State of the Art Oncology in EuropeFont: aaa

Cholangiocarcinoma – 2015

UPDATED JULY 2015

1. GENERAL INFORMATION

1.1 Epidemiological Data

1.1.1 Incidence

Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma which arises from the epithelial cells of bile ducts, anywhere along intrahepatic and extrahepatic biliary tree, excluding the papilla of Vater and the gall bladder (Callea 1993; Nakanuma 1992).
According to RARECAREnet project, in 2013 there were on average 13,000 new cases of CCA/year in Europe (RARECARE project).
For the period 2000-2007, the European crude incidence rate of CCA was 2.4 per 100,000/year. Incidence was lower for the intrahepatic ducts (0.97) than the extrahepatic ducts (1.4). The annual incidence rate was 1.25, while in the age group of 65 and more it was 10.3. CCA is very rare under the age of 65.
There are geographical difference in the occurrence of the disease, with the highest incidence in Central Europe and the lowest in Northern Europe. During the period 1999-2007, incidence rate statistically increased from 1.5 to 2, both for intrahepatic and extrahepatic cancers.
Incidence was 40% higher in men than in women (RARECARE project).
Cholangiocarcinoma incidence rates vary markedly worldwide (Figure 1) (Bridgewater 2014), presumably reflecting differences in local risk factors and genetics. The highest known rates are in Northeastern Thailand (>80/100,000/year), one of the lowest in Canada (0.3/100,000) (Lafaro 2015).

Figure 1. Incidence of cholangiocarcinoma worldwide (where reported) (Source: Bridgewater 2014).

Figure1_Cholangio

1.1.2 Survival

Prognosis of cholangiocarcinoma is generally poor. In Europe, according to the RARECAREnet project, five-year survival, for cases diagnosed between 2000-2007, was 5% and 17% for intra and extrahepatic ducts, respectively.
One-year survival for the intrahepatic CCA was 25%, after that survival decreased markedly to 8% and 5% at 3 and 5 years after diagnosis. In extrahepatic CCA outcome less rapidly reduced from 48% at 1 year to 23% at 3 years. Five-year survival was 52% in patients with 15-24 years of age, thereafter survival dramatically reduced to 19% at 25-64 and 11% at 65+ years of age patients. In Europe, 5-year survival significantly improved during the period 1999-2007, from 13% to 15% (RARECAREnet project).

1.1.3 Prevalence

In Europe (EU27), about 30,000 people live with a diagnosis of CCA (Gatta 2012) at the beginning of 2008. Sixty-one percent of all prevalent cases were people who had survived 5 years or less after diagnosis (slightly more than 18.000 cases at the beginning of 2008).
Long survivors (i.e., people surviving 15 years or more after their CCA diagnosis) were few, due to bad survival of CCA.
In Europe, estimated prevalence is 0.5/100,000: about 2,600 cases, most of which can be considered cured (RARECARE project).

1.2 Etiologic and risk factors

The peak age for CCA is the seventh decade, with a slightly higher incidence in men, because of the predominant occurrence of primary sclerosing cholangitis (Shaib 2004; Everhart 2009). Most cases of cholangiocarcinoma occur sporadically. There is good evidence that chronic inflammation and biliary duct cell injury induced by the obstruction of bile flow are two of the main conditions responsible for the development of cholangiocarcinoma. More specifically, it has been shown that the cytokines released in the biliary microenvironment during the process of inflammation are responsible for the malignant transformation (Fava 2007). Inflammation promotes carcinogenesis by imparting pro-survival signals and inducing genetic aberrations. Inflammatory pathways are not only key components in carcinogenesis, but also promote tumour invasion and migration. Inflammatory cells promote oxidative stress, which can promote genetic aberrations. Inducible nitric oxide synthase (iNOS) activation by inflammatory cytokines contributes to nitrosative stress by generation of excess nitric oxide. DNA repair enzymes are susceptible to nitric oxide-mediated nitrosylation. Consequently, iNOS activation results in inhibition of DNA repair proteins, and single-stranded, double-stranded, and oxidative DNA lesions. Enhanced iNOS expression occurs in CCA indicating that it is involved in tumor formation and progression (Jaiswal 2000; Jaiswal 2001). Oxidative stress via generation of oxysterols from biliary cholesterol creates a favourable milieu for tumour development. Oxysterols are cholesterol oxidation products present in human bile, and are increased in the bile of patients with biliary tract inflammation (Haigh 2001; Kuver 2012). Oxysterols activate the Hedgehog signaling pathway, a key developmental pathway implicated in CCA cell proliferation, migration, and invasion (Dwyer 2007; Nachtergaele 2012). Also cyclooxygenase-2, which is induced by various pro-inflammatory cytokines, such as bile acids, has been implicated in the carcinogenesis of CCA (Yoon 2002). In addition to inducing cyclooxygenase-2, bile acids also activate receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), which mediate cell proliferation (Yoon 2004). IL-6, an inflammatory mediator secreted by CCA and stromal inflammatory cells, can function in an autocrine or paracrine manner to promote cell survival and provide mitogenic signals (Park 1999; Kobayashi 2005).
In a minority of diagnoses (approximately 10%) well-known risk factors and conditions, all of which cause a chronic inflammation of the bile ducts, are associated with the tumour (Gores 2003). In Western Countries the most common disease associated with cholangiocarcinoma is primary sclerosing cholangitis (PSC) (Rizvi 2013). In a large Swedish trial (Broome 1996), 8% of patients with PSC developed the tumour within a mean follow-up period of 5 years. Seventy to eighty percent of these patients have associated ulcerative colitis. Occult cholangiocarcinoma was found in up to 36% of autopsy and 40% of specimens removed at transplantation. A recent US study confirmed a similar risk of developing cholangiocarcinoma in PSC patients (Burak 2004). In PSC patients cholangiocarcinoma tends to occur at a younger age (30-50 years) than otherwise seen, is frequently multifocal and seldom amenable to resection. Another well-known risk factor in early age is fibropolycystic malformation of the biliary tree. The association between choledochal cysts, also known as Caroli’s disease, and cholangiocarcinoma is well established. In patients with untreated cysts, the risk of tumour occurrence is 15-20% until the third decade of life (Lipsett 1994). This kind of cancer tends to present at an earlier age than the sporadic form. The increased risk of tumour may be related to an abnormal choledochopancreatic duct junction, which predisposes reflux of pancreatic secretions into the biliary tree, chronic inflammation, and bacterial contamination. In a study of 211 patients with PSC of whom 60% had inflammatory bowel disease (IBD), malignancies were the most frequent cause of death (44%); 41% of patients developed colorectal cancer (CRC) and 15 (39%) developed CCA (Claessen 2009). Median interval between PSC diagnosis and CCA was 2.5 years (range 0-9.8 years). Unfortunately, definitive conclusions on how the coexistence of IBD with PSC may increase CCA risk compared to IBD or PSC alone are still lacking. Infestation with liver flukes (Opistorchis viverrini, Clonorchis sinensis), known as pyogenic cholangiohepatitis or Oriental cholangiohepatitis, can lead to cholangiocarcinoma in 8-10% of cases (Tyson 2011). These liver flukes are endemic in Japan and Southeast Asia. Humans are infected by the consumption of raw or undercooked fish containing adult worms which then lay their eggs in the biliary system of their hosts. The parasite persists over years and progressively accumulates in the biliary system causing an inflammatory response and an increased risk of cholangiocarcinoma (Haswell-Elkins 1991). Less established but putative risk factors for CC include cirrhosis of any cause and chronic viral hepatitis B or C. Specifically, patients testing positive for hepatitis C virus (Yamamoto 2004; Shaib 2005; Welzel 2007) or hepatitis B virus surface antigen have an increased risk of developing intrahepatic cholangiocellular carcinoma (Okuda 2002). Exposure to several chemical agents (Adenugba 2009) and radionuclides has been identified as a risk factor for cholangiocarcinoma (exposure to nitrosamines, dioxin, asbestos, thorotrast, radon). IARC has classified thorium-232 and its decay products as carcinogenic for epithelial tumours of gallbladder and extra hepatic bile ducts with sufficient evidence (Chartbotel 2013). A combination of recent cohort, population-based, case-control and observational studies from around the world suggest that obesity, diabetes, fatty liver disease, alcohol, smoking, chronic intraductal gallstone, IBD without PSC and polymorphisms of genes coding for carcinogen metabolism, DNA repair, inflammation and biliary transporters may also be risk factors (Tyson 2011). Tobacco smoking has not been shown to be a risk factor in the general population, but in one large series was strongly associated with progression to cholangiocarcinoma in patients with PSC (Bergquist 1998). Recently obesity was identified as a risk factor for the development of extrahepatic cholangiocarcinoma (Ben-Menachem 2007).

