of tumor invasion is not part of the TNM classification, it has been identified as an independent predictor of outcome in patients with distal and hilar cholangiocarcinomas.54,55

The modified Bismuth-Corlette staging system56 and the Blumgart staging system57 are used to classify hilar cholangiocarcinomas. The modified Bismuth-Corlette staging system classifies hilar cholangiocarcinomas into 4 types based on the extent of biliary duct involvement. However, this does not include other clinicopathologic features, such as vascular encasement, lymph node involvement, distant metastases, and liver atopy. In addition, both the AJCC and the Bismuth-Corlette staging systems are not useful for predicting resectability or survival. The Blumgart staging system developed by Jarnagin et al57,58 is a useful preoperative staging system that predicts resectability, likelihood of metastatic disease, and survival. In this staging system, the hilar cholangiocarcinomas are classified into 3 stages (T1-3) based on the location and extent of bile duct involvement, the presence or absence of portal venous invasion, and hepatic lobar atrophy.57 Negative histologic margins, concomitant partial hepatectomy, and well-differentiated tumor histology were associated with improved outcome after resection; increasing T stage correlated significantly with reduced R0 resection rate, distant metastatic disease, and lower median survival.58

Diagnosis

Early-stage cholangiocarcinomas are typically asymptomatic. Patients with intrahepatic cholangiocarcinoma are more likely to present with non-specific symptoms, such as fever, weight loss, and/ or abdominal pain; symptoms of biliary obstruction are uncommon. Alternatively, intrahepatic cholangiocarcinoma may be detected incidentally as an isolated intrahepatic mass on imaging.59 In contrast, patients with extrahepatic cholangiocarcinoma are likely to present with jaundice followed by evidence of a biliary obstruction or abnormality on subsequent imaging.

Workup

The initial workup should include liver function tests. CEA and CA 19-9 testing can be considered, although these markers are not specific for cholangiocarcinoma; they are also associated with other malignancies and benign conditions.60 Early surgical consultation with a multidisciplinary team is recommended as part of the initial workup for the assessment of resectability in intrahepatic and extra-hepatic cholangiocarcinomas. The panel emphasizes that a multidisciplinary review of imaging studies involving experienced radiologists and surgeons is necessary to stage the disease and determine potential treatment options (ie, resection or other approach).

Direct visualization of the bile duct with directed biopsies is the ideal technique for the workup of cholangiocarcinoma. Delayed-contrast CT/MRI to assess the involvement of the liver, major vessels, nearby lymph nodes, and distant sites is also recommended when extrahepatic cholangiocarcinoma is suspected.61 Although no pathognomonic CT/MRI features are associated with intrahepatic cholangiocarcinoma, CT/MRI is used to help determine tumor resectability by characterizing the primary tumor, its relationship to nearby major vessels and the biliary tree, the presence of satellite lesions and distant metastases in the liver, and lymph node involvement, if present.61 In addition, chest imaging should be performed, and laparoscopy may be performed in conjunction with surgery if no distant metastasis is found. Endoscopic ultrasound may be useful in distal common bile duct cancers for defining a mass or abnormal thickening, which can direct biopsies. Esophagogastroduodenoscopy and colonoscopy are recommended as part of the initial workup for patients with intrahepatic cholangiocarcinoma.

MRCP is increasingly being used as a noninvasive alternative to ERCP for the diagnosis of bile duct cancers.62,63 It has been shown to have a higher sensitivity, specificity, and diagnostic accuracy than ERCP in the diagnosis and pretreatment staging of hilar cholangiocarcinomas.64 Recent data also support the use of MRCP and CT as a noninvasive alternative to ERCP for the assessment of bile duct tumors.65 ERCP/PTC should not be routinely recommended for the diagnosis of extrahepatic cholangiocarcinoma, because this is associated with complications and contamination of the biliary tree. For distal bile duct tumors in which a diagnosis is needed or when palliation is indicated, an ERCP allows for complete imaging of the bile duct and stenting of the obstruction. In addition, brushes of the bile duct can be obtained for pathologic evaluation. Because many of the patients with extrahepatic cholangiocarcinoma present with jaundice, additional workup should include noninvasive cholangiography with cross-sectional imaging to evaluate local tumor extent.61 Although the role of PET imaging has not been established in the evaluation of patients with cholangiocarcinoma, emerging evidence indicates that it may be useful for the detection of regional lymph node metastases and distant metastatic disease in patients with otherwise potentially resectable disease.17-19,66,67

Management of Intrahepatic Cholangiocarcinoma

Complete resection is the only potentially curative treatment for patients with resectable disease, although most patients are not candidates for surgery because of the presence of advanced disease at diagnosis. The optimal surgical margin associated with improved survival and reduced risk of recurrence in patients undergoing surgery remains uncertain, with some reports documenting R0 resection as a significant predictor of survival and recurrence,68-73 whereas others suggest that margin status is not a significant predictor of outcome.74,75 Ribero et al73 from the Italian Intrahepatic Cholangiocarcinoma Study Group reported that margin-negative resection was associated with significantly higher survival rates (estimated 5-year survival rates were 39.8% vs 4.7% for patients with a positive margin) and significantly lower recurrence rates (53.9% vs. 73.6% for those with a positive margin); however, in patients who had margin-negative resections, the margin width had no long-term impact on survival (P=.61) or recurrence (P>.05) after resection. Farges et al75 from the AFC-IHCC-2009 study group reported that although R1 resection was the strongest independent predictor of poor outcome in patients with pN0 disease undergoing surgery, its survival benefit was very small in those with pN+ disease (median survival of 18 and 13 months, respectively, after R0 and R1 resections, respectively; P=.1). In this study, a margin width greater than 5 mm was an independent predictor of survival among patients with pN0 disease with R0 resections, which is in contrast to the findings reported by Ribero et al.73

Available evidence (although not conclusive) supports the recommendation that hepatic resection with negative margins (wedge resections and segmental resections) should be the goal of surgical therapy for patients with potentially resectable disease.76 Extensive hepatic resections are often necessary to achieve clear margins, because most tumors present as large masses.73 Initial surgical exploration should include assessment of multifocal liver disease, lymph node metastases, and distant metastases. A preoperative biopsy is not always necessary before definitive and potentially curative resection. Although multifocal liver tumors, lymph node metastases to the porta hepatis, and distant metastases are considered contraindications to surgery, surgical approaches can be considered in highly selected patients. Patient selection for surgery is facilitated by careful preoperative staging, which may include laparoscopy to identify patients with unresectable or disseminated metastatic disease.77,78 Staging laparoscopy has been shown to identify peritoneal metastases and liver metastases, with a yield of 36% and 67% accuracy in patients with potentially resectable intrahepatic cholangiocarcinoma.77 A portal lymphadenectomy is reasonable because it provides accurate staging information. However, very few data support the therapeutic benefit of routine lymph node dissection in patients undergoing surgery, particularly in those with no lymph node involvement.79-82 However, because lymph node metastasis is an important prognostic indicator of survival, lymphadenectomy could be considered for patients with lymph node metastases.52,73

The optimal adjuvant treatment strategy for patients with resected intrahepatic cholangiocarcinoma has not been determined and limited clinical trial data support a standard regimen for adjuvant treatment. Lymphovascular and perineural invasion, lymph node metastasis, and tumor size of 5 cm or greater have been reported as independent predictors of recurrence and reduced overall survival after resection.83-85 Because recurrence after resection is common, these tumor-specific risk factors could be considered criteria for selecting patients for adjuvant treatment in clinical trials. Patients who have undergone an R0 resection may be followed with observation alone. For patients found to have microscopic tumor margins (R1) or residual local disease (R2) after resection, it is essential for a multidisciplinary team to review the available options on a case-by-case basis. Although the optimal treatment strategy has not been determined, adjuvant treatment options include fluoropyrimidine-based or gemcitabine-based chemotherapy for patients who have undergone R0 resection. Fluoropyrimidine chemoradiation or fluoropyrimidine-based or gemcitabine-based chemotherapy are included as options for patients with microscopic tumor margins (R1) or positive regional nodes (see “Adjuvant Chemotherapy and Chemoradiation for Biliary Tract Cancers,” page 1172). Patients with residual local disease (R2) should be managed as described herein for unresectable or metastatic disease.

Primary treatment options for patients with unresectable or metastatic disease include (1) a clinical trial, (2) fluoropyrimidine-based or gemcitabine-based chemotherapy, or (3) best supportive care. In addition, fluoropyrimidine chemoradiation is included as an option for patients with unresectable disease (see “Chemotherapy and Chemoradiation for Advanced Biliary Tract Cancers,” page 1174).

Locoregional therapies such as radiofrequency ablation (RFA),86,87 transarterial chemoembolization (TACE),88-90 TACE with drug-eluting microspheres (DEB-TACE),89,91,92 and transarterial radioembolization (TARE) with yttrium-90 microspheres90,93-98 have been shown to be safe and effective in a small series of patients with unresectable intrahepatic cholangiocarcinomas. In a series of 17 patients with primary unresectable intrahepatic cholangiocarcinoma, RFA resulted in a median progression-free survival (PFS) of 32 months and OS of 38.5 months.87 The results of 2 independent prospective studies showed that the efficacy of TACE with irinotecan DEB was similar to that of gemcitabine and oxaliplatin but was superior to that of TACE with mitomycin in terms of PFS and OS for patients with unresectable intrahepatic cholangiocarcinoma.89 In another series of 24 patients with unresectable intrahepatic cholangiocarcinoma, TARE with yttrium-90 microspheres induced greater than 50% tumor necrosis and 100% tumor necrosis in 77% and 9% of patients, respectively, with a median OS of 14.9 months.93 Other series have also reported favorable response rates and a survival benefit for patients with unresectable intrahepatic cholangiocarcinoma treated with TARE with yttrium-90 microspheres.96,98 However, because of the rarity of this disease, none of these approaches has been evaluated in randomized clinical trials. Nevertheless, based on the available evidence as discussed earlier, the panel has included locoregional therapy (category 2B) as an option for patients with unresectable or metastatic disease.

Photodynamic therapy (PDT) is a relatively new ablative therapy that involves intravenous injection of a photosensitizing drug followed by selective irradiation with light of a specific wavelength to initiate localized drug activation, and has been used for palliation in patients with cholangiocarcinoma. The combination of PDT with biliary stenting was reported to improve the OS of patients with unresectable cholangiocarcinoma in 2 small randomized clinical trials.99,100

Hepatic arterial infusion chemotherapy also has been used in select centers for the treatment of patients with advanced and unresectable intrahepatic cholangiocarcinoma.101-104 However, this approach has not yet been evaluated in prospective randomized clinical trials.

