Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Biliary tract cancer (BTC), comprising <1% of all human cancers and ∼10%–15% of all primary liver cancers, presents mostly in the seventh decade with a small male predominance (male:female ratio of 1.2–1.5:1.0) [1.Shaib Y. El-Serag H.B. The epidemiology of cholangiocarcinoma.Semin Liver Dis. 2004; 24: 115-125Google Scholar]. They are subclassified as intrahepatic cholangiocarcinoma (iCCA), originating from the biliary tree within the liver, and extrahepatic cholangiocarcinoma (eCCA), outside the liver parenchyma; the latter is further subdivided into perihilar cholangiocarcinoma (pCCA or Klatskin tumour) and distal cholangiocarcinoma (dCCA) [2.Nakeeb A. Pitt H.A. Sohn T.A. et al.Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors.Ann Surg. 1996; 224 (discussion 473–475): 463-473Google Scholar], with a frequency of 10%–20% iCCA, 50% pCCA and 30%–40% eCCA. In Europe, USA and Australasia, the incidence of cholangiocarcinoma (CCA) is low (0.3–3.5/100 000); in parts of the world where liver fluke infection is common (e.g. Thailand, China and Korea), rates are much higher [3.Bragazzi M.C. Cardinale V. Carpino G. et al.Cholangiocarcinoma: epidemiology and risk factors.Transl Gastrointest Cancer. 2012; 1: 21-32Google Scholar]. Northeast Thailand has the highest CCA rate in the world, with an annual incidence of 90/100 000, accounting for >80% of all primary liver cancers [4.Shin H.R. Oh J.K. Masuyer E. et al.Comparison of incidence of intrahepatic and extrahepatic cholangiocarcinoma - focus on East and South-Eastern Asia.Asian Pac J Cancer Prev. 2010; 11: 1159-1166Google Scholar]. CCA incidence and mortality rates have increased overall in the past few decades in most Western countries; specifically, iCCA rates are rising and eCCA rates falling [5.Patel T. Worldwide trends in mortality from biliary tract malignancies.BMC Cancer. 2002; 2: 10Google Scholar], with the exception of Denmark, Norway and the Czech Republic, where iCCA rates have fallen. CCA rates in Asia overall have remained static. These trends may be explained by:1)improved diagnostic tools and imaging;2)misclassification (particularly of pCCA during serial updates of the International Classification of Disease [6.Khan S.A. Emadossadaty S. Ladep N.G. et al.Rising trends in cholangiocarcinoma: is the ICD classification system misleading us?.J Hepatol. 2012; 56: 848-854Google Scholar]);3)changing migration patterns in the West [7.McLean L. Patel T. Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinoma in the United States.Liver Int. 2006; 26: 1047-1053Google Scholar];4)the increasing burden of chronic liver disease (e.g. viral hepatitis and fatty liver disease as specific risk factors for iCCA [8.Palmer W.C. Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma.J Hepatol. 2012; 57: 69-76Google Scholar, 9.Welzel T.M. Graubard B.I. El-Serag H.B. et al.Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study.Clin Gastroenterol Hepatol. 2007; 5: 1221-1228Google Scholar, 10.Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Google Scholar]); and5)the potential role of environmental toxins [11.Khan S.A. Thomas H.C. Davidson B.R. Taylor-Robinson S.D. Cholangiocarcinoma.Lancet. 2005; 366: 1303-1314Google Scholar, 12.Kumagai S. Kurumatani N. Arimoto A. Ichihara G. Cholangiocarcinoma among offset colour proof-printing workers exposed to 1,2-dichloropropane and/or dichloromethane.Occup Environ Med. 2013; 70: 508-510Google Scholar]. Furthermore, increased laparoscopic cholecystectomy rates over the past few decades have significantly reduced the prevalence of gallstone disease, a stronger risk factor for eCCA than iCCA [13.Nordenstedt H. Mattsson F. El-Serag H. Lagergren J. Gallstones and cholecystectomy in relation to risk of intra- and extrahepatic cholangiocarcinoma.Br J Cancer. 