Table 1. Summary of risk factors significantly associated to intra-hepatic cholangiocarcinomaa and/or extra-hepatic cholangiocarcinomab as assessed by case control studies (Odds ratios by multivariate analyses) (Source: Cardinale 2010).

 

Risk factors for IH-CCA Odds ratios for increased risk Risk factors for EH-CCA Odds ratios for increased risk
Bile ducts diseases and conditions
Choledochal cysts 10.7-36.9 Choledochal cysts 47.1
Cholangitis/PSC 64.2 Cholangitis/PSC 45.7
Biliary cirrhosis/PBC 19.8 Biliary cirrhosis/PBC 11.8
Cholelithiasis 13.5 Cholelithiasis 2.6-11.0
Choledocholithiasis 22.5-34.0 Choledocholithiasis 34.0
Cholecystis 8.5 Cholecystis 5.9
Cholecystectomy 3.6-5.4 Cholecystectomy 5.8-12.0
Hepatolithiasis 50.0-4.8; 6.7c
Liver flukes
Clonorchis sinensis infection 8.6-13.6 Clonorchis sinensis infection 6.5
Digestive diseases
IBD 4.0 IBD 2.1
Crohn disease 2.4 Crohn disease 2.8
Ulcerative colitis 4.5
Duodenal ulcer 3.4 Duodenal ulcer 1.9
Chronic pancreatitis 5.9 Chronic pancreatitis 9.3
Endocrine disorders
Diabetes mellitus type II 1.8-3.2 Diabetes mellitus type II 1.5-3.2
Thyrotoxicosis 1.5 Thyrotoxicosis 1.7
Miscellaneous conditions
Alcohol intake >80 g/d 5.9-6.6 Alcohol intake >80 g/d 3.6
Obesity 1.7
Smoking 1.8
Chronic liver diseases
Alcoholic liver disease 3.1 Alcoholic liver disease 4.5
Non specific cirrhosis 10.0-16.5 Non specific cirrhosis 5.4
Hemochromatosis 2.6
Hepatic schistosomiasis 11.0
Non alcoholic liver disease 3.0
HCV infectionc 4.4-7.9; 9.7c
HCV infection plus cirrhosis 8.5
HBsAg positive 2.3-9.7
HBsAg positive plus cirrhosis 13.0-8.0
a Histological verified cases;
b Histological verified cases comprise Klatskin tumour;
c IH-CCA cases comprise 2 cases of cHCC-CCA. The table is prepared summarising findings by case control studies investigating risk factors associated to IH-CCA and/or EH-CCA as assessed by multivariate analyses. The case-control studies are selected from the papers individuated by the follow terms searched on PubMed: [“cholangiocarcinoma”(MeSH Terms) OR “cholangiocarcinoma”(All Fields)] AND [“risk factors”(MeSH Terms) OR [“risk”(All Fields) and “factors”(All Fields)] OR “risk factors”(All Fields) OR [“risk”(All Fields) AND “factor”(All Fields)] OR “risk factor”(All Fields)]] NOT [“review”(Publication Type) OR “review literature as topic”(MeSH Terms) OR “review”(All Fields)] AND English(lang). The criteria selections of the works comprise moreover the case definition of CCA: Histological verified cases series of IH-CCA and/or EH-CCA with appropriate topographic classification (Klatskin tumours classified as EH-CCA and excluded from the IH-CCAs). In the 10 case control studies selected, several putative risk factors have been evaluated. The risk factors are collected together based on the patho-physiologic mechanisms lead to CCA (cells primarily targeted or activated by the diseases and therefore involved in the carcinogenic process) and on the homogeneity of the risk factors. IH-CCA: Intra-hepatic cholangiocarcinoma; EH-CCA: Extra-hepatic cholangiocarcinoma.

1.3 Prevention and screening

For patients with PSC, brush cytological examination or biopsy may be used as a surveillance tool for the early detection of cellular atypia. In high risk areas, where liver infection is endemic, prevention of cholangiocarcinoma may be achieved by early treatment of infection.