Management of Extrahepatic Cholangiocarcinoma

Complete resection with negative margins is the only potentially curative treatment for patients with resectable disease. The reported 5-year survival rates after radical surgery are 20% to 42% and 16% to 52%, respectively, for patients with hilar and distal cholangiocarcinomas.105

Surgical margin status and lymph node metastases are independent predictors of survival after resection.72,106 Regional lymphadenectomy of the porta hepatis should be considered along with curative resections.107,108 Because these surgical procedures are associated with postoperative morbidity, they should be performed in patients who are medically fit for a major operation. Surgery is contraindicated in patients with distant metastatic disease to the liver, peritoneum, or distant lymph nodes beyond the porta hepatis.

The type of surgical procedure for resectable disease is based on the tumor’s anatomic location on the biliary tract. Hilar resection of the involved biliary tract and en bloc liver resection is recommended for hilar tumors. Major bile duct excision with frozen section assessment of proximal and distal bile duct margins and pancreaticoduodenectomy are recommended for mid and distal tumors, respectively. Very rare cases of small mid bile duct tumors can be resected with an isolated bile duct resection. A pancreaticoduodenectomy and a hepatic resection would be required, in rare instances, for a bile duct tumor with an extensive biliary tract involvement. Combined hepatic and pancreatic resections to clear distant nodal disease are not recommended.

In patients with hilar cholangiocarcinoma, extended hepatic resection (to encompass the biliary confluence) with caudate lobectomy is strongly encouraged, because hilar tumors, by definition, abut or invade the central portion of the liver. The recommendation for extended liver resection is supported by retrospective analyses showing a survival benefit and decreased hepatic recurrence associated with extended hepatic resections.109-113 Because this association was maintained when only patients undergoing an R0 resection were considered, it cannot be solely attributed to the increased likelihood of an R0 resection when extended liver resection was performed, although some reports suggest that extended hepatic resections result in a higher probability of R0 resection.111,114 Resection and reconstruction of the portal vein and/or hepatic artery may be necessary for complete resection, especially in patients with more advanced disease.115,116

Patient selection for surgery is facilitated by careful preoperative staging, surgical exploration, biopsy, and laparoscopy to identify patients with unresectable or distant metastatic disease. A preoperative biopsy is not necessary if the index of suspicion is high. Laparoscopy can identify most patients with unresectable hilar cholangiocarcinoma, albeit with a lower yield.117,118 Connor et al117 reported that the yield of laparoscopy alone was 24% in identifying patients with unresectable hilar tumors, which increased to 42% with an overall accuracy of 53%, with the addition of intraoperative ultrasound. In another report, Weber et al118 reported a higher yield for T2/T3 tumors (36%) than T1 tumors (9%), suggesting that staging laparoscopy may be more useful for patients who are at higher risk for occult unresectable disease.

Although not routinely used in all patients undergoing resection, the consensus of the panel is that preoperative treatments, including biliary drainage (using an endoscopic [ERCP] or percutaneous approach [PTC])119-122 and contralateral portal vein embolization,123,124 should be considered for patients with hilar cholangiocarcinoma with very low future liver remnant volumes.

Among patients with resectable disease, those who have undergone an R0 resection and have negative regional nodes or those with carcinoma in situ at margin may be followed with observation alone, receive fluoropyrimidine chemoradiation, or receive fluoropyrimidine or gemcitabine chemotherapy. However, limited clinical trial data are available to define a standard regimen, and enrollment in a clinical trial is encouraged. Patients with microscopic positive tumor margins (R1), gross residual local disease (R2), or positive regional lymph nodes after resection should be evaluated by a multidisciplinary team to review the available treatment options on a case-by-case basis. Although the optimal treatment strategy has not been established, treatment options include fluoropyrimidine chemoradiation followed by additional fluoropyrimidine or gemcitabine chemotherapy; or fluoropyrimidine-based or gemcitabine-based chemotherapy for patients with positive regional nodes. Data to support particular chemoradiation and chemotherapy regimens are limited (see “Adjuvant Chemotherapy and Chemoradiation for Biliary Tract Cancers,” opposite column).

Patients with unresectable or metastatic disease should be considered for biliary drainage using either surgical bypass (although rarely used) or an endoscopic (ERCP) or percutaneous approach (PTC), most often involving biliary stent placement.125-128 Biopsy is recommended to confirm the diagnosis before the initiation of further treatment. Primary treatment options include (1) a clinical trial, (2) fluoropyrimidine-based or gemcitabine-based chemotherapy, or (3) best supportive care. In addition, fluoropyrimidine chemoradiation is included as an option for patients with unresectable disease. Data to support particular chemoradiation and chemotherapy regimens are limited (see “Chemotherapy and Chemoradiation for Advanced Biliary Tract Cancers,” page 1174).

Liver transplantation is the only other potentially curative option for selected patients with non-disseminated locally advanced hilar cholangiocarcinomas, with the 5-year survival rates ranging from 25% to 42%.129-132 There is retrospective evidence suggesting that neoadjuvant chemoradiation followed by liver transplantation is highly effective for selected patients with hilar cholangiocarcinoma.133-135 Results from 2 studies suggest that the combination of liver transplantation and neoadjuvant and/or adjuvant chemoradiation is associated with higher RFS than a potentially curative resection.136,137 However, in one of these studies substantial differences were seen in the characteristics of patients in the 2 treatment groups.136 The panel encourages the continuation of clinical research in this area. Liver transplantation should be considered only for highly selected patients with either unresectable disease with otherwise normal biliary and hepatic function or underlying chronic liver disease precluding surgery. The panel encourages continuation of clinical research in this area.

Surveillance

No data support aggressive surveillance in patients undergoing resection of cholangiocarcinoma; determination of appropriate follow-up schedule/imaging should include a careful patient/physician discussion. It is recommended that follow-up of patients undergoing resection of cholangiocarcinoma should include consideration of imaging studies every 6 months for 2 years. Reevaluation according to the initial workup should be considered in the event of disease progression.

Adjuvant Chemotherapy and Chemoradiation for Biliary Tract Cancers

Local recurrence after surgery is a primary limitation for cure in patients with biliary tract cancers, which provides an important justification for the use of adjuvant therapy. Nevertheless, the role of adjuvant chemotherapy or chemoradiation therapy in patients with resected biliary tract cancers is poorly defined.138

Because of the low incidence of biliary tract cancers, the efficacy and safety of adjuvant chemotherapy or chemoradiation therapy has been evaluated mostly in retrospective studies that have included only a small number of patients; these studies often combined patients with gallbladder and bile duct cancers, with a few exceptions. Despite the challenges associated with accruing large numbers of patients with biliary tract cancer for randomized phase III trials, it is widely recognized that efforts should be made to conduct studies in which the individual disease entities are evaluated separately.

Retrospective studies that have combined patients with gallbladder cancer and those with cholangiocarcinomas provide conflicting evidence regarding the role of adjuvant therapy.4,139 A retrospective analysis of 177 patients with either resected gallbladder cancer or hilar cholangiocarcinoma concluded that based on the pattern of initial recurrence, adjuvant treatment may not have a significant effect in patients with gallbladder cancer, whereas it could be a reasonable approach for patients with hilar cholangiocarcinoma. The initial recurrence rate involving a distant site was significantly higher for patients with gallbladder cancer than for those with hilar cholangiocarcinoma (85% and 41%, respectively; P<.001).4 In a more recent retrospective review of a prospective database of 157 patients with resected gallbladder cancer (n=63) and cholangiocarcinoma (n=94), the authors reported that adjuvant therapy did not significantly prolong survival for this group of patients but identified an early resection with 1-cm tumor-free margins as the best predictor of long-term survival.139 Conversely, in a recent systematic review and meta-analysis of 6712 patients with biliary tract cancers, Horgan et al140 reported an improvement in OS (although nonsignificant) with adjuvant therapy compared with surgery alone, with no difference between patients with gallbladder cancer and bile duct cancers. Chemotherapy or chemoradiation therapy was associated with statistically greater benefit than radiotherapy alone, with the greatest benefit observed in patients with lymph node-positive disease and macroscopic residual disease (R1 resection).

In the only phase III randomized trial that evaluated adjuvant chemotherapy in patients with resected pancreaticobiliary cancer, 508 patients (139 had cholangiocarcinoma and 140 had gallbladder cancer) were randomly assigned to adjuvant chemotherapy with fluorouracil and mitomycin C or to a control arm.141 Results from the subgroup analyses showed a significantly better 5-year disease-free survival rate for patients with gallbladder cancer treated with chemotherapy (20.3% vs 11.6% in the control group; P=.02), although no significant differences between the treatment arms were observed for patients with biliary duct cancers, suggesting that patients with gallbladder cancer undergoing noncurative resection may derive survival benefit with adjuvant chemotherapy.

Among the retrospective studies that included only the patients with gallbladder cancer, 2 large analyses did not show a clear benefit for adjuvant chemotherapy alone,13,142 although in one study the number of patients who received adjuvant chemotherapy was very limited (only 24 of 123 patients who underwent curative resection received adjuvant chemotherapy or chemoradiation or both),13 and the other study, which included patients treated during 1988 to 1997, did not include chemotherapy with newer agents.142 In contrast, more-recent retrospective studies have concluded that adjuvant chemoradiation after R0 resection might improve OS in selected patients with T2 or T3 tumors and lymph node-positive gallbladder cancer.143-145 In a series of 47 patients with gallbladder cancer who underwent resection followed by adjuvant chemoradiation, the 5-year OS rate was significantly higher after R0 resection (52.8% vs 20.0%, and 0% for those with R1 and R2 resections, respectively; P=.0038).145 Adjuvant chemoradiation after R0 resection was associated with a good long-term survival rate even in patients with lymph node metastases.

Retrospective studies that included only patients with resected extrahepatic cholangiocarcinoma suggest that adjuvant chemoradiation may improve local control and survival, although distant metastases was the most common pattern of failure.146-149 In one retrospective study of 168 patients with extrahepatic cholangiocarcinoma treated with curative resection followed by adjuvant chemoradiation, the 5-year local control (58.5% vs 44.4%; P=.007), DFS (32.1% vs 26.1%; P=.041), and OS rates (36.5% vs 28.2%; P=.049) were significantly better for patients who received chemoradiation than for those who were treated with surgery alone.149 Other studies have suggested that adjuvant chemoradiation may have a significant survival benefit only in a subgroup of patients with T3 or T4 tumors or those with a high risk of locoregional recurrence (R1 resection or positive lymph nodes).148,150,151 A nonrandomized, single-center study of 120 patients with curatively resected extrahepatic cholangiocarcinoma also showed that 5-FU-based adjuvant concurrent chemoradiation followed by 5-FU-based adjuvant chemotherapy resulted in a significant survival benefit, especially in patients with R1 resection or negative lymph nodes, compared with 5-FU-based adjuvant concurrent chemoradiation alone.148 The 3-year DFS rates for concurrent chemoradiation therapy alone and concurrent chemoradiation therapy followed by adjuvant chemotherapy were 27% and 45.2% (P=.04), respectively. The corresponding OS rates were 31% and 63% (P<.01), respectively. However, these findings were not observed for patients with R0 resection or positive lymph nodes and those with T1 or T2 tumors.