2012; 106: 1011-1015Google Scholar]. The incidence of gallbladder cancer (GBC) in Western Europe and the USA is low (1.6–2.0/100 000); however, it is a significant health problem in Chile, India and Central/Eastern Europe. In the Valdivia region of Chile, GBC incidence reaches 24.3/100 000 in females (and 8.6/100 000 in males) [14.Bertran E. Heise K. Andia M.E. Ferreccio C. Gallbladder cancer: incidence and survival in a high-risk area of Chile.Int J Cancer. 2010; 127: 2446-2454Google Scholar]. Gallstones are the strongest risk factor for GBC; other risk factors include porcelain gallbladder, gallbladder polyps, primary sclerosing cholangitis, chronic infection (e.g. salmonella typhi), congenital malformations and obesity. When diagnosing a BTC, it is important to distinguish the subtype (iCCA, pCCA, dCCA or GBC) as every subtype has its own specific characteristics, requiring individual workup. Overall, however, the best diagnostic tool is magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP), contrast-enhanced and diffusion-weighted imaging [15.Park M.J. Kim Y.K. Lim S. et al.Hilar cholangiocarcinoma: value of adding DW imaging to gadoxetic acid-enhanced MR imaging with MR cholangiopancreatography for preoperative evaluation.Radiology. 2014; 270: 768-776Google Scholar]. Computed tomography (CT) is generally less useful. Pathology diagnosis should be obtained before any non-surgical treatment modality (not essential in patients planned for curative surgery where radiological features are characteristic). Endoscopic retrograde cholangiopancreatography (ERCP)-guided biopsies are preferred to biliary brush cytology and should be carried out whenever possible [III, A]. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) is also useful for obtaining microbiopsies [16.Pitman M.B. Layfield L.J. Guidelines for pancreaticobiliary cytology from the Papanicolaou Society of Cytopathology: a review.Cancer Cytopathol. 2014; 122: 399-411Google Scholar] [II, C] and may be considered if ERCP-guided brush cytology or biopsies are negative or inconclusive. Cases of tumour seeding along the FNA needle track have been reported [17.Razumilava N. Gleeson F.C. Gores G.J. Awareness of tract seeding with endoscopic ultrasound tissue acquisition in perihilar cholangiocarcinoma.Am J Gastroenterol. 2015; 110: 200Google Scholar]; the exact level of risk is uncertain, though it appears to be low. Decisions to undertake biopsy should be made in a multidisciplinary setting, particularly in patients with potentially resectable tumours. Advances in pathology allow identification of distinct pathological subgroups based on immunohistochemistry, reflected in the updated World Health Organization (WHO) classification [18.Bosman F.T. World Health Organization; International Agency for Research on Cancer WHO Classification of Tumours of the Digestive System. IARC Press, Lyon, France2010Google Scholar], highlighting the importance of tissue acquisition. Serum carbohydrate antigen (CA)19-9 (with cut-off >129 U/ml) has some added value [III, C] [19.Levy C, Lymp J, Angulo P et al. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 2005; 50: 1734.Google Scholar]. In addition, there is an increasing understanding of different genomic profiles across BTC [20.Nakamura H. Arai Y. Totoki Y. et al.Genomic spectra of biliary tract cancer.Nat Genet. 2015; 47: 1003-1010Google Scholar], and although currently these differences do not direct therapy, they may do so in future. Staging needs to take into account the patient's performance status [using WHO or European Cooperative Oncology Group (ECOG) scores], past medical history/co-morbidities and liver function tests (LFTs). Imaging consists of MRI (for assessment of tumour [T]-stage and bile duct involvement), thorax CT (metastases (M)-stage) and EUS (lymph node (N)-stage). Whenever necessary (e.g. inconclusive MRCP), ERCP or percutaneous transhepatic cholangiography (PTC) should be carried out to improve assessment of T-stage, as this is crucial for surgical decision-making [IV, B]. Contrast CT is effective in defining the relationship between the tumour and the vasculature (portal vein and hepatic artery). The utility of positron emission tomography (PET)-CT