2. PATHOLOGY AND BIOLOGY

2.1 Molecular data

Recent advances in genome-wide technologies have provided deeper insight into the genetic basis of this challenging cancer. A few studies have assessed the roles of genetic factors, such as chromosome aberrations or genetic and epigenetic alterations in tumour suppressor genes and oncogenes, in the pathogenesis of human CCA (Jiao 2013; Rizvi 2014; Razumilava 2014). The development of CCA is a multistep process based on enhanced susceptibility to proliferative stimuli and escape from growth inhibitory stimuli, dysregulation of apoptotic signals, and the response to angiogenetic stimuli which are eventually responsible for tumour invasion and metastasis (Fava 2007; Sirica 2005). Several mutations in oncogenes and tumour-suppressor genes have been identified in CCA cancer, such as tumour protein 53 (TP53) found mutated in 44.4% of cases, Kristen ras sarcoma viral oncogene homolog (KRAS) mutated in 16.7% of cases, SMAD4 mutated in 16.7% of cases, MLL3 mutated in 14.8% of cases, ROBO2 mutated in 9.3% of cases, RNF43 mutated in 9.3%of cases, PEG3 mutated in 5.6% of cases, and GNAS mutated in 9.3% of cases. The biological functions of these genes broadly include deactivation of histone modifiers, G-protein activation, and loss of genomic stability (Jiao 2013; Gao 2014). Other common occurrences in CCA are represented by BRAF, EGFR, PIK3CA, NRAS, and APC mutations (Andersen 2012; Khan 2005; Tannapfel 2003). Their sequential occurrence may drive the pathogenesis of CCA and contributes to the stepwise transformation of normal epithelium into carcinoma, as has been observed with other gastrointestinal cancers. The overexpression of the p53 tumour suppressor gene or mutations of the K-ras oncogene are associated with increasing cytological atypia, tumour aggressiveness and worse prognosis (Isa 2002; Ong 2012). Moreover, TP53 mutations occurred with increased frequency in liver–fluke-related tumours: this finding implies that genetic alterations may vary according to aetiological associations and postulates a connection between epigenetic regulation and CCA (Chan-On 2013). Several growth factor tyrosine kinases are implicated in carcinogenesis and progression of CCAs. These include the ERBB family of receptor tyrosine kinases, fibroblast growth factor receptor (FGFR), and the hepatocyte growth factor (HGF) receptor, c-met. The ERBB family comprises four different receptors, ERBB1 or EGFR, ERBB2 or HER-2/neu, and ERBB3 and 4 (Sirica 2008).
The EGFR activation leads to downstream activation of mitogen-activated protein kinase (MAPK), a well-known oncogenic signalling pathway. Over-expression of ERBB2 has been linked to biliary epithelial tumour formation in mice (Kiguchi 2001). Moreover, ERBB2 amplification was recently described in a cohort of CCA patients (Graham 2014).
Erlotinib, an EGFR inhibitor, has been tested with a limited success in CCA clinical trials (Philip 2006; Lubner 2010) maybe due to an insufficient understanding of EGFR signalling. A recent study demonstrated significant upregulation of HER2 signalling in tumours with the most malignant phenotype (Andersen 2012): the HER2 upregulation was associated with poor prognosis and frequent coactivation of ERBB3 and EGFR.
Lapatinib, a dual inhibitor of EGFR and HER2, was more effective in inhibition of CCA cell lines. Mutations in KRAS have been frequently described in CCA, along with mutations in NRAS, BRAF, and downstream MAPK effector pathways. Strategies to therapeutically target tumours with KRAS mutations have focused on targeting downstream effector pathways of KRAS such as Raf/MEK/ERK and PI3K/AKT. Binding of HGF and FGF to their respective TK-receptors leads to activation of the PI3K/AKT signalling pathway, with the subsequent phosphorylation and activation of the mammalian target of rapamycin (mTOR) pathway (Voss 2013). Deregulation of this pathways and PTEN, due to different mutations, fosters tumour development, cell proliferation and survival, tumour invasion, and angiogenesis. Various PI3K/AKT pathway inhibitors are under investigation (GDC-0980, BAY 80-6946, everolimus), alone or in combination with chemotherapy (Sheppard 2012; Liu 2013; Wallin 2011; Costello 2014).
MET tyrosine kinase plays an important role in carcinogenesis by promoting tumour invasion, protection from apoptosis, and angiogenesis (Comoglio 2008). An integrative genomic analysis of intrahepatic CCA identified a proliferation class of tumours that is characterized by activation of the oncogenic signalling pathway of MET (Sia 2013). MET amplification has been described in other malignancies and it is associated with a poor clinical outcome (Appleman 2011; Ross 2014). MET amplification is also linked to resistance to EGFR and ERBB2 inhibitors and may predict sensitivity to MET inhibitors.
A recent study using DNA sequencing detected MET amplification in a few cases (7%). Crizotinib, cabozantinib, and tivozanib have therapeutic potential in targeted cancer chemotherapy of CCA tumours with MET amplification, and are currently being evaluated in clinical trials. FGFR is a tyrosine kinase receptor involved in cell transformation, angiogenesis, and tissue repair (Arai 2014). Fusions of the FGFR gene have been reported in solid cancers. Recently, FGFR2-BICC1 gene fusion was described in CCAs (Wu 2013), which resulted sensitive to FGFR inhibitors (ponatinib, dovitinib, BGJ398 and PD173072). This finding indicates the role for targeted FGFR kinase inhibition in patients with tumours containing these gene fusions (Borad 2014; Guagnano 2012; Escudier 2014). A few studies have investigated chromosomal aberrations in CCA. In a recent study, gene-expression profile, high-density single-nucleotide polymorphism array, and mutation analyses were performed in 149 cases of intrahepatic CCA (Sia 2013). This analysis identified two main biological classes of CCA: the inflammation class and the proliferation class. Activation of inflammatory pathways, cytokine over-expression, and STAT3 activation were hallmarks of the inflammation class, which comprised 38% of the analysed CCAs. Features of the proliferation class (62% of the analysed CCAs) included activation of oncogenic signalling pathways (such as RAS, mitogen-activated protein kinase, and MET), KRAS and BRAF mutations, DNA amplifications at 11q13.2, and deletions at 14q22.1. IL-6 is an inflammatory cytokine produced by cholangiocytes in the presence of inflammatory stimuli, but it is also secreted by CCA cells, participating in survival and mitogenic signalling. IL-6 upregulates the antiapoptotic Bcl-2 protein, myeloid cell leukaemia sequence 1 (Mcl-1), via an AKT-dependent mechanism. Mcl-1 is integral in tumour necrosis factor-related apoptosis inducing ligand (TRAIL) resistance in CCA (Taniai 2004). Consequently, IL-6 inhibition reduces Mcl-1 expression and enhances TRAIL-mediated apoptosis. IL-6 also acts, via a STAT3-dependent mechanism, to enhance Mcl-1 expression (Isomoto 2005). This information suggests several approaches to treating the inflammatory subtype of CCA: for example, neutralising antibodies to IL-6, inhibitors of the JAK kinases, which activate STAT3 downstream of IL-6 initiated signalling, and Mcl-1 antagonists (Tanaka 2014; Abulwerdi 2014; Yu 2005). The Notch signalling pathway has a central role in cell-fate determination during embryonic development in several organs including the biliary tree (Hofmann 2010). Notch dysregulation is implicated in inflammation and carcinogenesis. Notch expression is upregulated in PSC and CCA (Ishimura 2005). Two preclinical studies have demonstrated a role for Notch in conversion of mature adult hepatocytes into biliary precursors of intrahepatic CCA (Fan 2012; Sekiya 2012). Enhanced expression of the Notch intracellular domain (NICD) in hepatic cells is associated with intrahepatic CCA occurrence (Zender 2013). Several inhibitors of the Notch pathway are in development. ROS1 fusions proteins have been recently identified in CCA (Gu 2011) with a significant oncogenic role. Subsequent preclinical studies have validated fused-in-glioblastoma-c-ros-oncogene 1 (FIG-ROS) as a potent oncogene in a mouse model of CCA (Saborowski 2013). In this model, FIG-ROS mediated intrahepatic CCA development was Kras-dependent, and led to development of aggressive and metastatic tumours in the presence of Kras. In tumours harbouring Kras and p53 mutations, FIG-ROS inactivation led to the inhibition of tumour growth. Accordingly, ROS1 inhibitors, such as crizotinib, have potential as targeted therapy in a subset of patients harbouring ROS1 fusion proteins, even if recent reports have indicated that a specific ROS1 mutation, ROS1(G2032R), may confer resistance. IDH1 and IDH2 mutations have been reported in 10% to 28% of intrahepatic cholangiocarcinomas (Kipp 2012; Grassian 2014). IDH2 mutations are observed less frequently in intrahepatic CCA with a prevalence of 27% compared with 73% prevalence of IDH1 mutations. These mutations were associated with clear cell change, poorly differentiated histology, and longer overall survival and time to recurrence (Wang 2013a). Increased levels of p53 and DNA hypermethylation are observed in the setting of IDH-mutant tumours. Small molecule inhibitors of IDH1 and IDH2 are being developing (Wang 2013b; Rohle 2013).
The overexpression of Bcl-2 seems to reduce apoptosis in cholangiocarcinoma cell lines, while defective Fas-receptor or increasing Fas-ligand expression produce an escape of immune surveillance. Using tissue microarrays, two markers: fascin and mesothelin, showed expression with transition from carcinoma in situ to invasive adenocarcinoma, implicating a role of these markers in neoplastic progression, both in biliary tract cancer and pancreatic cancer (Swierczynski 2004).
VEGF has an important role in tumour-associated neoangiogenesis. Activation of the VEGF receptors leads to survival, proliferation and migration of endothelial cells (Tabernero 2007). VEGF has been found expressed in CCAs and its expression level correlates with poor prognosis (Park 2006). Moreover, a recent study showed that sorafenib, a multikinase inhibitor acting predominantly against BRAF and VEGFR, presents potent antitumor activity in both in vitro and in vivo preclinical models of human CCC (Sugiyama 2011). Cholangiocarcinomas have a characteristic hypovascular, desmoplastic stroma containing α-smooth muscle actin (α-SMA) positive cancer-associated fibroblasts (CAFs), which promotes, by production of matricellular proteins, growth factors, chemokines, and matrix metalloproteinases, tumour proliferation, tumour invasion, migration, and induce a profibrogenic response (Sirica 2012). The fibrogenic matrix precedes CCA development and fosters malignant growth. It has been postulated that the desmoplasia characteristic of CCA may serve as a niche fostering tumour development rather than as a response to the tumour (DeClerck 2012). This notion underscores the importance of fibrosis in CCA carcinogenesis, and supports the potential of antifibrotic therapies in CCA chemoprevention. Preclinical studies have demonstrated a reduction in fibrosis and carcinogenesis in CCA with agents as Navitoclax and 1D11, a transforming growth factor β (TGF-β) antagonist (Ling 2013; Mertens 2013). Desmoplastic response may be induced also by paracrine sonic Hedgehog signalling; reduction of the desmoplastic response via Hedgehog inhibition increased intratumour vascular density, and the intratumoural concentration of gemcitabine, contributing to transient stabilisation of the disease (Olive 2009). Clinical studies using Hedgehog antagonists as combination therapy are underway. Finally, paracrine EGF and PDGF signalling has been implicated in tumour-stroma crosstalk. Myofibroblast-derived EGF and PDGF induced EGFR activation, enhance migratory and invasive properties and protect CCA cells from TRAIL-induced apoptosis via a Hedgehog-dependent mechanism respectively (Clapéron 2013; Fingas 2011). Inhibition of EGFR and PDGFR by gefitinib and imatinib abolish these effects. Intrahepatic CCA is a histologically diverse hepatobiliary malignancy considered to develop from biliary epithelial cells or hepatic progenitor cells. Recent studies proposed a model according to which CCA arises from de/transdifferentiation and subsequent neoplastic conversion of normal hepatocytes into malignant cholangiocytes (Fan 2012; Sekiya 2012; Holczbauer 2013). Mice overexpression and activation of Notch1 and AKT resulted in development of invasive carcinomas via conversion of hepatocytes into precursors of intrahepatic CCA. As Notch signalling pathway regulates embryonic development and proliferation of the biliary tree, not surprisingly its disregulation also can be implicated in cancerogenesis. Another experience showed that transformed hepatocytes, hepatoblasts, and hepatic progenitor cells can give rise to a broad spectrum of liver tumours, ranging from HCC to CCA. Therefore, CCA may derive from different cells of origin.

Figure 2. Multiple cells of origin in cholangiocarcinoma (Source: Raggi 2015).