Most of the collective experience of chemoradiation in biliary tract cancers involves concurrent chemoradiation and fluorouracil. More recently, concurrent chemoradiation with capecitabine has also been used.148,152 Concurrent chemoradiation with gemcitabine is not recommended because of the limited experience and toxicity associated with this treatment.153 Because of the limited data and the heterogeneity of patient populations included in many of the published studies, in most cases the recommendations in these NCCN Guidelines on the use of adjuvant chemotherapy or chemoradiation therapy are not specific to the particular type of biliary tract cancer. Specific recommendations for fluoropyrimidine-based or gemcitabine-based chemotherapy listed in these NCCN Guidelines are based on the extrapolation of data from studies of patients with advanced disease. Additionally, some of the recommendations are primarily based on practice patterns at NCCN Member Institutions and retrospective studies from single-center experiences.

Chemotherapy and Chemoradiation for Advanced Biliary Tract Cancers

The prognosis of patients with advanced biliary tract cancers is poor and the median survival for those undergoing supportive care alone is short.154 The survival benefit of chemotherapy (fluorouracil, leucovorin, and etoposide) over best supportive care for patients with advanced biliary tract cancers was initially suggested in a phase III trial of 90 patients with advanced pancreatic and biliary tract cancers, 37 of whom had advanced biliary tract cancers.155 In a recent single-center randomized study of 81 patients with unresectable gallbladder cancer, Sharma et al156 reported that modified gemcitabine and oxaliplatin (GEMOX) improved PFS and OS compared with best supportive care or fluorouracil. Median OS was 4.5, 4.6, and 9.5 months, respectively, for the best supportive care, fluorouracil, and modified GEMOX arms (P=.039). The corresponding PFS was 2.8, 3.5, and 8.5 months (P<.001).

Several phase II studies have also demonstrated the efficacy of chemotherapy in the treatment of patients with advanced biliary tract cancers.157,158 The results of a pooled analysis of 104 trials that included 2810 patients with advanced biliary tract cancers showed that response and tumor control rates were higher for the subgroup of patients receiving a combination of gemcitabine and platinum-based agents.159 In a retrospective study of 304 patients with unresectable biliary tract cancers who were treated with gemcitabine alone, a cisplatin-based regimen, or a fluoropyrimidine-based regimen, those receiving gemcitabine were shown to have a lower risk of death.160 Most importantly, the support for the use of gemcitabine-based or fluoropyrimidine-based chemotherapy for patients with advanced biliary tract cancers comes from 4 randomized studies.161-164

In a randomized phase II study of 51 patients, Kornek et al161 established the efficacy and tolerance of mitomycin in combination with gemcitabine or capecitabine in previously untreated patients with advanced biliary tract cancers. Mitomycin and capecitabine was associated with superior complete response rate (31% vs 20%), median PFS (5.3 vs 4.2 months), and OS (9.25 vs 6.7 months). The results of the 40955 EORTC trial showed that cisplatin and fluorouracil was more active than high-dose fluorouracil in terms of overall response rates (19% and 7.1%, respectively) and OS (8 and 5 months, respectively), but the PFS was similar in both treatment arms (3.3 months).162 The randomized, controlled, phase III ABC-02 study, which enrolled 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer, showed that the combination of gemcitabine and cisplatin improved OS and PFS by 30% over gemcitabine alone.163 Median OS was 11.7 versus 8.1 months, respectively (hazard ratio, 0.64; 95% CI, 0.52-0.80; P<.001), and median PFS was 8.0 versus 5.0 months, respectively (hazard ratio, 0.63; 95% CI, 0.51-0.77; P<.001), both in favor of the combination arm. Although the rate of neutropenia was higher in the group receiving gemcitabine and cisplatin, no significant difference was seen in the rate of neutropenia-associated infections between the arms. Okusaka et al164 also reported similar findings in a phase II randomized study of 84 patients with advanced biliary tract cancers. Based on these results, the combination of gemcitabine and cisplatin is considered to be the standard of care for first-line chemotherapy for patients with advanced or metastatic biliary tract cancers. Examples of other gemcitabine-based or fluoropyrimidine-based (fluorouracil or capecitabine) regimens with demonstrated activity in phase II trials include gemcitabine and cisplatin or oxaliplatin165-173; gemcitabine and fluoropyrimidine174-179; and fluoropyrimidine and oxaliplatin or cisplatin.180-183 Triple-drug chemotherapy regimens also have been shown to be effective in patients with advanced biliary tract cancers, albeit in a very small number of patients.184-186 The phase III trial that evaluated fluorouracil, leucovorin, and etoposide versus fluorouracil, cisplatin, and epirubicin did not show one regimen to be significantly superior with respect to OS (12 vs 9 months, respectively) in patients with advanced biliary tract cancers, although the trial was underpowered to detect such a difference.184 In a phase II trial, the combination of gemcitabine and irinotecan with panitumumab (a monoclonal anti-epidermal growth factor receptor antibody) showed encouraging efficacy with good tolerability in patients with advanced cholangiocarcinoma, with a 5-month PFS rate of 69%.187 The median PFS and OS were 9.7 and 12.9 months, respectively.

The panel has included combination therapy with gemcitabine and cisplatin with a category 1 recommendation for patients with unresectable or metastatic biliary tract cancers. Based on the experiences from phase II studies, the following gemcitabine-based and fluoropyrimidine-based combination chemotherapy regimens are included with a category 2A recommendation for the treatment of patients with advanced biliary tract cancer: gemcitabine with oxaliplatin or capecitabine; capecitabine with cisplatin or oxaliplatin; fluorouracil with cisplatin or oxaliplatin; and single-agent fluorouracil, capecitabine, and gemcitabine. The combination of gemcitabine and fluorouracil is not included because of the increased toxicity and decreased efficacy observed with this regimen when compared with results of studies of the gemcitabine and capecitabine regimen in the setting of advanced biliary tract cancer.174

Chemoradiation in the setting of advanced biliary tract cancers can provide control of symptoms caused by local tumor effects and may prolong OS. However, limited clinical trial data are available define a standard regimen or definitive benefit. In a retrospective analysis of 37 patients treated with chemoradiation for unresectable extrahepatic cholangiocarcinoma, the actuarial OS rates at 1 and 2 years were 59% and 22%, respectively, although effective local control was observed in most patients during this period (actuarial local control rates of 90% and 71% at 1 and 2 years, respectively).188 Fluorouracil is the most extensively investigated chemotherapeutic agent for use in concurrent chemoradiation in the treatment of biliary tract cancers,189,190 although capecitabine has been substituted for fluorouracil in some studies.152 The panel recommends that concurrent chemoradiation should be limited to either fluorouracil or capecitabine, and that this treatment should be restricted to patients without evidence of metastatic disease. Concurrent chemoradiation with gemcitabine is not recommended because of the limited experience and toxicity associated with this treatment.

Summary

Hepatobiliary cancers are associated with a poor prognosis, and patients with biliary tract cancers commonly present with advanced disease. In the past few years, several advances have been made in the therapeutic approaches for patients with hepatobiliary cancers. Careful patient selection for treatment and active multidisciplinary cooperation are essential. There are very few high-quality randomized clinical trials of patients with hepatobiliary cancers, and patient participation in prospective clinical trials is the preferred option for the treatment of patients with all stages of disease.

Individual Disclosure for the NCCN Hepatobiliary Cancers Panel

T1

References

  • 1.

    SiegelRMaJZouZJemalA. Cancer statistics, 2014. CA Cancer J Clin2014;64:929.

  • 2.

    DonohueJHStewartAKMenckHR. The National Cancer Data Base report on carcinoma of the gallbladder, 1989-1995. Cancer1998;83:26182628.

  • 3.

    LevyADMurakataLARohrmannCAJr. Gallbladder carcinoma: radiologic-pathologic correlation. Radiographics2001;21:295314; questionnaire 549-255.

    • Search Google Scholar
    • Export Citation
  • 4.

    JarnaginWRRuoLLittleSA. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer2003;98:16891700.

    • Search Google Scholar
    • Export Citation
  • 5.

    ShethSBedfordAChopraS. Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol2000;95:14021410.

    • Search Google Scholar
    • Export Citation
  • 6.

    TazumaSKajiyamaG. Carcinogenesis of malignant lesions of the gall bladder. The impact of chronic inflammation and gallstones. Langenbecks Arch Surg2001;386:224229.

    • Search Google Scholar
    • Export Citation
  • 7.

    KhanZSLivingstonEHHuertaS. Reassessing the need for prophylactic surgery in patients with porcelain gallbladder: case series and systematic review of the literature. Arch Surg2011;146:11431147.

    • Search Google Scholar
    • Export Citation
  • 8.

    SchnelldorferT. Porcelain gallbladder: a benign process or concern for malignancy?J Gastrointest Surg2013;17:11611168.

  • 9.

    ElnemrAOhtaTKayaharaM. Anomalous pancreaticobiliary ductal junction without bile duct dilatation in gallbladder cancer. Hepatogastroenterology2001;48:382386.

    • Search Google Scholar
    • Export Citation
  • 10.

    ReidKMRamos-De la MedinaADonohueJH. Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg2007;11:671681.

    • Search Google Scholar
    • Export Citation
  • 11.

    EdgeSBByrdDRComptonCC. AJCC Cancer Staging Manual. 7th ed.New York, NY: Springer; 2010.

  • 12.

    FongYWagmanLGonenM. Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database. Ann Surg2006;243:767771; discussion 771-764.

    • Search Google Scholar
    • Export Citation
  • 13.

    DuffyACapanuMAbou-AlfaGK. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol2008;98:485489.

    • Search Google Scholar
    • Export Citation
  • 14.

    ItoHItoKD’AngelicaM. Accurate staging for gallbladder cancer: implications for surgical therapy and pathological assessment. Ann Surg2011;254:320325.

    • Search Google Scholar
    • Export Citation
  • 15.

    HawkinsWGDeMatteoRPJarnaginWR. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol2004;11:310315.

    • Search Google Scholar
    • Export Citation
  • 16.

    FurlanAFerrisJVHosseinzadehKBorhaniAA. Gallbladder carcinoma update: multimodality imaging evaluation, staging, and treatment options. AJR Am J Roentgenol2008;191:14401447.