is controversial and should only be used on a case-by-case basis. Staging is carried out according to the TNM 2010 system and is specific for every subtype of BTC (see Table 1) [21.In Edge S.B. Byrd D.R. Compton C.C. et al.Cancer Staging Handbook from the AJCC Cancer Staging Manual. Springer, New York, NY2010: 247-276Google Scholar]; pCCA may be further subclassified according to the Bismuth–Corlette classification (Table 2).Table 1The AJCC/UICC staging of cholangiocarcinoma and gallbladder cancer [21.In Edge S.B. Byrd D.R. Compton C.C. et al.Cancer Staging Handbook from the AJCC Cancer Staging Manual. Springer, New York, NY2010: 247-276Google Scholar]CholangiocarcinomaGallbladder cancerCholangiocarcinoma - intrahepaticCholangiocarcinoma - perihilarCholangiocarcinoma - distalGallbladder cancerPrimary tumour (T)Primary tumour (T)Primary tumour (T)Primary tumour (T)TXPrimary tumour cannot be assessedTXPrimary tumour cannot be assessedTXPrimary tumour cannot be assessedTXPrimary tumour cannot be assessedT0No evidence of primary tumourT0No evidence of primary tumourT0No evidence of primary tumourT0No evidence of primary tumourTisCarcinoma in situ (intraductal tumour)TisCarcinoma in situTisCarcinoma in situTisCarcinoma in situT1Solitary tumour without vascular invasionT1Tumour confined to the bile duct, with extension up to the muscle layer or fibrous tissueT1Tumour confined to the bile duct histologicallyT1Tumour invades the lamina propria or muscular layerT2aSolitary tumour with vascular invasionT2aTumour invades beyond the wall of the bile duct to the surrounding adipose tissueT2Tumour invades beyond the wall of the bile ductT1aTumour invades the lamina propriaT2bMultiple tumours, with or without vascular invasionT2bTumour invades the adjacent hepatic parenchymaT3Tumour invades the gallbladder, pancreas, duodenum or other adjacent organs without involvement of the coeliac axis, or the superior mesenteric arteryT1bTumour invades the muscular layerT3Tumour perforating the visceral peritoneum or involving the local extrahepatic structures by direct invasionT3Tumour invades unilateral branches of the portal vein or the hepatic arteryT4Tumour involves the coeliac axis, or the superior mesenteric arteryT2Tumour invades the perimuscular connective tissue; no extension beyond the serosa or into the liverT4Tumour with periductal invasionT4Tumour invades the main portal vein or its branches bilaterally; or the common hepatic artery; or the second-order biliary radicals bilaterally; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvementT3Tumour perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum or extrahepatic bile ductsT4Tumour invades the main portal vein or the hepatic artery or invades two or more extrahepatic organs or structuresRegional lymph nodes (N)Regional lymph nodes (N)Regional lymph nodes (N)Regional lymph nodes (N)NXRegional lymph nodes cannot be assessedNXRegional lymph nodes cannot be assessedNXRegional lymph nodes cannot be assessedNXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN0No regional lymph node metastasisN0No regional lymph node metastasisN0No regional lymph node metastasisN1Regional lymph node metastasis presentN1Regional lymph node metastasis (including nodes along the cystic duct, common bile duct, hepatic artery and portal vein)N1Regional lymph node metastasisN1Metastases to nodes along the cystic duct, common bile duct, hepatic artery and/or portal veinN2Metastasis to periaortic, pericaval, superior mesenteric artery and/or coeliac artery lymph nodesN2Metastases to periaortic, pericaval, superior mesenteric artery and/or coeliac artery lymph nodesDistant metastasis (M)Distant metastasis (M)Distant metastasis (M)Distant metastasis (M)M0No distant metastasisM0No distant metastasisM0No distant metastasisM0No distant metastasisM1Distant metastasis presentM1Distant metastasisM1Distant metastasisM1Distant metastasisStage groupingStage groupingStage groupingStage groupingStage 0TisN0M0Stage 0TisN0M0Stage 0TisN0M0Stage 0TisN0M0Stage IT1N0M0Stage IT1N0M0Stage IAT1N0M0Stage IT1N0M0Stage IIT2N0M0Stage IIT2a–bN0M0Stage IBT2N0M0Stage IIT2N0M0Stage IIIT3N0M0Stage IIIAT3N0M0Stage IIAT3N0M0Stage IIIAT3N0M0Stage IVAT4N0M0Stage IIIBT1–3N1M0Stage IIBT1N1M0Stage IIIBT1–3N1M0Any TN1M0Stage IVAT4N0–1M0T2N1M0Stage IVAT4N0–1M0Stage IVBAny TAny NM1Stage IVBAny TN2M0T3N1M0Stage IVBAny TN2M0Any TAny NM1Stage IIIT4Any NM0Any TAny NM1Stage IVAny TAny NM1AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control.Edge et al. [20.Nakamura H. Arai Y. Totoki Y. et al.Genomic spectra of biliary tract cancer.Nat Genet. 