Figure2_Cholangio

 

2.2 Classification and histological types

Cholangiocarcinomas are hepatobiliary cancers with features of cholangiocyte differentiation; they can develop anywhere along the biliary tree, and are anatomically classified as intrahepatic (10%), perhilar (50-60%) and distal CCA (20-30%) (figure 3) (Blechacz 2011; Rizvi 2013). Less than 10% of all cholangiocarcinomas are multifocal or diffuse. Based on their appearance, lesions can be defined as mass-like, periductal, intraductal or mixed. CCAs can be well, moderately differentiated and undifferentiated tumours.
Special features of cholangiocarcinoma include early invasion of adjacent organs (when tumour is located to the hilum, direct invasion of liver or perihepatic structures such as hepatic artery and portal vein), nodal metastases in up 1/3 of cases (Tsuzuki 1983), invasive spread with neural, perineural and lymphatic involvement, and subepithelial extention (Weinbren 1983). There is only a limited tendency to metastasise, and only one third of patients demonstrate lymph node, hepatic or peritoneal metastasis at the time of surgery.
The complexity of CCA is a subject of concern even at the anatomical level, since this malignancy comprises three distinct entities, which emerge at diverse sites with different gross clinical presentation and outcome. Intrahepatic cholangiocarcinomas are malignancies which arise from the small bile ducts in the liver. They can be divided into mass-forming, periductal infiltrating and intraductal growth types (Yamasaki 2003). According to the WHO classification criteria, they can also be adenocarcinomas and mucinous carcinomas (Blechacz 2011). Approximately 60% of patients survive for 5 years after curative surgery. Factors associated with recurrence and reduced survival time after resection include vascular invasion, lymph node metastasis, multiple tumours and cirrhosis (DeOliveira 2007; Li 2011). Perihilar CCAs originate in the main hepatic ducts or at the bifurcation of the common biliary tract (also termed Klatskin’s tumours). They can have exophytic (forming-mass) or intraductal macroscopic growth patterns. The only curative option is surgical resection. The Bismuth-Corlette staging classification (table 2) is based on the anatomic location of the CCA within the biliary tree; it classifies peri-hilar tumours in 4 subtypes of cancer and is meant to help guide decision making. Recently, it was expanded to take into account vascular encasement and parenchymal value of the potential remnant lobe (DeOliveira 2011). 5 years survival rates after complete surgery range from 11% to 41% (Nagorney 2006). Distal CCAs arise from the point of insertion of the cystic duct to the ampulla of Vater; they have been grouped with perhilar CCA as extrahepatic CCA. Surgical treatment typically entails a Whipple procedure. Only 27% of patients survive for 5 years after a radical excision.
Histological types are listed in table 3. Over 90% of cholangiocarcinoma are well differentiated and mucin-producing adenocarcinomas. Other rare cell types include carcinoid tumours arising in the biliary tree. Macroscopic subtypes are: sclerosing tumours, nodular (often both types sclerosing and nodular) and papillary. The papillary type is a low-grade adenocarcinoma associated with a better prognosis (Martin 2002). Survival is related to the pathological grading of the tumour: better survival is seen with well-differentiated cancers (mean survival 10 months, anaplastic tumours 2 months). A recent publication describes a worse survival-rate in younger (< 40 years) than in older patients after curative resection in case of peripheral carcinoma of the biliary tract (Yeh 2004).

Figure 3. Intrahepatic, perhilar and distal cholangiocarcinoma (Source: Rizvi 2013).

Table 2. The Bismuth-Corlette classification

 

Type I Tumour involves the common hepatic duct
Type II Tumour involves the bifurcation of the common hepatic duct
Type IIIa Tumour involves the right hepatic duct
Type IIIb Tumour involves the left hepatic duct
Type IV Tumour involves both the right and left hepatic duct
Table 3. Histological types of cholangiocarcinoma (extrahepatic) (Sobin 2002)

 

CARCINOMA IN SITU
Adenocarcinoma, NOS
Adenocarcinoma, intestinal type
Mucinous adenocarcinoma
Clear cell adenocarcinoma
Signet-ring cell adenocarcinoma
Adenosquamous carcinoma
Squamous cell carcinoma
Small cell (oat cell) carcinoma
Undifferentiated carcinoma (Spindle and giant cell type; small cell type)
Papillomatosis
Papillary carcinoma, non invasive
Papillary carcinoma, invasive
Carcinoma, NOS
MALIGNANT MESENCHIMAL TUMOURS (RARE)
Embryonal rhabdomyosarcoma
Leiomyosarcoma
Malignant fibrous histiocytoma

3. DIAGNOSIS

3.1 Signs and symptoms

Diagnosis of CCA can be a challenge because of its anatomic location and silent clinical character. For these reasons, diagnosis requires a multidisciplinary approach. The clinical signs and symptoms depend on the location and the extension of the tumour. Patients with early stage disease are usually asymptomatic. At more advanced stages, patients may present with weight loss, malaise, abdominal discomfort, hepatomegaly. Jaundice without pain is a leading symptom (>90% of patients) in extrahepatic bile duct cancer, while it is less frequent in patients with intrahepatic CCAs. Other clinical features common in biliary obstruction are pale stools, dark urine, and pruritus; further physical signs are right upper abdominal mass and fever. Patients presenting the triad cholestasis, abdominal pain and weight loss should be evaluated for cancer and the differential diagnosis includes the diseases listed in table III. Great diagnostic care needs to be taken specifically in patients with known primary sclerosing cholangitis (PSC).

Table 4. Differential diagnosis in patients with cholestasis, pain and weight of loss.

 

Pancreatic head cancer
Carcinoma of duodenum
Carcinoma of gallbladder
Carcinoma of Vater’s ampulla
Choledocholithiasis
Primary sclerosing cholangitis
Benign biliary obstruction (post-operative)
Mirizzi’s syndrome

3.2 Diagnostic procedures

3.2.1 Laboratory tests

In cholangiocarcinoma the markers of cholestasis, such as bilirubin, alkaline phosphatase, and ƒ×-glutamyltransferase are typically elevated. Serum carcinoembryonic antigen (CEA) alone has a low predictive value, while carbohydrate antigen 19-9 (CA 19-9) >100 U/mL has a sensitivity of 89% and a specificity of 86% (Siqueira 2002). Bile duct obstruction and acute cholangitis may affect CA 19-9 levels (Aljiffry 2009). In a recent prospective study, serum CA19-9 was of clinical usefulness in diagnosing cholangiocarcinoma, in deciding whether the tumour had been radically resected and in monitoring the effect of treatment. Analysis of data suggested that serum CA19-9 and CEA concentrations were significantly elevated in patients with cholangiocarcinoma compared with patients showing benign biliary disease or healthy individuals. After curative resection, both serum levels decrease from a preoperative level (Qin 2004). Other studies failed to demonstrate a predictive value of CA 19-9, and the optimal cut-off level for suspicion of CCA is not known.

3.2.2 Radiological techniques and their indication according to the diagnostic question

Unlike other types of gastrointestinal cancer, diagnosis of biliary tract tumours can be very difficult. Radiographic exams are essential in planning the best management of these patients, estimating the curative resection or establishing palliative treatment. The initial diagnostic exams include ultrasound or CT scan which can demonstrate the level of biliary obstruction or focal biliary dilatation in the absence of stones. The sensitivity of ultrasound in demonstrating the site of biliary obstruction is 94% (Sharma 1999). In experienced centres, the duplex ultrasound can be considered equivalent to CT scan, portography and angiography in predicting vascular invasion and resectability (Hann 1997). Endoscopic ultrasound may be useful for distal common bile duct cancers for defining a mass, an abnormal thickening and to perform direct biopsies. Triple-phase helical CT scan and MRI can detect a cholangiocarcinoma greater than 1 cm, the relationship between tumour and adjacent organs and the vascular structures; it can predict resectability in 60% of cases (Zhang 1999). Magnetic resonance cholangiopancreatography (MRCP) has a better sensitivity and specificity and diagnostic accuracy compared to endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis and pretreatment staging of hilar CCAs. Ideally MRCP should be performed before biliary drainage to avoid the collapse of the biliary tree; moreover, it is not recommended for the diagnosis of extrahepatic CCAs, since it is associated with complications and contaminations of the biliary tree. In distal tumours instead, ERCP is indicated, since it allows a complete imaging of the biliary duct and provide stenting of possible obstructions. Since MRI can also detect tumour blood vessels, lymph nodes and intra- and extrahepatic metastases, it is presently viewed as the best imaging modality for diagnosis and staging (Slattery 2006). FDG-PET performed in expert centres, can detect cholangiocarcinoma as small as 1 cm, distant metastases not seen with standard radiological exams (30%) and cancer in patients with PSC (Anderson 2004). False positive results have to be taken into account in biliary tract infections and inflammatory cholangiopathies.
The role of FDG-PET in the management of CAA is still controversial. Some data have suggested the potential benefit of PET resides largely in its ability to detect otherwise unsuspected metastasis (Kim 2003; Anderson 2004; Corvera 2008). In fact, FDG-PET was found to change the surgical management in up to 30% of patients.
A cytological diagnosis can be obtained with invasive procedures such as ERCP or percutaneous transhepatic cholangiography (PTC). Both techniques can be required for therapeutic biliary drainage. It is important to point out that only laparoscopic exploration can define the true resectability of a tumour, but imaging can be of help. Radiological criteria of unresectability for hilar cholangiocarcinoma include bilateral hepatic duct involvement up to secondary radicals, encasement or occlusion of the portal vein proximal to its bifurcation, atrophy of one liver lobe with contralateral portal vein branch encasement, involvement of bilateral hepatic arteries, atrophy of one liver lobe with contralateral secondary biliary involvement, and distant metastases. Radical surgery is precluded for distal bile duct cancers in case of involvement of portal vein (sometimes the involvement of a short segment of the portal vein, does not preclude the resection), superior mesenteric artery, or common hepatic artery, and in the presence of metastatic disease (M1). Peripheral CCAs cannot be radically resected in cases of vascular invasion, intrahepatic or extrahepatic metastases, or inability to achieve a radical resection. EGDS and colonscopy are recommended as initial workup in intrahepatic CCAs since a mass diagnosed as adenocarcinoma can be metastatic disease.