    • Search Google Scholar
    • Export Citation
  • 17.

    PetrowskyHWildbrettPHusarikDB. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol2006;45:4350.

    • Search Google Scholar
    • Export Citation
  • 18.

    CorveraCUBlumgartLHAkhurstT. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg2008;206:5765.

    • Search Google Scholar
    • Export Citation
  • 19.

    LeeSWKimHJParkJH. Clinical usefulness of 18F-FDG PET-CT for patients with gallbladder cancer and cholangiocarcinoma. J Gastroenterol2010;45:560566.

    • Search Google Scholar
    • Export Citation
  • 20.

    StromBLMaislinGWestSL. Serum CEA and CA 19-9: potential future diagnostic or screening tests for gallbladder cancer?Int J Cancer1990;45:821824.

    • Search Google Scholar
    • Export Citation
  • 21.

    DixonEVollmerCMJrSahajpalA. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg2005;241:385394.

    • Search Google Scholar
    • Export Citation
  • 22.

    FuksDRegimbeauJMLe TreutYP. Incidental gallbladder cancer by the AFC-GBC-2009 Study Group. World J Surg2011;35:18871897.

  • 23.

    LeeSEJangJYLimCS. Systematic review on the surgical treatment for T1 gallbladder cancer. World J Gastroenterol2011;17:174180.

  • 24.

    FosterJMHoshiHGibbsJF. Gallbladder cancer: Defining the indications for primary radical resection and radical re-resection. Ann Surg Oncol2007;14:833840.

    • Search Google Scholar
    • Export Citation
  • 25.

    CoburnNGClearySPTanJCLawCH. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg2008;207:371382.

  • 26.

    YouDDLeeHGPaikKY. What is an adequate extent of resection for T1 gallbladder cancers?Ann Surg2008;247:835838.

  • 27.

    JensenEHAbrahamAHabermannEB. A critical analysis of the surgical management of early-stage gallbladder cancer in the United States. J Gastrointest Surg2009;13:722727.

    • Search Google Scholar
    • Export Citation
  • 28.

    DowningSRCadoganKAOrtegaG. Early-stage gallbladder cancer in the surveillance, epidemiology, and end results database: effect of extended surgical resection. Arch Surg2011;146:734738.

    • Search Google Scholar
    • Export Citation
  • 29.

    ShiraiYSakataJWakaiT. “Extended” radical cholecystectomy for gallbladder cancer: long-term outcomes, indications and limitations. World J Gastroenterol2012;18:47364743.

    • Search Google Scholar
    • Export Citation
  • 30.

    D’AngelicaMDalalKMDeMatteoRP. Analysis of the extent of resection for adenocarcinoma of the gallbladder. Ann Surg Oncol2009;16:806816.

    • Search Google Scholar
    • Export Citation
  • 31.

    PawlikTMGleisnerALViganoL. Incidence of finding residual disease for incidental gallbladder carcinoma: implications for re-resection. J Gastrointest Surg2007;11:14781486; discussion 1486-1477.

    • Search Google Scholar
    • Export Citation
  • 32.

    FongYJarnaginWBlumgartLH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg2000;232:557569.

    • Search Google Scholar
    • Export Citation
  • 33.

    ShihSPSchulickRDCameronJL. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg2007;245:893901.

  • 34.

    AgarwalAKKalayarasanRJavedA. Role of staging laparoscopy in primary gall bladder cancer—an analysis of 409 patients: a prospective study to evaluate the role of staging laparoscopy in the management of gallbladder cancer. Ann Surg2013;258:318323.

    • Search Google Scholar
    • Export Citation
  • 35.

    ButteJMGonenMAllenPJ. The role of laparoscopic staging in patients with incidental gallbladder cancer. HPB (Oxford)2011;13:463472.

  • 36.

    MakerAVButteJMOxenbergJ. Is port site resection necessary in the surgical management of gallbladder cancer?Ann Surg Oncol2012;19:409417.

    • Search Google Scholar
    • Export Citation
  • 37.

    FuksDRegimbeauJMPessauxP. Is port-site resection necessary in the surgical management of gallbladder cancer?J Visc Surg2013;150:277284.

    • Search Google Scholar
    • Export Citation
  • 38.

    RegimbeauJMFuksDBachellierP. Prognostic value of jaundice in patients with gallbladder cancer by the AFC-GBC-2009 study group. Eur J Surg Oncol2011;37:505512.

    • Search Google Scholar
    • Export Citation
  • 39.

    WangSJFullerCDKimJS. Prediction model for estimating the survival benefit of adjuvant radiotherapy for gallbladder cancer. J Clin Oncol2008;26:21122117.

    • Search Google Scholar
    • Export Citation
  • 40.

    WangSJLemieuxAKalpathy-CramerJ. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol2011;29:46274632.

    • Search Google Scholar
    • Export Citation
  • 41.

    LimJH. Cholangiocarcinoma: morphologic classification according to growth pattern and imaging findings. AJR Am J Roentgenol2003;181:819827.

    • Search Google Scholar
    • Export Citation
  • 42.

    DeOliveiraMLCunninghamSCCameronJL. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg2007;245:755762.

    • Search Google Scholar
    • Export Citation
  • 43.

    ChapmanRW. Risk factors for biliary tract carcinogenesis. Ann Oncol1999;10(Suppl 4):308311.

  • 44.

    TysonGLEl-SeragHB. Risk factors for cholangiocarcinoma. Hepatology2011;54:173184.

  • 45.

    DonatoFGelattiUTaggerA. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control2001;12:959964.

    • Search Google Scholar
    • Export Citation
  • 46.

    YamamotoSKuboSHaiS. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci2004;95:592595.

  • 47.

    ShaibYHEl-SeragHBDavilaJA. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology2005;128:620626.

    • Search Google Scholar
    • Export Citation
  • 48.

    WelzelTMMellemkjaerLGloriaG. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer2007;120:638641.

    • Search Google Scholar
    • Export Citation
  • 49.

    ChangKYChangJYYenY. Increasing incidence of intrahepatic cholangiocarcinoma and its relationship to chronic viral hepatitis. J Natl Compr Canc Netw2009;7:423427.

    • Search Google Scholar
    • Export Citation
  • 50.

    EndoIGonenMYoppAC. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg2008;248:8496.

    • Search Google Scholar
    • Export Citation
  • 51.

    NathanHAloiaTAVautheyJN. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol2009;16:1422.

  • 52.

    de JongMCNathanHSotiropoulosGC. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol2011;29:31403145.

    • Search Google Scholar
    • Export Citation
  • 53.

    FargesOFuksDLe TreutYP. AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma. Cancer2011;117:21702177.

    • Search Google Scholar
    • Export Citation
  • 54.

    de JongMCHongSMAugustineMM. Hilar cholangiocarcinoma: tumor depth as a predictor of outcome. Arch Surg2011;146:697703.

  • 55.

    HongSMPawlikTMChoH. Depth of tumor invasion better predicts prognosis than the current American Joint Committee on Cancer T classification for distal bile duct carcinoma. Surgery2009;146:250257.

    • Search Google Scholar
    • Export Citation
  • 56.

    BismuthHNakacheRDiamondT. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg1992;215:3138.

  • 57.

    JarnaginWRFongYDeMatteoRP. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg2001;234:507517; discussion 517-509.

    • Search Google Scholar
    • Export Citation
  • 58.

    MatsuoKRochaFGItoK. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am Coll Surg2012;215:343355.

    • Search Google Scholar
    • Export Citation
  • 59.

    MillerGSchwartzLHD’AngelicaM. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am2007;16:343368.

    • Search Google Scholar
    • Export Citation
  • 60.

    AljiffryMWalshMJMolinariM. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990-2009. World J Gastroenterol2009;15:42404262.

    • Search Google Scholar
    • Export Citation
  • 61.

    SainaniNICatalanoOAHolalkereNS. Cholangiocarcinoma: current and novel imaging techniques. Radiographics2008;28:12631287.

  • 62.

    HalefogluAM. Magnetic resonance cholangiopancreatography: a useful tool in the evaluation of pancreatic and biliary disorders. World J Gastroenterol2007;13:25292534.

    • Search Google Scholar
    • Export Citation
  • 63.

    HekimogluKUstundagYDusakA. MRCP vs. ERCP in the evaluation of biliary pathologies: review of current literature. J Dig Dis2008;9:162169.

    • Search Google Scholar
    • Export Citation
  • 64.

    VoglTJSchwarzWOHellerM. Staging of Klatskin tumours (hilar cholangiocarcinomas): comparison of MR cholangiography, MR imaging, and endoscopic retrograde cholangiography. Eur Radiol2006;16:23172325.

    • Search Google Scholar
    • Export Citation
  • 65.

    HyodoTKumanoSKushihataF. CT and MR cholangiography: advantages and pitfalls in perioperative evaluation of biliary tree. Br J Radiol2012;85:887896.

    • Search Google Scholar
    • Export Citation
  • 66.

    KimJYKimMHLeeTY. Clinical role of 18F-FDG PET-CT in suspected and potentially operable cholangiocarcinoma: a prospective study compared with conventional imaging. Am J Gastroenterol2008;103:11451151.

    • Search Google Scholar
    • Export Citation
  • 67.

    RuysATBenninkRJvan WestreenenHL. FDG-positron emission tomography/computed tomography and standardized uptake value in the primary diagnosis and staging of hilar cholangiocarcinoma. HPB (Oxford)2011;13:256262.

    • Search Google Scholar
    • Export Citation
  • 68.

    NakagohriTAsanoTKinoshitaH. Aggressive surgical resection for hilar-invasive and peripheral intrahepatic cholangiocarcinoma. World J Surg2003;27:289293.

    • Search Google Scholar
    • Export Citation
  • 69.

    KonstadoulakisMMRoayaieSGomatosIP. Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery2008;143:366374.

    • Search Google Scholar
    • Export Citation
  • 70.

    PaikKYJungJCHeoJS. What prognostic factors are important for resected intrahepatic cholangiocarcinoma?J Gastroenterol Hepatol2008;23:766770.

    • Search Google Scholar
    • Export Citation
  • 71.

    LangHSotiropoulosGCSgourakisG. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg2009;208:218228.

    • Search Google Scholar
    • Export Citation
  • 72.

    MurakamiYUemuraKSudoT. Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol2011;18:651658.

    • Search Google Scholar
    • Export Citation
  • 73.

    RiberoDPinnaADGuglielmiA. Surgical Approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients. Arch Surg2012;147:11071113.

    • Search Google Scholar
    • Export Citation
  • 74.

    TamandlDHerbergerBGruenbergerB. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol2008;15:27872794.