2015; 47: 1003-1010Google Scholar]. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL, USA. The original source for this material is the AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Open table in a new tab Table 2The Bismuth–Corlette classification of perihilar cholangiocarcinomaType ITumour involves the common hepatic ductType IITumour involves the bifurcation of the common hepatic ductType IIIaTumour involves the right hepatic ductType IIIbTumour involves the left hepatic ductType IVTumour involves both the right and left hepatic ductsBismuth et al. [22.Bismuth H. Nakache R. Diamond T. Management strategies in resection for hilar cholangiocarcinoma.Ann Surg. 1992; 215: 31-38Google Scholar]. Reprinted with permission. Open table in a new tab AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control. Edge et al. [20.Nakamura H. Arai Y. Totoki Y. et al.Genomic spectra of biliary tract cancer.Nat Genet. 2015; 47: 1003-1010Google Scholar]. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL, USA. The original source for this material is the AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Bismuth et al. [22.Bismuth H. Nakache R. Diamond T. Management strategies in resection for hilar cholangiocarcinoma.Ann Surg. 1992; 215: 31-38Google Scholar]. Reprinted with permission. Risk assessment is different for every CCA subtype. When considering pCCA, patients suffering from primary sclerosing cholangitis (PSC) in the Western world and patients with hepatobiliary flukes or hepatolithiasis in Asian countries are at an increased risk. Guidelines for surveillance of PSC patients are available [23.European Association for the Study of the Liver EASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Google Scholar]. Cirrhosis and hepatotropic viruses are risk factors for iCCA, with odds ratios (ORs) of 22.92 [95% confidence interval (CI): 18.24–28.79] for cirrhosis, 4.84 (95% CI: 2.41–9.71) for hepatitis C and 5.10 (95% CI: 2.91–8.95) for hepatitis B, according to a recent meta-analysis [8.Palmer W.C. Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma.J Hepatol. 2012; 57: 69-76Google Scholar]. The presence of iCCA should be considered in cirrhotic patients although the development of a hepatocellular carcinoma, for which patients are already undergoing screening, is more likely. Screening for CCA in newly defined at-risk groups (e.g. with obesity and the metabolic syndrome [8.Palmer W.C. Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma.J Hepatol. 2012; 57: 69-76Google Scholar]) has not been established. Patients with premalignant lesions predisposing to GBC warrant surveillance; the risk of malignancy is related to the size of gallbladder polyps (the most prevalent finding), which are often found incidentally. Lesions ≥20 mm should be managed as GBC after completion of staging investigations. Ultrasound surveillance is recommended for polyps measuring 6–9 mm (6-monthly for 1 year, then annually for 5 years), with resection only in enlarging polyps (to 10–20 mm in size) [24.Andrén-Sandberg A. Diagnosis and management of gallbladder polyps.N Am J Med Sci. 2012; 4: 203-211Google Scholar]. The therapeutic strategy varies for each type of BTC depending on its site of origin. A treatment algorithm is shown in Figure 1. iCCAs usually arise within normal background liver parenchyma, and their radiological appearance is, most typically, of a mass-forming arterially enhancing tumour. Radical surgical removal with clear margins is the only potentially curative therapy [III, A]. There are well-known prognostic parameters that should be taken into account when assessing prognosis including the presence of lymph node involvement; this has led to the recommendation of routine lymphadenectomy at the level of the hepato-duodenal ligament during surgery [II, A] [25.de Jong M.C. Nathan H. Sotiropoulos G.C. et al.Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment.J Clin Oncol. 2011; 29: 3140-3145Google Scholar]. Several other factors including size and number of tumours, grade, the presence of satellite nodules, vascular and/or perineural invasion should be reported by the pathologist to guide decisions regarding adjuvant therapy, although robust evidence for its use is lacking [IV, B]. Diagnosis of a pCCA and assessment of resectability according to the Bismuth–Corlette classification can only be determined in a considerable number of patients with surgical exploration. It is important that, for patients presenting with jaundice, initial radiological imaging is carried out before an ERCP or PTC is undertaken, as the inserted drains/stents obscure the diagnosis and assessment of the extent of disease [III, A]. The practice of biliary drainage before resection (versus immediate surgery) remains controversial and has to be decided on by the treating team taking into consideration non-tumour related factors, such as performance status and co-morbidities [II, B]. The anatomically longer left hepatic duct before segmental distribution usually implies that an extended right hemi-hepatectomy is necessary for curative intent and may require portal vein embolisation (including the segment IV branches) to induce hypertrophy of the future liver remnant (preservable segments II and III) [IV, A] [26.Matsumoto N. Ebata T. Yokoyama Y. et al.Role of anatomical right hepatic trisectionectomy for perihilar cholangiocarcinoma.Br J Surg. 2014; 101: 261-268Google Scholar]. Segment I, which drains into the ductal bifurcation, where the cancer lies, has to be removed in any curative procedure. Vascular resections at the hilum are possible but their invasion affects prognosis. Lymphadenectomy should be a standard addition in every CCA surgery. Liver transplantation in locally unresectable cases has been explored in a multidisciplinary approach including a strategy consisting of neoadjuvant chemoradiotherapy followed by liver transplantation by the Mayo Clinic; however, this has not become the standard of care [III, C]. The ongoing French phase III TRANSPHIL trial compares this strategy with standard surgical resection. In contrast to the other forms of CCA, this type requires the removal of the pancreatic head, usually a partial duodeno-pancreatectomy (PDP) with extended bile duct resection up to the hilum. PDP is a standard procedure that includes draining lymph node dissection and reconstruction of the stomach and the remaining pancreas in various ways to achieve macroscopic cure. The prognosis of dCCA is better than that of adenocarcinoma of the head of the pancreas [III, A] [27.Dickson P.V. Behrman S.W. Distal cholangiocarcinoma.Surg Clin North Am. 2014; 94: 325-342Google Scholar]. GBC has two typical presentations: either (a) incidentally diagnosed in the histological workup of simple cholecystectomies or (b) as a symptomatic right upper quadrant tumour at an advanced stage. The former requires staging with appropriate imaging (MRI or CT) and detailed histopathological analysis to decide whether further resection is necessary, including T-stage, cystic duct margin, involvement of resected lymph nodes, grade, perineural and/or vascular invasion. Every T-stage above T1a and positivity of any mentioned parameters requires a reoperation where a segment IVb/V liver resection together with a ligamentary lymphadenectomy should be carried out [II, A] [28.Ito H. Ito K. D'Angelica M. et al.Accurate staging for gallbladder cancer: implications for surgical therapy and pathological assessment.Ann Surg. 2011; 254: 320-325Google