3.3 Pathological diagnosis

Making a tissue diagnosis of cholangiocarcinoma is not easy because of its location, size and desmoplastic characteristics. Bile cytology can be obtained with fine needle aspiration with ultrasound or CT guidance; brush cytology can be obtained with endoscopic retrograde cholangiography (ERCP), endoscopic transpapillary biopsy or with percutaneous transhepatic cholangiography (PTC).

4. STAGING

4.1 Staging Procedures

In the revised 7th edition of the AJCC staging system, CCA has a new classification, in contrast with the previous edition in which intrahepatic tumours were staged identically to HCC and extrahepatic CCAs (perhilar and distal) grouped together as a unique entity. The new classification for intrahepatic CCAs (table 5) focuses on three risk factors and it is useful in predicting survival according with TNM stage (Edge 2010). For perhilar and distal CCAs, the 7th edition includes separate TNM classifications (table 6 and 7), basing on the extent of liver involvement and distant metastatic spread.

Table 5. Intrahepatic cholangiocarcinoma (Edge 2010).

 

TNM CLASSIFICATION
Primary tumour (T)
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ (intraductal tumour)
T1 Solitary tumour without vascular invasion
T2a Solitary tumour with vascular invasion
T2b Multiple tumours with or without vascular invasion
T3 Tumour perforating the visceral peritoneum or involving the local extrahepatic structures by direct invasion
T4 Tumour with periductal invasion
Regional lymph nodes (N)
Nx Regional nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastases
Distant metastasis (M)
Mx Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
STAGE GROUPING
Stage 0 Tis, N0, M0 (carcinoma in situ)
Stage I T1, N0, M0
Stage II T2, N0, M0
Stage III T3, N0, M0
Stage IVa T4, N0, M0
Any T, N1, M0
Stage IVb any T, any N, M1
Table 6. Perhilar cholangiocarcinoma (Edge 2010).

 

TNM CLASSIFICATION
Primary tumour (T)
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour confined to the bile duct, with the extension up to the muscle layer or fibrous tissue
T2a Tumour invades beyond the wall of the bile duct to surrounding adipose tissue
T2b Tumour invades adjacent hepatic parenchyma
T3 Tumour invades unilateral branches of the portal vein or hepatic artery
T4 Tumour invades main portal vein or its branches bilaterally, or the common hepatic artery, or the second-order biliary radicals bilaterally, or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement
Regional lymph nodes (N)
Nx Regional nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Lymph node metastases to hepatoduodenal ligament (including nodes along the cystic duct, common bile duct, hepatic artery, portal vein)
N2 Metastasis to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes
Distant metastases (M)
Mx Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
STAGE GROUPING
Stage 0 Tis, N0, M0 (carcinoma in situ)
Stage I T1, N0, M0
Stage II T2a-b, N0, M0
Stage IIIa T3, N0, M0
Stage IIIb T1-3, N1, M0
Stage IIIc Any T, N1, M0
Stage IVa T4, N0-1, M0
Stage IVb Any T, N2, M0
any T, any N, M1
Table 7. Distal cholangiocarcinoma (Edge 2010).

 

TNM CLASSIFICATION
Primary tumour (T)
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour confined to the bile duct, histologically
T2 Tumour invades beyond the wall of the bile duct
T3 Tumour invades gallbladder, pancreas, duodenum, or other adjacent organs without involvement of the celiac axis, or the superior mesenteric artery
T4 Tumour involves the celiac axis, or the superior mesenteric artery
Regional lymph nodes (N)
Nx Regional nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Lymph node metastases
Distant metastases (M)
Mx Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
STAGE GROUPING
Stage 0 Tis, N0, M0 (carcinoma in situ)
Stage Ia T1, N0, M0
Stage Ib T2, N0, M0
Stage IIa T3, N0, M0
Stage IIb T1-3, N1, M0
Stage III T4, Any N, M0
Stage IV Any T, Any N, M1

5. PROGNOSIS

5.1 Prognostic factors

Prognosis is not influenced by the location of the cancer and the extension of resection if radical surgery is performed (no difference in survival between various bile duct cancers when adjusted for stage and completeness of resection. Surgical treatment remains the only curative treatment option for CCAs. Life expectancy for patients with unresectable intrahepaticCCA is <5% at 5 years, whereas it increases to 20–44% at 5 years for patients undergoing resection at early T1-T2 stages. The best prognosis has been observed in patients with negative resection margins and no lymph node involvement (Jarnagin 2004). For intrahepatic cholangiocarcinoma recent data suggest that poor prognosis is related to angiogenesis and intrahepatic metastasis (Klempnauer 1997). Survival is related to the macroscopic subtype (better for papillary) and grading of tumour (better if well-differentiated). Some authors also suggest that younger patients (<40 years) with peripheral cholangiocarcinoma had a significantly worse survival rate than older patients (Yeh 2000).
The 7th AJCC staging system includes specific predictive clinic-pathologic features that are specific to intrahepatic CCA, as multiple tumours, regional nodal involvement, large tumour size (Endo 2008). In recent reports, tumour size had any effect on survival after surgery (Nathan 2009; de Jong 2011), whereas the presence of multiple lesions and vascular invasion predicted adverse prognosis. Lymph node status seems to be prognostic only in M0 patients. 5-years survival rate is superior for patients who lack all three risk factors (multiple tumours, vascular invasion and nodal involvement) than those with >1 risk factors: 38.3% vs. 27.3% vs. 18.1%. Vascular invasion and tumour number are prognostic only in N0 patients. For extrahepatic neoplasms, the depth of tumour invasion has been identified as an independent predictor of outcome. AJCC classification, as well as Bismuth-Corlette staging system, is not useful for predict resecability and survival. The preoperative Blumgart staging system, instead, can predict resecability, likelihood of metastatic spread and survival (Jarnagin 2001; Matsuo 2012). In this system, cholangiocarcinomas are classified into 3 stages (T1-T3) based on the location and extent of biliary involvement, the presence/absence of portal venous invasion, the hepatic lobar atrophy. Increasing T-stage correlates with a reduction of R0 resection, lower median survival and presence of distant metastases. Negative margins at histology, well-differentiated tumours, and concomitant partial hepatectomy are associated with improved outcome after resection.

6. TREATMENT

6.1 Surgery

Surgery is the only potentially curative treatment option for cholangiocarcinoma; otherwise surgical approach is feasible in about 30-40% of patients (Nathan 2007; Tan 2008; Bridgewater 2014).
Despite all the progresses achieved during the last decades, prognosis of cholangiocarcinoma is dismal even after surgical resection, with 5-year overall survival rate of 40% in R0 resection, reducing to 20% in case of N1 stage and vascular invasion; median overall survival ranging from 20-60 months (DeOliveira 2007; de Jong 2011; Niu 2015; Hyder 2014a).
Presurgical evaluation should comprehend: full blood exam, comprehending CEA, CA 19.9 value and AFP, tumour staging with CT scan and/or MRI, fully liver function in patient with underlying cirrhosis.
Many factors predict patients prognosis after surgery: the most important being surgical margin status, followed by nodal involvement, CEA serum level and AJCC stage and adjuvant chemotherapy, site of primary tumour, concomitant cirrhosis (Hyder 2014b).
Radical resection (R0) results to be the most important prognostic factor in cholangiocarcinoma undergoing resection, and it is mandatory to achieve a long-survival. As complete resection is the only potentially curative treatment and hope for long-survival in patients with cholangiocarcinoma, it is possible to hypothesise aggressive surgery, with resection of up to 70-80% of healthy liver. In patients with borderline liver remnant portal embolisation should be considered, in order to achieve liver hypertrophy (Ebata 2012).
Nodal involvement is another important prognostic factor, although the need for nodal dissection and its role in the surgical treatment of cholangiocarcinoma is still under discussion. Many studies support the role of lymphoadenectomy, although it has even been demonstrated that extended nodal dissection did not gain any survival advantage over standard nodal dissection in advance stage disease with N2 stage (Niu 2015). Lymphoadenctomy appears to have more a prognostic than curative significance, indeed it has been observed different survival time among N0 stage disease according to the number of resected locoregional nodes (more or less than 3 resected nodes). Additionally, defining nodal status could improve surgical outcome, or avoid useless surgery (for example in N2 stage disease) (Guglielmi 2013).
Due to the high mortality and morbidity rate, and considering the aggressive behaviour of cholangiocarcinoma, often associated to liver dysfunction (cirrhosis) and biliary obstruction and infection, it is important to select patients who can really benefit from surgery. Preoperative assessment should comprehend:

