This article appears in the following Annals of Oncology issue: ESMO Clinical Recommendations [View the issue table of contents]
ESMO clinical recommendations |
Biliary cancer: ESMO Clinical Recommendation for diagnosis, treatment and follow-up
1 Department of Internal Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
2 Internal Medicine Service, Institute of Oncology and Radiology, Belgrade, Serbia
* Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations{at}esmo.org
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incidence |
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 Top incidence diagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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The crude incidence of gallbladder and extrahepatic biliary cancer (ICD-10:C23-C24) in the European Union is
3.2 and 5.4/100 000 per year for males and females, respectively. Age-adjusted mortality is 1.4 and 1.9/100 000 for males and females, respectively. Incidence of intrahepatic cholangiocarcinoma (ICD-10:C22.1) is increasing and may be estimated as 0.9–1.3 and 0.4–0.7/100 000 for males and females, respectively, as 10–15% of primary liver cancer (ICD-10:C22). In high risk areas in Europe (south Italy) incidence is estimated up to 4.9–7.4 and 2.9–4.3/100 000 for males and females, respectively, and worldwide, e.g. in northeast Thailand up to 96/100 000. |
diagnosis |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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Diagnosis should be made on the basis of radiological investigations (magnetic resonance and CT are both useful) and pathomorphological assessment according to the World Health Organization classification from a biopsy, fine needle aspiration or biliary brush cytology. Final pathologic diagnosis has to be obtained before any chemotherapy, but is not critical for planning surgery in patients with characteristic findings of resectable biliary cancer.
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staging |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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Staging consists of complete history and physical examination, blood counts, liver function tests, chest X-ray, imaging of the abdomen by sonography and computed tomography scan or magnetic resonance, endoscopic retrograde or percutaneous transhepatic cholangiography, and possibly endoscopic ultrasonography, cholangioscopy and laparoscopy. Upper and lower endoscopy has to be performed in patients with an isolated intrahepatic mass. The staging is to be given according to the TNM 2002 system separately for gallbladder cancer, extrahepatic bile duct tumors, and liver cancer including intrahepatic bile duct cancer. TNM classification for gallbladder and bile duct tumors is presented in Tables 1 and 2. TNM classification for liver cholangiocarcinoma is the same as for hepatocellular liver cancer. Hilar cholangiocarcinoma (Klatskin's Tumor) is clinically staged depending on the involvement of the hepatic ducts according to the Bismuth-Corlette classification, which is presented in Table 3.
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treatment after incidental finding of gallbladder cancer on pathologic review |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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A radical re-resection (after a complete staging including laparoscopy demonstrating resectability) is highly recommended for patients with incidental gallbladder carcinoma stage T1b (tumor invades muscle layer) or greater. Patients with T1a tumors (tumor invades lamina propria) do not further benefit from re-resection if the gallbladder was removed intact and should be observed only [III, B].
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treatment after incidental finding of gallbladder cancer at surgery |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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After incidental finding of gallbladder cancer at surgery staging has to be performed intraoperatively and extended cholecystectomy including en bloc hepatic resection and lymphadenectomy with or without bile duct excision has to be considered depending on resectability and expertise of the surgeon.
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treatment of resectable tumors |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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Complete surgical resection is the only potentially curative treatment available. Resection of gallbladder cancer consists of extended cholecystectomy including en bloc hepatic resection and lymphadenectomy (porta hepatis, gastrohepatic ligament, retroduodenal) with or without bile duct excision. Major hepatectomy including caudate lobectomy such as extended right lobe resection with portal vein resection increases resectability and radicality for stage 3 and 4 hilar cholangiocarcinomas and has been associated with higher 5-year survival rates [III, B]. Preoperative transartial or portal vein embolisation increases the remnant liver volume in patients with estimated postresection volumes of <25% and appears to reduce postoperative liver dysfunction. Indication of biliary drainage should be systematically discussed with specialized surgeons before surgery.
Even in patients undergoing aggressive surgery 5-year survival rates are 5–10% for gallbladder cancer and 10–40% for cholangiocarcinoma.
Additive fluorouracil-based chemotherapy has been associated with a small survival benefit after noncurative resection of gallbladder cancer [II, B]. Postoperative treatment after noncurative resection of cholangiocarcinoma remains controversial, and both supportive care and palliative chemotherapy and/or radiotherapy may be taken into consideration.
As both gallbladder and biliary tract neoplasms present a high incidence of local failure after surgical resection reaching 52%, a locoregional adjuvant treatment should be considered. Several retrospective reports on adjuvant radiotherapy suggest survival benefit both in gallbladder and biliary duct cancer and postoperative chemoirradiation could be considered as an option.
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treatment of unresectable tumors |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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Liver transplantation is indicated under strict research protocols at selected centers, for patients with early stage cholangiocarcinoma and anatomically unresectable lesions, but this approach is experimental and should not be offered outside the scope of clinical trials. Data on photodynamic therapy are slightly more advanced. In cholangiocarcinoma photodynamic therapy after decompression of the biliary tree has been proven to induce survival benefit in two small randomised trials [II, B]. In patients with a large mass visible on radiographic studies the effect of photodynamic therapy may be limited and combination with chemotherapy may be considered although appropriate trials are lacking. Palliative chemotherapy added to both quantity and quality of life in advanced biliary cancer in a single phase III study [II, B], but the survival benefit for chemotherapy in general is not yet clearly established. Lacking randomised controlled trials and an accepted standard, 5-fluorouracil or gemcitabine are routinely used. Based on the results of a pooled analysis of predominantly phase II trials, gemcitabine combined with platinum compounds could also be an acceptable chemotherapy modality, since this combination offered the highest rates of objective response and tumor control in advanced biliary cancer [III, B]. Concurrent chemoirradiation is an additional therapeutic option and high radiation doses delivered by use of brachytherapy boost may improve local control of disease. Palliation of jaundice can be accomplished by endoscopic or percutaneous stenting of the biliary tree or by operative biliary-enteric bypass. Urgent biliary drainage and broad-spectrum antibiotics are crucial in patients with cholangitis due to obstructive jaundice.
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response evaluation |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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Response evaluation is recommended 3 months after photodynamic therapy by means of cholangiography during routine stent exchange and after two or three cycles (8–12 weeks) of chemotherapy by clinical evaluation, subjective symptom evaluation, blood tests and repeating the initially abnormal radiologic or ultrasound examinations.
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follow-up |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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There is no evidence that regular follow-up after initial therapy may influence the outcome. Follow-up visits after complete resection should be restricted to history and physical examination considering symptoms, nutrition and psychosocial problems.
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note |
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Topincidencediagnosisstagingtreatment after incidental...treatment after incidental...treatment of resectable tumorstreatment of unresectable tumorsresponse evaluationfollow-upnotereferences |
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Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
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footnotes |
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Approved by the ESMO Guidelines Working Group: August 2008
Conflict of interest: The authors have reported no conflicts of interest
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references |
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9. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology (2003) 125:1355–1363.[CrossRef][Web of Science][Medline]
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