Scholar]. If the gallbladder was not removed with a bag during laparoscopic resection or the gallbladder perforated (an adverse prognostic factor), the port sites should also be resected [IV, A]. If GBC is diagnosed during imaging (for symptomatic patients) or when patients present with jaundice, evaluation of potential resectability is the key factor. Advanced T-stage (including T4 tumours) is not a contraindication for resectability provided they are located in the fundus; these tumours require major liver resection with potential resection of the transverse colon. Achieving a curative resection of an advanced tumour located at the infundibulum is much more difficult, because it requires the resection of the bile duct, the duodenal bulb and, potentially, the pancreatic head together with a major hepatectomy, especially if right-sided vessels (right hepatic artery, right portal vein) are involved [III, A]. The prognosis of a gallbladder cancer, if not diagnosed at a very early stage, is somewhat inferior to all other types of CCA. The high rates of local and distant recurrence following surgery justify the consideration of an adjuvant treatment. The role of adjuvant chemoradiotherapy in this setting is not well defined because of a lack of data from randomised trials. Indeed, most of the published studies are retrospective, including small numbers of patients with a mix of gallbladder and bile duct tumours. In a recent meta-analysis of published data, adjuvant chemotherapy or chemoradiotherapy appears to be associated with a survival benefit in patients with BTC with lymph node-positive disease or with microscopically involved margins (R1 resection) [29.Horgan A.M. Amir E. Walter T. Knox J.J. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis.J Clin Oncol. 2012; 30: 1934-1940Google Scholar]. However, major limitations (including selection bias, heterogeneity of treatments, stage migration over time and variable data quality) preclude definitive conclusions. Moreover, a differentiation between the two modalities (chemotherapy versus chemoradiotherapy) have not been compared in this setting. When employed, the recommended dose of radiotherapy is 45 Gy in fractions of 1.8 or 2 Gy with concurrent 5-fluorouracil (5-FU) or capecitabine [IV, C]. Recently, two prospective trials have assessed a regimen combining a gemcitabine-based adjuvant chemotherapy followed by chemoradiotherapy with concurrent 5-FU [30.Ben-Josef E. Guthrie K.A. El-Khoueiry A.B. et al.SWOG S0809: a phase II Intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma.J Clin Oncol. 2015; 33: 2617-2622Google Scholar, 31.Thet Cho M. Adjuvant gemcitabine plus docetaxel followed by 5FU chemoradiation for patients with resected pancreaticobiliary cancers: a single-institution, phase II study.J Clin Oncol. 2014; 32 (abstr e22243)Google Scholar]. The results of two phase III studies that have completed accrual and are awaiting maturation of data [BilCap (observation versus adjuvant capecitabine; UK, NCT00363584) and Prodige-12 (observation versus gemcitabine/oxaliplatin; France, NCT01313377)] are awaited and are likely to define future adjuvant strategies. A further study [ACTICCA-1 (observation versus cisplatin/gemcitabine; Germany, NCT02170090)] is open and recruiting patients. In the absence of level-1 data, the multidisciplinary team may offer adjuvant therapy (radiotherapy, chemoradiotherapy or chemotherapy alone) to patients on the best available evidence and only after a risk–benefit assessment. The role of radiation therapy remains unclear in the treatment of locally advanced but non-metastatic BTC. Chemoradiotherapy has been considered a possible option according to non-randomised studies with median survival rates between 9 and 14 months. The French FFCD 9902 phase III trial compared chemoradiotherapy with chemotherapy alone in this setting [32.Phelip J.M. Vendrely V. Rostain F. et al.Gemcitabine plus cisplatin versus chemoradiotherapy in locally advanced biliary tract cancer: Fédération Francophone de Cancérologie Digestive 9902 phase II randomised study.Eur J Cancer. 