  • clinical patients characteristics: age, performance status, comorbidities, jaundice and liver function impairment;
  • liver function, biliary duct obstruction and/or infection: cholangiocarcinoma is often associated to cirrhosis, that could represent a contraindication to extent liver surgery and it is associated to higher risk of liver failure; Jaundice is quite frequently related to cholangiocarcinoma (mainly hilar primary site). It is debated whether biliary drainage before surgery can be useful, it has demonstrated to improve patients outcome, but it is associated in some reports to higher percentage of local complication such as infectious cholangitis. Despite misperception, covered self-expandable metal stents do not contraindicate surgery or radiotherapy; although it is preferable to use plastic stent before defining treatment strategy (van der Gaag 2010; Deviere 1988);
  • tumour stage: nodal involvement or locally advanced primary tumour (vascular invasion, multiple sites) could contraindicate surgery due to the high risk of early relapse. Laparoscopy could be a useful staging tool, able to identify the actual locoregional extent of primary tumour, nodal or occult peritoneal metastasis; but it should not be yet considered as a standard of care;
  • site of primary disease: the site of primary tumour is probably one of the most important prognostic and predictive factor for resected cholangiocarcinoma. According to tumour site, cholangiocarcinoma can be classified into three categories: intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) (Bridgewater 2014). Each primary tumour site has a different clinical behaviour and needs for different treatment approach.
 6.1.1 Surgery for intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma represents about 20-30% of cholangiocarcinoma, it is quite often related to cirrhosis. Due to its location, intrahepatic spread is quite frequent, making surgical resection feasible only in 30-40% of patients with intrahepatic cholangiocarcinoma (Hemming 2005). This is the reason why extended liver and biliary tract resection is mandatory for radically and it requires: resection of the involved extrahepatic bile ducts, en-bloc liver resection of the hemi-liver with most extensive tumour involvement, and lymphadenectomy are the standard operations. The future liver remnant should be at least 25-30% of the whole liver. Preoperative palliation of jaundice and accurate clinical evaluation must be considered as extended surgical resection (liver), lymphadenectomy can be related to high risk of perioperative morbidity. In patients with borderline liver remnant portal embolisation should be considered, in order to achieve liver hypertrophy.
Other than clinical patients characteristics, tumour characteristics for resectability should be considered.
The following tumour characteristics represent surgery contraindication:

  • encasement or occlusion of main portal vein or hepatic artery (bilateral arterial involvement or arterial involvement proximal to the bifurcation)
  • involvement of bilateral secondary (sectorial) ducts or unilateral ductal involvement with contralateral vascular involvement or compromise;
  • atrophy of one hemi-liver with contralateral secondary ductal or portal venous involvement
  • metastatic disease beyond regional (hepato-duodenal ligament) lymph nodes (Brown 2014).

Despite extended liver and biliary resection, the 5-years overall survival ranges from 25% to 35% in most series, but the main part of the studies have great limits due to the retrospective nature and the small number of patients analysed. Postsurgical outcome appears to improve in patients treated in high specialty centres, with a 75% of extended hepatic resection rate with 80% of R0 resection.

6.1.2 Surgery for distal cholangiocarcinoma

Distal cholangiocarcinoma is the less frequent presentation, accounting for 10-15% of cholangiocarcinoma. It has a less aggressive behaviour than other cholangiocarcinomas, it is often associated with desmoplastic reaction and with surrounding structure infiltration (duodenum pancreas, celiac axis vascular structure). Duodenocephalopancreasectomy is the adequate surgical treatment for patients with distal cholangiocarcinoma (Nakeeb 2004), occasionally requiring portal and mesenteric vein resection and reconstruction. Vascular infiltration requiring venal resection has long been discussed to represent resectable disease, in fact, in case of vascular invasion R0 resection is achievable only in 10-30% of cases, otherwise prognosis is similar in patients without venal involvement and R0 margin. These data support a more aggressive approach in case of venal involvement, but the debate has not finished yet (Riediger 2006; Chua 2010). Lymphadenectomy should include a thorough dissection of regional nodes. Specific to DCC, all nodes surrounding the common bile duct and portal hepatitis should be carefully excised as potential draining basins from distal common bile duct cancers. Hepatic artery nodes should be considered for resection if there is clinical suspicion of involvement (DeOliveira 2007; Murakami 2011; Murakami 2007; He 2002; Dickson 2014).

6.1.3 Surgery for Hilar Cholangiocarcinoma

Hilar Cholangiocarcinoma accounts for 60-70% of cholangiocarcinoma. It is a rare cancer, very aggressive, not responding to chemotherapy, with high risk of developing hepatic failure or major biliary infection. Due to its location, prone to local invasion, adjacent structure and organ infiltration and metastatisation surgical approach is very difficult and quite often no radical. Only selected patients, with good performance status and adequate liver function, should be considered for surgery, and even in this case perioperative mortality range from 5% to 10%, and morbidity from 30% to 60%.
Despite dismal prognosis, in the last decade surgical strategy significantly improved accounting for better results in hilar cholangiocarcinoma; standard resection treatment should comprehend major surgery with hepatic and biliary resection, lymphoadenectomy and occasionally vein resection (Nagorney 2006; Jonas 2008; Konstadoulakis 2008; Nagino 2013; de Groen 1999; Bismuth 1992).
Some years ago, portal vein invasion was considered as an absolute contraindication to surgery, although in the last decades many studies have been performed investigating portal vein resection and reconstruction. A meta-analysis by Chen evaluated the results of 13 studies analysing effectiveness portal vein resection in the surgical management of hilar cholangiocarcinoma; the result showed not higher postoperative mortality and morbidity in portal vein resection group. The results of most studies demonstrated a worse survival in patients treated with portal vein resection compared with those who did not underwent vascular intervention. The subgroup undergoing more aggressive surgery had a significantly higher percentage of vascular invasion, nodal metastasis and higher stage of disease representing poor prognostic factors, which could in some way explain the poor outcome of portal vein resection. In this meta-analysis patients with locally advanced disease with vascular invasion had a significantly longer survival when radically resected (Chen 2014; Miyazaki 2007). Instead concomitant arterial resection did not increased survival rate and it is associated with a higher percentage of perioperative mortality, confirming arterial invasion as an exclusion criteria for surgery.
Proposed respectability criteria foe excluding surgery (Zaydfudim 2014):

  1. distant metastases;
  2. lymph node metastases beyond hepatoduodenal ligament (N2 involvement);
  3. bilateral ductal extension to the secondary (or segmental) biliary radicles;
  4. encasement or occlusion of the main portal vein (or common hepatic artery) proximal to its bifurcation;
  5. unilateral involvement of secondary (or segmental) biliary radicles with contralateral vascular involvement;
  6. lobar atrophy with involvement of contralateral secondary (or segmental) biliary radicles;
  7. lobar atrophy with involvement of contralateral portal vein or hepatic artery.

In selected cases of unresectable hilar cholangiocarcinoma without nodal or metastatic spread preoperative chemoradiation followed by liver transplantation could represent a valid alternative to major hepatic resection.