    • Search Google Scholar
    • Export Citation
  • 75.

    FargesOFuksDBoleslawskiE. Influence of surgical margins on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter study by the AFC-IHCC-2009 study group. Ann Surg2011;254:824829; discussion 830.

    • Search Google Scholar
    • Export Citation
  • 76.

    CarpizoDRD’AngelicaM. Management and extent of resection for intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am2009;18:289305viii-ix.

    • Search Google Scholar
    • Export Citation
  • 77.

    GoereDWagholikarGDPessauxP. Utility of staging laparoscopy in subsets of biliary cancers: laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc2006;20:721725.

    • Search Google Scholar
    • Export Citation
  • 78.

    JosephSConnorSGardenOJ. Staging laparoscopy for cholangiocarcinoma. HPB (Oxford)2008;10:116119.

  • 79.

    ShimadaMYamashitaYAishimaS. Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma. Br J Surg2001;88:14631466.

    • Search Google Scholar
    • Export Citation
  • 80.

    ChoiSBKimKSChoiJY. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol2009;16:30483056.

    • Search Google Scholar
    • Export Citation
  • 81.

    ClarkCJWood-WentzCMReid-LombardoKM. Lymphadenectomy in the staging and treatment of intrahepatic cholangiocarcinoma: a population-based study using the National Cancer Institute SEER database. HPB (Oxford)2011;13:612620.

    • Search Google Scholar
    • Export Citation
  • 82.

    MorineYShimadaMUtsunomiyaT. Clinical impact of lymph node dissection in surgery for peripheral-type intrahepatic cholangiocarcinoma. Surg Today2012;42:147151.

    • Search Google Scholar
    • Export Citation
  • 83.

    FisherSBPatelSHKoobyDA. Lymphovascular and perineural invasion as selection criteria for adjuvant therapy in intrahepatic cholangiocarcinoma: a multi-institution analysis. HPB (Oxford)2012;14:514522.

    • Search Google Scholar
    • Export Citation
  • 84.

    HyderOHatzarasISotiropoulosGC. Recurrence after operative management of intrahepatic cholangiocarcinoma. Surgery2013;153:811818.

  • 85.

    RiberoDRossoSPinnaAD. Postoperative nomogram for predicting survival after resection for intrahepatic cholangiocarcinoma [abstract]. J Clin Oncol2013;31(Suppl):Abstract 4129.

    • Search Google Scholar
    • Export Citation
  • 86.

    CarrafielloGLaganaDCottaE. Radiofrequency ablation of intrahepatic cholangiocarcinoma: preliminary experience. Cardiovasc Intervent Radiol2010;33:835839.

    • Search Google Scholar
    • Export Citation
  • 87.

    KimJHWonHJShinYM. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Roentgenol2011;196:W205209.

    • Search Google Scholar
    • Export Citation
  • 88.

    KieferMVAlbertMMcNallyM. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer2011;117:14981505.

    • Search Google Scholar
    • Export Citation
  • 89.

    KuhlmannJBEuringerWSpangenbergHC. Treatment of unresectable cholangiocarcinoma: conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy. Eur J Gastroenterol Hepatol2012;24:437443.

    • Search Google Scholar
    • Export Citation
  • 90.

    HyderOMarshJWSalemR. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol2013;20:37793786.

    • Search Google Scholar
    • Export Citation
  • 91.

    PoggiGQuarettiPMinoiaC. Transhepatic arterial chemoembolization with oxaliplatin-eluting microspheres (OEM-TACE) for unresectable hepatic tumors. Anticancer Res2008;28:38353842.

    • Search Google Scholar
    • Export Citation
  • 92.

    SchiffmanSCMetzgerTDubelG. Precision hepatic arterial irinotecan therapy in the treatment of unresectable intrahepatic cholangiocellular carcinoma: optimal tolerance and prolonged overall survival. Ann Surg Oncol2011;18:431438.

    • Search Google Scholar
    • Export Citation
  • 93.

    IbrahimSMMulcahyMFLewandowskiRJ. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer2008;113:21192128.

    • Search Google Scholar
    • Export Citation
  • 94.

    SaxenaABesterLChuaTC. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol2010;17:484491.

    • Search Google Scholar
    • Export Citation
  • 95.

    WijlemansJWVan ErpecumKJLamMG. Trans-arterial (90)yttrium radioembolization for patients with unresectable tumors originating from the biliary tree. Ann Hepatol2011;10:349354.

    • Search Google Scholar
    • Export Citation
  • 96.

    HoffmannRTPaprottkaPMSchonA. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol2012;35:105116.

    • Search Google Scholar
    • Export Citation
  • 97.

    RafiSPiduruSMEl-RayesB. Yttrium-90 radioembolization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety study. Cardiovasc Intervent Radiol2013;36:440448.

    • Search Google Scholar
    • Export Citation
  • 98.

    MouliSMemonKBakerT. Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis. J Vasc Interv Radiol2013;24:12271234.

    • Search Google Scholar
    • Export Citation
  • 99.

    OrtnerMECacaKBerrF. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology2003;125:13551363.

    • Search Google Scholar
    • Export Citation
  • 100.

    ZoepfTJakobsRArnoldJC. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol2005;100:24262430.

    • Search Google Scholar
    • Export Citation
  • 101.

    MambriniAGuglielmiAPacettiP. Capecitabine plus hepatic intra-arterial epirubicin and cisplatin in unresectable biliary cancer: a phase II study. Anticancer Res2007;27:30093013.

    • Search Google Scholar
    • Export Citation
  • 102.

    ShitaraKIkamiIMunakataM. Hepatic arterial infusion of mitomycin C with degradable starch microspheres for unresectable intrahepatic cholangiocarcinoma. Clin Oncol (R Coll Radiol)2008;20:241246.

    • Search Google Scholar
    • Export Citation
  • 103.

    InabaYAraiYYamauraH. Phase I/II study of hepatic arterial infusion chemotherapy with gemcitabine in patients with unresectable intrahepatic cholangiocarcinoma (JIVROSG-0301). Am J Clin Oncol2011;34:5862.

    • Search Google Scholar
    • Export Citation
  • 104.

    KemenyNESchwartzLGonenM. Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: does the addition of systemic bevacizumab improve results?Oncology2011;80:153159.

    • Search Google Scholar
    • Export Citation
  • 105.

    AkamatsuNSugawaraYHashimotoD. Surgical strategy for bile duct cancer: advances and current limitations. World J Clin Oncol2011;2:94107.

    • Search Google Scholar
    • Export Citation
  • 106.

    QiaoQLZhangTPGuoJC. Prognostic factors after pancreatoduodenectomy for distal bile duct cancer. Am Surg2011;77:14451448.

  • 107.

    SchwarzRESmithDD. Lymph node dissection impact on staging and survival of extrahepatic cholangiocarcinomas, based on U.S. population data. J Gastrointest Surg2007;11:158165.

    • Search Google Scholar
    • Export Citation
  • 108.

    ItoKItoHAllenPJ. Adequate lymph node assessment for extrahepatic bile duct adenocarcinoma. Ann Surg2010;251:675681.

  • 109.

    NishioHNaginoMNimuraY. Surgical management of hilar cholangiocarcinoma: the Nagoya experience. HPB (Oxford)2005;7:259262.

  • 110.

    ItoFAgniRRettammelRJ. Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence. Ann Surg2008;248:273279.

    • Search Google Scholar
    • Export Citation
  • 111.

    van GulikTMKloekJJRuysAT. Multidisciplinary management of hilar cholangiocarcinoma (Klatskin tumor): extended resection is associated with improved survival. Eur J Surg Oncol2011;37:6571.

    • Search Google Scholar
    • Export Citation
  • 112.

    ChengQBYiBWangJH. Resection with total caudate lobectomy confers survival benefit in hilar cholangiocarcinoma of Bismuth type III and IV. Eur J Surg Oncol2012;38:11971203.

    • Search Google Scholar
    • Export Citation
  • 113.

    ChoMSKimSHParkSW. Surgical outcomes and predicting factors of curative resection in patients with hilar cholangiocarcinoma: 10-year single-institution experience. J Gastrointest Surg2012;16:16721679.

    • Search Google Scholar
    • Export Citation
  • 114.

    LeeSGSongGWHwangS. Surgical treatment of hilar cholangiocarcinoma in the new era: the Asan experience. J Hepatobiliary Pancreat Sci2010;17:476489.

    • Search Google Scholar
    • Export Citation
  • 115.

    de JongMCMarquesHClaryBM. The impact of portal vein resection on outcomes for hilar cholangiocarcinoma: a multi-institutional analysis of 305 cases. Cancer2012;118:47374747.

    • Search Google Scholar
    • Export Citation
  • 116.

    WuXSDongPGuJ. Combined portal vein resection for hilar cholangiocarcinoma: a meta-analysis of comparative studies. J Gastrointest Surg2013;17:11071115.

    • Search Google Scholar
    • Export Citation
  • 117.

    ConnorSBarronEWigmoreSJ. The utility of laparoscopic assessment in the preoperative staging of suspected hilar cholangiocarcinoma. J Gastrointest Surg2005;9:476480.

    • Search Google Scholar
    • Export Citation
  • 118.

    WeberSMDeMatteoRPFongY. Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg2002;235:392399.

    • Search Google Scholar
    • Export Citation
  • 119.

    NimuraY. Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB (Oxford)2008;10:130133.

  • 120.

    KennedyTJYoppAQinY. Role of preoperative biliary drainage of liver remnant prior to extended liver resection for hilar cholangiocarcinoma. HPB (Oxford)2009;11:445451.

    • Search Google Scholar
    • Export Citation
  • 121.

    LiuFLiYWeiYLiB. Preoperative biliary drainage before resection for hilar cholangiocarcinoma: whether or not? A systematic review. Dig Dis Sci2011;56:663672.

    • Search Google Scholar
    • Export Citation
  • 122.

    FargesORegimbeauJMFuksD. Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg2013;100:274283.

    • Search Google Scholar
    • Export Citation
  • 123.

    AbulkhirALimongelliPHealeyAJ. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg2008;247:4957.

    • Search Google Scholar
    • Export Citation
  • 124.

    ShindohJVautheyJNZimmittiG. Analysis of the efficacy of portal vein embolization for patients with extensive liver malignancy and very low future liver remnant volume, including a comparison with the associating liver partition with portal vein ligation for staged hepatectomy approach. J Am Coll Surg2013;217:126133.

    • Search Google Scholar
    • Export Citation
  • 125.

    DavidsPHGroenAKRauwsEA. Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet1992;340:14881492.

    • Search Google Scholar
    • Export Citation
  • 126.

    PratFChapatODucotB. A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct. Gastrointest Endosc1998;47:17.