2014; 50: 2975-2982Google Scholar]. Patients were randomised between chemoradiotherapy (50 Gy with concurrent 5-FU and cisplatin) or chemotherapy with a combination of gemcitabine and oxaliplatin (GemOx). This trial was closed before the completion of planned inclusions, after enrolment of 34 patients. There was an advantage for GemOx, both in terms of progression-free survival (median PFS, 11 versus 5.8 months) and overall survival (OS, 20 versus 13.5 months). Recently, intensity-modulated radiotherapy (IMRT) was shown to allow safe dose escalation [33.Fuller C.D. Dang N.D. Wang S.J. et al.Image-guided intensity-modulated radiotherapy (IG-IMRT) for biliary adenocarcinomas: initial clinical results.Radiother Oncol. 2009; 92: 249-254Google Scholar]. Whether a dose escalation could improve the local control and survival remains unknown. Experience is growing in the use of radioembolisation using 90Y-microspheres for patients with iCCA. Prospective, randomised data are lacking; a pooled analysis of 12 studies including 298 patients showed a median OS of 15.5 months and response rate of 28% [34.Al-Adra D.P. Gill R.S. Axford S.J. et al.Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis.Eur J Surg Oncol. 2015; 41: 120-127Google Scholar]. Importantly, 7/73 (10%) patients in three selected studies were converted to resectable disease, highlighting the importance of reassessment of patients in the multidisciplinary team in the event of a good response to any treatment [IV, B]. Prospective randomised, controlled studies have shown that systemic chemotherapy extends survival in patients with advanced BTC compared with best supportive care [35.Glimelius B. Hoffman K. Sjödén P.O. et al.Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer.Ann Oncol. 1996; 7: 593-600Google Scholar, 36.Sharma A. Dwary A.D. Mohanti B.K. et al.Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study.J Clin Oncol. 2010; 28: 4581-4586Google Scholar]. The phase III UK ABC-02 study has established the cisplatin/gemcitabine combination as a standard of care in this disease [I, A], achieving a median survival close to a year (11.7 months) for cisplatin/gemcitabine, compared with 8.1 months for gemcitabine alone (95% CI: 0.53-0.79; P<0.001) [37.Valle J. Wasan H. Palmer D.H. et al.Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.N Engl J Med. 2010; 362: 1273-1281Google Scholar] with a similar benefit in the randomised phase II Japanese study [38.Okusaka T. Nakachi K. Fukutomi A. et al.Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan.Br J Cancer. 2010; 103: 469-474Google Scholar]. A meta-analysis of these studies has shown that patients benefit from the combination independent of age (<65 versus ≥65 years), gender, primary tumour site (intra- versus extrahepatic versus gallbladder versus ampullary), stage of disease (locally advanced versus metastatic) and prior therapy (surgery or stenting); however, patients with performance status 2 may derive the least benefit from the combination [39.Valle J.W. Furuse J. Jitlal M. et al.Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials.Ann Oncol. 2014; 25: 391-398Google Scholar]. In patients where there is a concern about renal function, oxaliplatin may be substituted for cisplatin [II, B]; in patients with performance status 2, gemcitabine monotherapy may be considered [I, B]. There is no established second-line systemic therapy following progression after first-line treatment although fluoropyrimidine-based therapy (either in monotherapy or in combination with other cytotoxics) is sometimes used [III, C]. A systematic review including 761 patients showed disappointing median PFS (3.2 months; 95% CI: 2.7–3.7) and response rates (7.7%; 95% CI: 4.6–10.9); the mean OS was 7.2 months (95% CI: 6.2–8.2) and no recommendation could be made about the most appropriate second-line regimen [40.Lamarca A. Hubner R.A. David Ryder W. Valle J.W. Second-line chemotherapy in advanced biliary cancer: a sy