6.1.4 Surgery for Gallbladder cancer

Gallbladder cancer is very rare; the most part is accidentally diagnosed after surgery for apparently benign gallbladder disease, with early stage of disease at presentation. In case of T1 and Tis disease, simple cholecystectomy can be considered an appropriate treatment. In more advance stages, reoperation is indicated in patients with accidentally diagnosed gallbladder cancer in order to perform radical surgery comprehensive of liver resection and nodal dissection. It has been demonstrated that reoperation has a high percentage of R0 resection in this subgroup of patients (85%), while radical resection is much more difficult to achieve (25%) in patients presenting with symptomatic and, therefore, more advanced disease (Shih 2007; Pawlik 2007). Patients with occasionally diagnosed gallbladder cancer should undergo reoperation in case of T1b (invasion into muscular layer), T2 (invasion into perimuscular connective tissue), and T3 (perforates the serosa and/or directly penetrates the liver and/ or one other adjacent organ) tumors (D’Hondt 2013).
Laparoscopy has an important role in surgical management of gallbladder cancer, in order to preoperatively define tumour extension and discover potential peritoneal metastasis or macroscopic residual disease (about 60% of accidentally diagnosed cancer). In case of residual disease, reoperation should be considered a standard of treatment in occasional cancer; in fact, it is associated to a very poor prognosis (Pawlik 2007), this could explain the reason why lack of radicalisation in accidental tumour is associated to a worse prognosis (Foster 2007).
Additionally, residual disease even after extended surgical intervention is the most frequent cause of surgery failure; it is present in about 60% of tumour and it is associated with a significantly worst survival (DFS 11.2 vs. 93 .2 months, p <0.0001; OS 25.2 months vs. not reached, p <0.0001) (Butte 2014).
Appropriate radical surgery should comprehend: cholecistectomy, en block liver resection, lymphoadenectomy and bile duct resection as necessary. Even in this case, there is not clear benefit from lymphoadenectomy, but nodal status represents an important prognostic factor, therefore local lymphoadenectomy should be performed even in absence of clearly metastatic lymphnodes. In most cases, extended hepatectomy is unnecessary. Although there are clearly large variations in extent of liver resection performed for curative intent, the inability to achieve an R0 resection may be an indicator of aggressive biology and, as such, a marker of poor prognosis (Wernberg 2014).
Locally advanced disease should not undergo surgery; if R0 resection is not achievable, T3 and T4 stage are contraindication to surgery (Birnbaum 2014).

6.1.5 Surgery for recurrent cancer

Despite the recent advances in surgical treatment of cholangiocarcinoma, about 50% of patients have a recurrent disease after curative radical surgery. Historically, the treatment of recurrent disease has been limited to the use of chemotherapy and/or radiotherapy, with limited data regarding surgical treatment. A retrospective analysis compared result of 532 patients with recurrent disease treated with systemic chemotherapy, compared with 74 who underwent surgery for recurrent disease. Survival after recurrence was significantly better in patients treated with surgery compared with those treated with standard treatment (3-year overall survival 32% vs. 3%; p<0.0001). Although not all patients had benefit from surgery, favourable prognostic factor were: longer disease free survival before first recurrence (more than 2 years), no nodal involvement at diagnosis, liver or locoregional recurrence (not thoracic or abdominal wall) (Takahashi 2014).

6.1.6 Liver transplantation

Available data support liver transplantation selected cases of hilar cholangiocarcinoma (not suitable for liver resection for local extension, or cirrhosis, but without nodal or metastatic involvement), while it is contraindicated in intrahepatic cholangiocarcinoma.
Data regarding the role of liver transplantation in intrahepatic cholangiocarcinoma are still controversial, due to the small number of sample size, the heterogeneity of perioperative treatment (neoadjuvant, adjuvant). Although the small number of data, poor prognostic factors that should contraindicate liver transplantation in intrahepatic cholangiocarcinoma have been identified: multiple tumour, perineural, vascular and liver infiltration, lack of adjuvant and/or neoadjuvant therapy. Future studies should focus on standardised selection criteria plus adjuvant and/or neoadjuvant therapy with liver transplantation as definite therapy for intrahepatic cholangiocarcinoma (Bridgewater 2014; Fu 2011; Sotiropoulos 2008).
A novel optional treatment for cholangiocarcinoma is preoperative chemo-radiotherapy followed by liver transplantation (Rea 2005) (see section 6.2.4).
According to the available data, liver transplantation should be precluded to patients with the following characteristics (Heimbach 2004; Rosen 2010; Rea 2009):

  1. intrahepatic, gallbladder, or distal cholangiocarcinoma (below the level of the cystic duct);
  2. primary tumour greater than 3 cm in radial diameter (perpendicular to the duct);
  3. any nodal or distant metastases;
  4. any surgical attempt at exploration for resection or transperitoneal tumour biopsy or FNA, including endoscopic ultrasound-directed aspiration (EUS) of the tumour; conversely, EUS/FNA of suspicious regional lymph nodes should be performed to exclude nodal metastases;
  5. previous treatment with radiotherapy or chemotherapy that precludes full-dose neoadjuvant therapy;
  6. history of other malignancy within 5 years.

6.2 Adjuvant and neoadjuvant treatment

Prognosis of cholangiocarcinoma remains poor even with aggressive surgical therapy because of the high incidence of local or regional recurrence and distant metastasis. Both radiation and chemotherapy have been analysed in the adjuvant setting (both apart and concomitantly). Probably one of the most important results regarding adjuvant treatment in cholangiocarcinoma derives from a large meta-analysis by Horgan et al (Horgan 2012). The authors analysed 21 studies of adjuvant treatment (both radiotherapy and chemotherapy) in gallbladder (6 studies) and cholangiocarcinoma (16 studies) for a total of 6,712 patients, among which 1,792 received adjuvant treatment. Non-survival benefit emerged from the analysis of the overall population (even though with a trend for a better outcome, PR 0.74), while the analysis of specific treatment demonstrated that chemotherapy (OR 0.39; p<0.001) and chemo-radiotherapy (OR 0.61, p=0.049) were associated with longer survival, while no benefit was observed in the radiation alone group. Finally, patients with R1 resection (OR, 0.36; p<0 .002) and nodal involvement (OR, 0.49; p=0.004) seemed to achieve the greatest benefit from adjuvant treatment (Horgan 2012).
In conclusion, no clear evidence demonstrated the role of adjuvant chemotherapy or chemoradiation, the most part of the studies being retrospective, on small sample, quite frequently very heterogeneous (tumour sites, surgical treatment, adjuvant treatment).

6.2.1 Adjuvant chemotherapy

The role of adjuvant chemotherapy in resected cholangiocarcinoma is still debated; no randomized clinical trial demonstrated a significant survival advantage from adjuvant chemotherapy, mainly due to the small number of enrolled patients and extreme heterogeneity of tumour characteristics and treatment modality. Actually, few randomised trials and clinical results are available for adjuvant chemotherapy, the most of them deriving from retrospective analysis or performed on heterogeneous patients population (pancreatic and biliary tract cancer often associated) (Klinkencijl 1999) and on small number of patients.
In 2002, a randomised Japanese trial (Takada 2002) of adjuvant chemotherapy was published. A total of 508 patients entered the study after surgery and 139 had a bile duct carcinoma with positive lymph nodes. Chemotherapy (mitomycin C + 5-fluorouracil (5-FU) continuous infusion + oral 5-FU until progression) was compared with surgery alone. No benefit was demonstrated, neither in patients with positive resection margins, nor in those with negative ones (Takada 2002).
Probably the lack of effectiveness observed in clinical trials is due to the small number of patients and heterogeneity of the tumour and primary tumour site. In addition, we need to remember that surgery for cholangiocarcinoma has a relevant post-interventional morbidity (8-10%), with high risk of liver failure, biliary infections and clinical patients worsening which often contraindicate any adjuvant treatment at all.
Although, retrospective analysis and meta-analysis often show adjuvant chemotherapy as an independent favourable prognostic factor for better outcome after radical tumour resection, related with a longer survival and disease control rate. It is not yet clear which subgroup of patient really has a benefit from adjuvant treatment, even though the main part of retrospective data demonstrated a trend toward advantage from adjuvant treatment. Meta-analysis and retrospective analysis identified the subgroup with R1 resection and nodal involvement as those achieving real benefit from a post-surgical treatment. A recent meta-analysis by Horgan failed to demonstrate survival benefit from any adjuvant treatment in resected cholangiocarcinoma, but observed that adjuvant chemotherapy (both chemotherapy alone and plus radiotherapy) is associated with improved survival among patients with R1 resection and N1 stage (Horgan 2012).
Even though retrospective studies and meta-analysis support the adjuvant chemotherapy as associated with a better outcome, any phase III clinical trial has actually proved.
Although, even with the lack of strong clinical results, adjuvant chemotherapy should not be considered a standard of treatment in cholangiocarcinoma, but could be discussed in patients with high risk of tumour recurrence (such as R1 and N1 stage and intrahepatic cholangiocarcinoma). Both gemcitabine and 5fluoruracile should be considered in this setting, even though gemcitabine appear to be associated with better results. Combination chemotherapy – gemcitabine and S1 (Murakami 2009) and Gemcitabine and cisplatin (Toyoda 2014) – are under evaluation at the moment in the adjuvant setting.