    • Search Google Scholar
    • Export Citation
  • 127.

    AbrahamNSBarkunJSBarkunAN. Palliation of malignant biliary obstruction: a prospective trial examining impact on quality of life. Gastrointest Endosc2002;56:835841.

    • Search Google Scholar
    • Export Citation
  • 128.

    PaikWHParkYSHwangJH. Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach. Gastrointest Endosc2009;69:5562.

    • Search Google Scholar
    • Export Citation
  • 129.

    RoblesRFiguerasJTurrionVS. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg2004;239:265271.

    • Search Google Scholar
    • Export Citation
  • 130.

    BeckerNSRodriguezJABarshesNR. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg2008;12:117122.

    • Search Google Scholar
    • Export Citation
  • 131.

    KaiserGMSotiropoulosGCJauchKW. Liver transplantation for hilar cholangiocarcinoma: a German survey. Transplant Proc2008;40:31913193.

    • Search Google Scholar
    • Export Citation
  • 132.

    FrimanSFossAIsoniemiH. Liver transplantation for cholangiocarcinoma: selection is essential for acceptable results. Scand J Gastroenterol2011;46:370375.

    • Search Google Scholar
    • Export Citation
  • 133.

    Darwish MuradSKimWRHarnoisDM. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology2012;143:8898.

    • Search Google Scholar
    • Export Citation
  • 134.

    PanjalaCNguyenJHAl-HajjajAN. Impact of neoadjuvant chemoradiation on the tumor burden before liver transplantation for unresectable cholangiocarcinoma. Liver Transpl2012;18:594601.

    • Search Google Scholar
    • Export Citation
  • 135.

    DuignanSMaguireDRavichandCS. Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinoma: a single-centre national experience. HPB (Oxford)2014;16:9198.

    • Search Google Scholar
    • Export Citation
  • 136.

    ReaDJHeimbachJKRosenCB. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg2005;242:451458.

    • Search Google Scholar
    • Export Citation
  • 137.

    HongJCJonesCMDuffyJP. Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center. Arch Surg2011;146:683689.

    • Search Google Scholar
    • Export Citation
  • 138.

    CeredaSBelliCReniM. Adjuvant treatment in biliary tract cancer: to treat or not to treat?World J Gastroenterol2012;18:25912596.

  • 139.

    GlazerESLiuPAbdallaEK. Neither neoadjuvant nor adjuvant therapy increases survival after biliary tract cancer resection with wide negative margins. J Gastrointest Surg2012;16:16661671.

    • Search Google Scholar
    • Export Citation
  • 140.

    HorganAMAmirEWalterTKnoxJJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol2012;30:19341940.

    • Search Google Scholar
    • Export Citation
  • 141.

    TakadaTAmanoHYasudaH. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer2002;95:16851695.

    • Search Google Scholar
    • Export Citation
  • 142.

    KayaharaMNagakawaT. Recent trends of gallbladder cancer in Japan: an analysis of 4,770 patients. Cancer2007;110:572580.

  • 143.

    GoldDGMillerRCHaddockMG. Adjuvant therapy for gallbladder carcinoma: the Mayo Clinic Experience. Int J Radiat Oncol Biol Phys2009;75:150155.

    • Search Google Scholar
    • Export Citation
  • 144.

    ChoSYKimSHParkSJ. Adjuvant chemoradiation therapy in gallbladder cancer. J Surg Oncol2010;102:8793.

  • 145.

    KimKChieEKJangJY. Postoperative chemoradiotherapy for gallbladder cancer. Strahlenther Onkol2012;188:388392.

  • 146.

    HughesMAFrassicaDAYeoCJ. Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct. Int J Radiat Oncol Biol Phys2007;68:178182.

    • Search Google Scholar
    • Export Citation
  • 147.

    NelsonJWGhafooriAPWillettCG. Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys2009;73:148153.

    • Search Google Scholar
    • Export Citation
  • 148.

    LimKHOhDYChieEK. Adjuvant concurrent chemoradiation therapy (CCRT) alone versus CCRT followed by adjuvant chemotherapy: which is better in patients with radically resected extrahepatic biliary tract cancer?: a non-randomized, single center study. BMC Cancer2009;9:345.

    • Search Google Scholar
    • Export Citation
  • 149.

    KimTHHanSSParkSJ. Role of adjuvant chemoradiotherapy for resected extrahepatic biliary tract cancer. Int J Radiat Oncol Biol Phys2011;81:e853859.

    • Search Google Scholar
    • Export Citation
  • 150.

    BorgheroYCraneCHSzklarukJ. Extrahepatic bile duct adenocarcinoma: patients at high-risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard-risk treated with surgery alone. Ann Surg Oncol2008;15:31473156.

    • Search Google Scholar
    • Export Citation
  • 151.

    ParkJHChoiEKAhnSD. Postoperative chemoradiotherapy for extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys2011;79:696704.

  • 152.

    DasPWolffRAAbbruzzeseJL. Concurrent capecitabine and upper abdominal radiation therapy is well tolerated. Radiat Oncol2006;1:4141.

  • 153.

    LinLLPicusJDrebinJA. A phase II study of alternating cycles of split course radiation therapy and gemcitabine chemotherapy for inoperable pancreatic or biliary tract carcinoma. Am J Clin Oncol2005;28:234241.

    • Search Google Scholar
    • Export Citation
  • 154.

    ParkJKimMHKimKP. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study. Gut Liver2009;3:298305.

    • Search Google Scholar
    • Export Citation
  • 155.

    GlimeliusBHoffmanKSjodenPO. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol1996;7:593600.

    • Search Google Scholar
    • Export Citation
  • 156.

    SharmaADwaryADMohantiBK. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol2010;28:45814586.

    • Search Google Scholar
    • Export Citation
  • 157.

    HezelAFZhuAX. Systemic therapy for biliary tract cancers. Oncologist2008;13:415423.

  • 158.

    GeynismanDMCatenacciDV. Toward personalized treatment of advanced biliary tract cancers. Discov Med2012;14:4157.

  • 159.

    EckelFSchmidRM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer2007;96:896902.

  • 160.

    YonemotoNFuruseJOkusakaT. A multi-center retrospective analysis of survival benefits of chemotherapy for unresectable biliary tract cancer. Jpn J Clin Oncol2007;37:843851.

    • Search Google Scholar
    • Export Citation
  • 161.

    KornekGVSchuellBLaengleF. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol2004;15:478483.

    • Search Google Scholar
    • Export Citation
  • 162.

    DucreuxMVan CutsemEVan LaethemJL. A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial. Eur J Cancer2005;41:398403.

    • Search Google Scholar
    • Export Citation
  • 163.

    ValleJWasanHPalmerDH. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med2010;362:12731281.

  • 164.

    OkusakaTNakachiKFukutomiA. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer2010;103:469474.

    • Search Google Scholar
    • Export Citation
  • 165.

    DovalDCSekhonJSGuptaSK. A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer2004;90:15161520.

    • Search Google Scholar
    • Export Citation
  • 166.

    ThongprasertSNapapanSCharoentumCMoonprakanS. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol2005;16:279281.

    • Search Google Scholar
    • Export Citation
  • 167.

    GiulianiFGebbiaVMaielloE. Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM). Ann Oncol2006;17Suppl 7:7377.

    • Search Google Scholar
    • Export Citation
  • 168.

    LeeJKimTYLeeMA. Phase II trial of gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas. Cancer Chemother Pharmacol2008;61:4752.

    • Search Google Scholar
    • Export Citation
  • 169.

    MeyerhardtJAZhuAXStuartK. Phase-II study of gemcitabine and cisplatin in patients with metastatic biliary and gallbladder cancer. Dig Dis Sci2008;53:564570.

    • Search Google Scholar
    • Export Citation
  • 170.

    AndreTReyes-VidalJMFartouxL. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J Cancer2008;99:862867.

    • Search Google Scholar
    • Export Citation
  • 171.

    HarderJRieckenBKummerO. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer2006;95:848852.

    • Search Google Scholar
    • Export Citation
  • 172.

    KimHJLeeNSLeeSC. A phase II study of gemcitabine in combination with oxaliplatin as first-line chemotherapy in patients with inoperable biliary tract cancer. Cancer Chemother Pharmacol2009;64:371377.

    • Search Google Scholar
    • Export Citation
  • 173.

    JangJSLimHYHwangIG. Gemcitabine and oxaliplatin in patients with unresectable biliary cancer including gall bladder cancer: a Korean Cancer Study Group phase II trial. Cancer Chemother Pharmacol2010;65:641647.

    • Search Google Scholar
    • Export Citation
  • 174.

    AlbertsSRAl-KhatibHMahoneyMR. Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Cancer2005;103:111118.

    • Search Google Scholar
    • Export Citation
  • 175.

    ChoJYPaikYHChangYS. Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. Cancer2005;104:27532758.

    • Search Google Scholar
    • Export Citation
  • 176.

    KnoxJJHedleyDOzaA. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol2005;23:23322338.

    • Search Google Scholar
    • Export Citation
  • 177.

    RiechelmannRPTownsleyCAChinSN. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer2007;110:13071312.

    • Search Google Scholar
    • Export Citation
  • 178.

    KoeberleDSalettiPBornerM. Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol2008;26:37023708.

    • Search Google Scholar
    • Export Citation
  • 179.

    IqbalSRankinCLenzHJ. A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: Southwest Oncology Group study S0202. Cancer Chemother Pharmacol2011;68:15951602.

    • Search Google Scholar
    • Export Citation
  • 180.

    NehlsOKlumpBArkenauHT. Oxaliplatin, fluorouracil and leucovorin for advanced biliary system adenocarcinomas: a prospective phase II trial. Br J Cancer2002;87:702704.

    • Search Google Scholar
    • Export Citation
  • 181.

    NehlsOOettleHHartmannJT. Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer2008;98:309315.

    • Search Google Scholar
    • Export Citation
  • 182.

    KimTWChangHMKangHJ. Phase II study of capecitabine plus cisplatin as first-line chemotherapy in advanced biliary cancer. Ann Oncol2003;14:11151120.

    • Search Google Scholar
    • Export Citation
  • 183.

    KobayashiKTsujiAMoritaS. A phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and low-dose consecutive (Cisplatin) CDDP) in advanced biliary tract carcinoma. BMC Cancer2006;6:121121.

    • Search Google Scholar
    • Export Citation
  • 184.

    RaoSCunninghamDHawkinsRE. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer2005;92:16501654.

    • Search Google Scholar
    • Export Citation
  • 185.

    YamashitaYTaketomiAFukuzawaK. Gemcitabine combined with 5-fluorouracil and cisplatin (GFP) in patients with advanced biliary tree cancers: a pilot study. Anticancer Res2006;26:771775.

    • Search Google Scholar
    • Export Citation
  • 186.

    WagnerADBuechner-SteudelPMoehlerM. Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials. Br J Cancer2009;101:18461852.

    • Search Google Scholar
    • Export Citation
  • 187.

    SohalDPMykulowyczKUeharaT. A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma. Ann Oncol2013;24:30613065.

    • Search Google Scholar
    • Export Citation
  • 188.

    GhafooriAPNelsonJWWillettCG. Radiotherapy in the treatment of patients with unresectable extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys2011;81:654659.

    • Search Google Scholar
    • Export Citation
  • 189.

    MacdonaldOKCraneCH. Palliative and postoperative radiotherapy in biliary tract cancer. Surg Oncol Clin N Am2002;11:941954.

  • 190.

    CzitoBGAnscherMSWillettCG. Radiation therapy in the treatment of cholangiocarcinoma. Oncology (Williston Park)2006;20:873884.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Sections

Figures

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

    Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

    Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

    Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

    Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, Version 2.2014

    Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

References

  • 1.

    SiegelRMaJZouZJemalA. Cancer statistics, 2014. CA Cancer J Clin2014;64:929.

  • 2.

    DonohueJHStewartAKMenckHR. The National Cancer Data Base report on carcinoma of the gallbladder, 1989-1995. Cancer1998;83:26182628.

  • 3.

    LevyADMurakataLARohrmannCAJr. Gallbladder carcinoma: radiologic-pathologic correlation. Radiographics2001;21:295314; questionnaire 549-255.

    • Search Google Scholar
    • Export Citation
  • 4.

    JarnaginWRRuoLLittleSA. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer2003;98:16891700.

    • Search Google Scholar
    • Export Citation
  • 5.

    ShethSBedfordAChopraS. Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol2000;95:14021410.

    • Search Google Scholar
    • Export Citation
  • 6.

    TazumaSKajiyamaG. Carcinogenesis of malignant lesions of the gall bladder. The impact of chronic inflammation and gallstones. Langenbecks Arch Surg2001;386:224229.

    • Search Google Scholar
    • Export Citation
  • 7.

    KhanZSLivingstonEHHuertaS. Reassessing the need for prophylactic surgery in patients with porcelain gallbladder: case series and systematic review of the literature. Arch Surg2011;146:11431147.

    • Search Google Scholar
    • Export Citation
  • 8.

    SchnelldorferT. Porcelain gallbladder: a benign process or concern for malignancy?J Gastrointest Surg2013;17:11611168.

  • 9.

    ElnemrAOhtaTKayaharaM. Anomalous pancreaticobiliary ductal junction without bile duct dilatation in gallbladder cancer. Hepatogastroenterology2001;48:382386.

    • Search Google Scholar
    • Export Citation
  • 10.

    ReidKMRamos-De la MedinaADonohueJH. Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg2007;11:671681.

    • Search Google Scholar
    • Export Citation
  • 11.

    EdgeSBByrdDRComptonCC. AJCC Cancer Staging Manual. 7th ed.New York, NY: Springer; 2010.

  • 12.

    FongYWagmanLGonenM. Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database. Ann Surg2006;243:767771; discussion 771-764.

    • Search Google Scholar
    • Export Citation
  • 13.

    DuffyACapanuMAbou-AlfaGK. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol2008;98:485489.

    • Search Google Scholar
    • Export Citation
  • 14.

    ItoHItoKD’AngelicaM. Accurate staging for gallbladder cancer: implications for surgical therapy and pathological assessment. Ann Surg2011;254:320325.

    • Search Google Scholar
    • Export Citation
  • 15.

    HawkinsWGDeMatteoRPJarnaginWR. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol2004;11:310315.

    • Search Google Scholar
    • Export Citation
  • 16.

    FurlanAFerrisJVHosseinzadehKBorhaniAA. Gallbladder carcinoma update: multimodality imaging evaluation, staging, and treatment options. AJR Am J Roentgenol2008;191:14401447.

    • Search Google Scholar
    • Export Citation
  • 17.

    PetrowskyHWildbrettPHusarikDB. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol2006;45:4350.

    • Search Google Scholar
    • Export Citation
  • 18.

    CorveraCUBlumgartLHAkhurstT. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg2008;206:5765.

    • Search Google Scholar
    • Export Citation
  • 19.

    LeeSWKimHJParkJH. Clinical usefulness of 18F-FDG PET-CT for patients with gallbladder cancer and cholangiocarcinoma. J Gastroenterol2010;45:560566.

    • Search Google Scholar
    • Export Citation
  • 20.

    StromBLMaislinGWestSL. Serum CEA and CA 19-9: potential future diagnostic or screening tests for gallbladder cancer?Int J Cancer1990;45:821824.

    • Search Google Scholar
    • Export Citation
  • 21.

    DixonEVollmerCMJrSahajpalA. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg2005;241:385394.

    • Search Google Scholar
    • Export Citation
  • 22.

    FuksDRegimbeauJMLe TreutYP. Incidental gallbladder cancer by the AFC-GBC-2009 Study Group. World J Surg2011;35:18871897.

  • 23.

    LeeSEJangJYLimCS. Systematic review on the surgical treatment for T1 gallbladder cancer. World J Gastroenterol2011;17:174180.

  • 24.

    FosterJMHoshiHGibbsJF. Gallbladder cancer: Defining the indications for primary radical resection and radical re-resection. Ann Surg Oncol2007;14:833840.

    • Search Google Scholar
    • Export Citation
  • 25.

    CoburnNGClearySPTanJCLawCH. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg2008;207:371382.

  • 26.

    YouDDLeeHGPaikKY. What is an adequate extent of resection for T1 gallbladder cancers?Ann Surg2008;247:835838.

  • 27.

    JensenEHAbrahamAHabermannEB. A critical analysis of the surgical management of early-stage gallbladder cancer in the United States. J Gastrointest Surg2009;13:722727.

    • Search Google Scholar
    • Export Citation
  • 28.

    DowningSRCadoganKAOrtegaG. Early-stage gallbladder cancer in the surveillance, epidemiology, and end results database: effect of extended surgical resection. Arch Surg2011;146:734738.

    • Search Google Scholar
    • Export Citation
  • 29.

    ShiraiYSakataJWakaiT. “Extended” radical cholecystectomy for gallbladder cancer: long-term outcomes, indications and limitations. World J Gastroenterol2012;18:47364743.

    • Search Google Scholar
    • Export Citation
  • 30.

    D’AngelicaMDalalKMDeMatteoRP. Analysis of the extent of resection for adenocarcinoma of the gallbladder. Ann Surg Oncol2009;16:806816.

    • Search Google Scholar
    • Export Citation
  • 31.

    PawlikTMGleisnerALViganoL. Incidence of finding residual disease for incidental gallbladder carcinoma: implications for re-resection. J Gastrointest Surg2007;11:14781486; discussion 1486-1477.

    • Search Google Scholar
    • Export Citation
  • 32.

    FongYJarnaginWBlumgartLH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg2000;232:557569.

    • Search Google Scholar
    • Export Citation
  • 33.

    ShihSPSchulickRDCameronJL. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg2007;245:893901.

  • 34.

    AgarwalAKKalayarasanRJavedA. Role of staging laparoscopy in primary gall bladder cancer—an analysis of 409 patients: a prospective study to evaluate the role of staging laparoscopy in the management of gallbladder cancer. Ann Surg2013;258:318323.

    • Search Google Scholar
    • Export Citation
  • 35.

    ButteJMGonenMAllenPJ. The role of laparoscopic staging in patients with incidental gallbladder cancer. HPB (Oxford)2011;13:463472.

  • 36.

    MakerAVButteJMOxenbergJ. Is port site resection necessary in the surgical management of gallbladder cancer?Ann Surg Oncol2012;19:409417.

    • Search Google Scholar
    • Export Citation
  • 37.

    FuksDRegimbeauJMPessauxP. Is port-site resection necessary in the surgical management of gallbladder cancer?J Visc Surg2013;150:277284.

    • Search Google Scholar
    • Export Citation
  • 38.

    RegimbeauJMFuksDBachellierP. Prognostic value of jaundice in patients with gallbladder cancer by the AFC-GBC-2009 study group. Eur J Surg Oncol2011;37:505512.

    • Search Google Scholar
    • Export Citation
  • 39.

    WangSJFullerCDKimJS. Prediction model for estimating the survival benefit of adjuvant radiotherapy for gallbladder cancer. J Clin Oncol2008;26:21122117.

    • Search Google Scholar
    • Export Citation
  • 40.

    WangSJLemieuxAKalpathy-CramerJ. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol2011;29:46274632.

    • Search Google Scholar
    • Export Citation
  • 41.

    LimJH. Cholangiocarcinoma: morphologic classification according to growth pattern and imaging findings. AJR Am J Roentgenol2003;181:819827.

    • Search Google Scholar
    • Export Citation
  • 42.

    DeOliveiraMLCunninghamSCCameronJL. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg2007;245:755762.

    • Search Google Scholar
    • Export Citation
  • 43.

    ChapmanRW. Risk factors for biliary tract carcinogenesis. Ann Oncol1999;10(Suppl 4):308311.

  • 44.

    TysonGLEl-SeragHB. Risk factors for cholangiocarcinoma. Hepatology2011;54:173184.

  • 45.

    DonatoFGelattiUTaggerA. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control2001;12:959964.

    • Search Google Scholar
    • Export Citation
  • 46.

    YamamotoSKuboSHaiS. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci2004;95:592595.

  • 47.

    ShaibYHEl-SeragHBDavilaJA. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology2005;128:620626.

    • Search Google Scholar
    • Export Citation
  • 48.

    WelzelTMMellemkjaerLGloriaG. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer2007;120:638641.

    • Search Google Scholar
    • Export Citation
  • 49.

    ChangKYChangJYYenY. Increasing incidence of intrahepatic cholangiocarcinoma and its relationship to chronic viral hepatitis. J Natl Compr Canc Netw2009;7:423427.

    • Search Google Scholar
    • Export Citation
  • 50.

    EndoIGonenMYoppAC. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg2008;248:8496.

    • Search Google Scholar
    • Export Citation
  • 51.

    NathanHAloiaTAVautheyJN. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol2009;16:1422.

  • 52.

    de JongMCNathanHSotiropoulosGC. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol2011;29:31403145.

    • Search Google Scholar
    • Export Citation
  • 53.

    FargesOFuksDLe TreutYP. AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma. Cancer2011;117:21702177.

    • Search Google Scholar
    • Export Citation
  • 54.

    de JongMCHongSMAugustineMM. Hilar cholangiocarcinoma: tumor depth as a predictor of outcome. Arch Surg2011;146:697703.

  • 55.

    HongSMPawlikTMChoH. Depth of tumor invasion better predicts prognosis than the current American Joint Committee on Cancer T classification for distal bile duct carcinoma. Surgery2009;146:250257.

    • Search Google Scholar
    • Export Citation
  • 56.

    BismuthHNakacheRDiamondT. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg1992;215:3138.

  • 57.

    JarnaginWRFongYDeMatteoRP. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg2001;234:507517; discussion 517-509.

    • Search Google Scholar
    • Export Citation
  • 58.

    MatsuoKRochaFGItoK. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am Coll Surg2012;215:343355.

    • Search Google Scholar
    • Export Citation
  • 59.

    MillerGSchwartzLHD’AngelicaM. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am2007;16:343368.

    • Search Google Scholar
    • Export Citation
  • 60.

    AljiffryMWalshMJMolinariM. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990-2009. World J Gastroenterol2009;15:42404262.

    • Search Google Scholar
    • Export Citation
  • 61.

    SainaniNICatalanoOAHolalkereNS. Cholangiocarcinoma: current and novel imaging techniques. Radiographics2008;28:12631287.

  • 62.

    HalefogluAM. Magnetic resonance cholangiopancreatography: a useful tool in the evaluation of pancreatic and biliary disorders. World J Gastroenterol2007;13:25292534.

    • Search Google Scholar
    • Export Citation
  • 63.

    HekimogluKUstundagYDusakA. MRCP vs. ERCP in the evaluation of biliary pathologies: review of current literature. J Dig Dis2008;9:162169.

    • Search Google Scholar
    • Export Citation
  • 64.

    VoglTJSchwarzWOHellerM. Staging of Klatskin tumours (hilar cholangiocarcinomas): comparison of MR cholangiography, MR imaging, and endoscopic retrograde cholangiography. Eur Radiol2006;16:23172325.

    • Search Google Scholar
    • Export Citation
  • 65.

    HyodoTKumanoSKushihataF. CT and MR cholangiography: advantages and pitfalls in perioperative evaluation of biliary tree. Br J Radiol2012;85:887896.

    • Search Google Scholar
    • Export Citation
  • 66.

    KimJYKimMHLeeTY. Clinical role of 18F-FDG PET-CT in suspected and potentially operable cholangiocarcinoma: a prospective study compared with conventional imaging. Am J Gastroenterol2008;103:11451151.

    • Search Google Scholar
    • Export Citation
  • 67.

    RuysATBenninkRJvan WestreenenHL. FDG-positron emission tomography/computed tomography and standardized uptake value in the primary diagnosis and staging of hilar cholangiocarcinoma. HPB (Oxford)2011;13:256262.

    • Search Google Scholar
    • Export Citation
  • 68.

    NakagohriTAsanoTKinoshitaH. Aggressive surgical resection for hilar-invasive and peripheral intrahepatic cholangiocarcinoma. World J Surg2003;27:289293.

    • Search Google Scholar
    • Export Citation
  • 69.

    KonstadoulakisMMRoayaieSGomatosIP. Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery2008;143:366374.

    • Search Google Scholar
    • Export Citation
  • 70.

    PaikKYJungJCHeoJS. What prognostic factors are important for resected intrahepatic cholangiocarcinoma?J Gastroenterol Hepatol2008;23:766770.

    • Search Google Scholar
    • Export Citation
  • 71.

    LangHSotiropoulosGCSgourakisG. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg2009;208:218228.

    • Search Google Scholar
    • Export Citation
  • 72.

    MurakamiYUemuraKSudoT. Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol2011;18:651658.

    • Search Google Scholar
    • Export Citation
  • 73.

    RiberoDPinnaADGuglielmiA. Surgical Approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients. Arch Surg2012;147:11071113.

    • Search Google Scholar
    • Export Citation
  • 74.

    TamandlDHerbergerBGruenbergerB. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol2008;15:27872794.

    • Search Google Scholar
    • Export Citation
  • 75.

    FargesOFuksDBoleslawskiE. Influence of surgical margins on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter study by the AFC-IHCC-2009 study group. Ann Surg2011;254:824829; discussion 830.

    • Search Google Scholar
    • Export Citation
  • 76.

    CarpizoDRD’AngelicaM. Management and extent of resection for intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am2009;18:289305viii-ix.

    • Search Google Scholar
    • Export Citation
  • 77.

    GoereDWagholikarGDPessauxP. Utility of staging laparoscopy in subsets of biliary cancers: laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc2006;20:721725.

    • Search Google Scholar
    • Export Citation
  • 78.

    JosephSConnorSGardenOJ. Staging laparoscopy for cholangiocarcinoma. HPB (Oxford)2008;10:116119.

  • 79.

    ShimadaMYamashitaYAishimaS. Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma. Br J Surg2001;88:14631466.

    • Search Google Scholar
    • Export Citation
  • 80.

    ChoiSBKimKSChoiJY. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol2009;16:30483056.

    • Search Google Scholar
    • Export Citation
  • 81.

    ClarkCJWood-WentzCMReid-LombardoKM. Lymphadenectomy in the staging and treatment of intrahepatic cholangiocarcinoma: a population-based study using the National Cancer Institute SEER database. HPB (Oxford)2011;13:612620.

    • Search Google Scholar
    • Export Citation
  • 82.

    MorineYShimadaMUtsunomiyaT. Clinical impact of lymph node dissection in surgery for peripheral-type intrahepatic cholangiocarcinoma. Surg Today2012;42:147151.

    • Search Google Scholar
    • Export Citation
  • 83.

    FisherSBPatelSHKoobyDA. Lymphovascular and perineural invasion as selection criteria for adjuvant therapy in intrahepatic cholangiocarcinoma: a multi-institution analysis. HPB (Oxford)2012;14:514522.

    • Search Google Scholar
    • Export Citation
  • 84.

    HyderOHatzarasISotiropoulosGC. Recurrence after operative management of intrahepatic cholangiocarcinoma. Surgery2013;153:811818.

  • 85.

    RiberoDRossoSPinnaAD. Postoperative nomogram for predicting survival after resection for intrahepatic cholangiocarcinoma [abstract]. J Clin Oncol2013;31(Suppl):Abstract 4129.

    • Search Google Scholar
    • Export Citation
  • 86.

    CarrafielloGLaganaDCottaE. Radiofrequency ablation of intrahepatic cholangiocarcinoma: preliminary experience. Cardiovasc Intervent Radiol2010;33:835839.

    • Search Google Scholar
    • Export Citation
  • 87.

    KimJHWonHJShinYM. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Roentgenol2011;196:W205209.

    • Search Google Scholar
    • Export Citation
  • 88.

    KieferMVAlbertMMcNallyM. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer2011;117:14981505.

    • Search Google Scholar
    • Export Citation
  • 89.

    KuhlmannJBEuringerWSpangenbergHC. Treatment of unresectable cholangiocarcinoma: conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy. Eur J Gastroenterol Hepatol2012;24:437443.

    • Search Google Scholar
    • Export Citation
  • 90.

    HyderOMarshJWSalemR. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol2013;20:37793786.

    • Search Google Scholar
    • Export Citation
  • 91.

    PoggiGQuarettiPMinoiaC. Transhepatic arterial chemoembolization with oxaliplatin-eluting microspheres (OEM-TACE) for unresectable hepatic tumors. Anticancer Res2008;28:38353842.

    • Search Google Scholar
    • Export Citation
  • 92.

    SchiffmanSCMetzgerTDubelG. Precision hepatic arterial irinotecan therapy in the treatment of unresectable intrahepatic cholangiocellular carcinoma: optimal tolerance and prolonged overall survival. Ann Surg Oncol2011;18:431438.

    • Search Google Scholar
    • Export Citation
  • 93.

    IbrahimSMMulcahyMFLewandowskiRJ. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer2008;113:21192128.

    • Search Google Scholar
    • Export Citation
  • 94.

    SaxenaABesterLChuaTC. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol2010;17:484491.

    • Search Google Scholar
    • Export Citation
  • 95.

    WijlemansJWVan ErpecumKJLamMG. Trans-arterial (90)yttrium radioembolization for patients with unresectable tumors originating from the biliary tree. Ann Hepatol2011;10:349354.

    • Search Google Scholar
    • Export Citation
  • 96.

    HoffmannRTPaprottkaPMSchonA. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol2012;35:105116.

    • Search Google Scholar
    • Export Citation
  • 97.

    RafiSPiduruSMEl-RayesB. Yttrium-90 radioembolization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety study. Cardiovasc Intervent Radiol2013;36:440448.

    • Search Google Scholar
    • Export Citation
  • 98.

    MouliSMemonKBakerT. Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis. J Vasc Interv Radiol2013;24:12271234.

    • Search Google Scholar
    • Export Citation
  • 99.

    OrtnerMECacaKBerrF. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology2003;125:13551363.

    • Search Google Scholar
    • Export Citation
  • 100.

    ZoepfTJakobsRArnoldJC. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol2005;100:24262430.

    • Search Google Scholar
    • Export Citation
  • 101.

    MambriniAGuglielmiAPacettiP. Capecitabine plus hepatic intra-arterial epirubicin and cisplatin in unresectable biliary cancer: a phase II study. Anticancer Res2007;27:30093013.

    • Search Google Scholar
    • Export Citation
  • 102.

    ShitaraKIkamiIMunakataM. Hepatic arterial infusion of mitomycin C with degradable starch microspheres for unresectable intrahepatic cholangiocarcinoma. Clin Oncol (R Coll Radiol)2008;20:241246.

    • Search Google Scholar
    • Export Citation
  • 103.

    InabaYAraiYYamauraH. Phase I/II study of hepatic arterial infusion chemotherapy with gemcitabine in patients with unresectable intrahepatic cholangiocarcinoma (JIVROSG-0301). Am J Clin Oncol2011;34:5862.

    • Search Google Scholar
    • Export Citation
  • 104.

    KemenyNESchwartzLGonenM. Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: does the addition of systemic bevacizumab improve results?Oncology2011;80:153159.

    • Search Google Scholar
    • Export Citation
  • 105.

    AkamatsuNSugawaraYHashimotoD. Surgical strategy for bile duct cancer: advances and current limitations. World J Clin Oncol2011;2:94107.

    • Search Google Scholar
    • Export Citation
  • 106.

    QiaoQLZhangTPGuoJC. Prognostic factors after pancreatoduodenectomy for distal bile duct cancer. Am Surg2011;77:14451448.

  • 107.

    SchwarzRESmithDD. Lymph node dissection impact on staging and survival of extrahepatic cholangiocarcinomas, based on U.S. population data. J Gastrointest Surg2007;11:158165.