6.2.2 Adjuvant radiotherapy

The main purpose of adjuvant radiotherapy is to sterilise the surgical margins and reduce local failure. Unfortunately, the most part of clinical trial and retrospective analysis did not demonstrate a real improvement in tumour control and survival with adjuvant radiation therapy, so radiotherapy has no a standard role in the adjuvant setting. Controversial results from retrospective analysis and meta-analysis have been observed, showing potential advantage form adjuvant radiotherapy in selected patients group. Pitt et al. compared outcome of patients with peri-hilar cholangiocarcinoma treated with surgery with or without adjuvant radiotherapy (Pitt 1995); the results showed no difference in outcome in the subgroup (20 months both) and the lack of efficacy was confirmed in other retrospective analysis (Cameron 1990; Sagawa 2005; Hyder 2014b).
A retrospective study (Shinoara 2008) analysed 3,839 patients with intrahepatic cholangiocarcinoma collected from SEER. Patients received surgery alone (25%), adjuvant radiation (7%), radiation alone (25%), and no treatment at all. Median overall survival resulted significantly longer in patients treated with adjuvant radiation than those treated with surgery alone (11 vs. 6 months), and for those treated with definitive radiation compared with no treatment (7 vs. 3 months). This retrospective analysis demonstrated that adjuvant radiation therapy could have a role in improving surgical outcome, even though local control rate remain dismal. Similar results have been observed in a retrospective study of 112 patients with perihilar tumours, in which patients who received adjuvant radiation after resection had statistically improved survival compared to resection alone (median survival: 19 vs. 8.3 months; 3-year survival: 31% vs. 10%, p = 0.0005) (Heron 2003). Although these interesting results in overall population, a retrospective analysis suggested that adjuvant radiation therapy can achieve survival advantage just in selected patients subgroup, especially in R1 resection (but apparently not in R2) and in gross hilar tumour that underwent surgery (Cheng 2007; Todoroki 2000; Kim 2002).
One retrospective study (Todoroki 2000) analysed the survival rate of 28 patients with microscopic residual tumour after resection and treated with radiotherapy (IORT + external-beam radiotherapy vs. IORT alone, vs. external-beam radiotherapy alone). The 5-year survival rate after treatment with IORT and postoperative external-beam radiotherapy was 39.2% compared to 16.7% for IORT alone and 0% for external-beam radiotherapy alone. Patients treated with radiotherapy (IORT + postoperative external-beam radiotherapy) had a statistically improved 5-year survival rate (39.2%) compared with those treated with surgery alone (13.5%).
Similar results derived from retrospective analysis about 296 Canadian patients by McNamara: adjuvant treatment (chemotherapy +/- radiotherapy) was associated with a longer OS (hazard ratio, 0.41; p=0.02); the most benefit being achieved by patients with R1 resection (p=0.02) and nodal involvement (hazard ratio, 0.60; 95%CI 0.38-0.95; p=0.03) (McNamara 2013).
In conclusion, there are no randomised trials assessing the role of adjuvant radiotherapy, retrospective data are inconclusive in demonstrating or denying activity of radiation therapy; therefore, radiation cannot be considered a standard of treatment in the adjuvant setting, although it could be discussed in selected patients (for example, R1 resection).

6.2.3 Adjuvant chemoradiation

Again no prospective clinical trial has been performed to assess the role of adjuvant chemoradiation, the main data resulting from retrospective analysis. The most commonly used concomitant chemotherapeutic agents were 5-fluorouracile and Gemcitabine.
Many studies showed that concomitant chemoradiation could achieve survival advantage in patients undergoing surgical treatment, significantly reducing percentage of local recurrence and with a trend for longer overall survival (16 vs. 10 months) (Nakeeb 2002). Even John Hopkins investigators reported their results with chemo-radiotherapy, demonstrating a significantly longer survival (36.9 months vs. 22 months; p<0.04) than patients treated with surgery alone (Hughes 2007). Similar results have been demonstrated in a number of other retrospective analysis (Kim 2002; Serafini 2001; Kim 2011).
Although, according to the extreme data heterogeneity, opposite results have been presented showing no survival difference among patients treated with surgery alone or with adjuvant chemo-radiotherapy (4.8 vs. 4.2 years). Although the subgroup of patients receiving adjuvant therapy had a higher percentage of stage II an N1 disease, the multivariate analysis demonstrated adjuvant chemoradiation as and independent prognostic factor for better outcome (Gold 2009).
Combined treatment has been evaluated; a Korean trial investigating the role of chemotherapy (fluoropirimidine-based) following adjuvant chemo-radiotherapy (with 5-year follow-up) in 120 patients with resected cholangiocarcinoma demonstrate a significant improvement both in overall survival and 3-years disease free survival (26.6% vs. 45.2%, p<0.04 for chemoradiation vs. chemoradiation followed by chemotherapy respectively) and 3-year OS rate (30.8% and 62.6%; p<0.01). This result confirms the central role of chemotherapy (maybe most of radiotherapy) in the adjuvant setting for resected cholangiocarcinoma, above all in R1 resection (Lim 2009).
Another recent meta-analysis, evaluating clinical trials about adjuvant chemotherapy and chemoradiation, confirmed the survival benefit derived from the chemotherapy, but not from concomitant treatment (Zhu 2014). The authors analysed 12 studies, for a total of 1,361 patients treated with surgery followed by adjuvant chemotherapy (gemcitabine and/or 5fluoruracile) or chemo-radiotherapy. Concomitant treatment failed to demonstrate survival benefit, while chemotherapy improved patients’ outcome. Gemcibtabine appears to be the most efficient treatment with a significant impact on disease recurrence and 5-years overall survival, in comparison with both 5-fluorouracile (OR 1.56; 95%CI 0.77-3.35) and chemo-radiotherapy (OR 0.46; 95% CI 0.20-0.97).
Finally, other studies demonstrate activity of adjuvant chemoradiation only in selected case, in particular in patients with N1-2 stage and R1 resection. Park et al. retrospectively analysed the outcome of 101 patients who received adjuvant chemo-radiotherapy, among them 45% had R1 o R2 resection (Park 2011). The results demonstrated a trend (but not statistically significant difference) for a better local disease control and longer survival among patients with R1 resection (Park 2011). Borghero et al (Borghero 2008) reviewed 65 patients with resected hilar cholangiocarcinoma; among them, patients with high risk of recurrence (R1, R2, N1 stage) received postoperative chemoradiation achieving similar results in term of overall survival (36% vs. 42%; p=0.6) and 5 year disease free survival rate (36% vs. 37%; p=0.13) of patients with good prognostic factor treated with surgery alone. This result could define a role for chemoradiation in high-risk patients undergoing surgery (surgical margin involvement, nodal metastases) (Borghero 2008).
In conclusion, adjuvant chemoradiation cannot be considered a standard of treatment, as no conclusive data are available in this setting. It could have a role in R1-R2 and N1 stage disease, but further investigations are needed to confirm retrospective data.

6.2.4 Neoadjuvant treatment

Neoadjuvant chemo-radiotherapy can be an option for selected patients. McMasters (McMasters 1997) reported 9 patients with extrahepatic bile duct cancer who underwent preoperative chemoradiation. A pathological complete response was obtained in 3 patients, and negative margins in 100% (McMasters 1997). In patients with stage I or II of cholangiocarcinoma, Rea and colleagues reported a 1-, 3-, and 5-year survival of 82%, 48%, and 21%, respectively, after neoadjuvant radiotherapy, chemosensitisation and resection and 25% of recurrence (Rea 2005). This treatment requires further confirmation. As a consequence, the role of neoadjuvant therapy remains investigational.
A novel optional treatment for cholangiocarcinoma is preoperative chemo-radiotherapy followed by liver transplantation (Rea 2005).
It has been demonstrated, even if in small number series, that preoperative chemoradiation followed by liver transplantation in hilar cholangiocarcinoma improves patients outcome in term of relapse rate over standard surgical treatment (with 5 year disease free survival 33% vs. 0% in liver transplantation and resection respectively) (Casavilla 1997; Shimoda 2001).
One of the most relevant studies supporting this approach is the analysis of 12 institutions results in treating hilar cholangiocarcinoma with neoadjuvant treatment and liver transplantation. A total of 287 records have been analysed, patients with locally advanced unresectable hilar cholangiocarcinoma without nodal or distant metastasis received preoperative radiation or chemoradiation followed by maintenance chemotherapy (65%) until liver transplantation. Patients undergoing liver transplantation had very good results, with 5-year survival rate of 65% (Muras 2012). A novel approach has been proposed by Welling at al. (Welling 2014) who show promising results from stereotactic radiotherapy followed by chemotherapy and liver transplantation in small series of patients with hilar cholangiocarcinoma (Welling 2014; Darwish Murad 2012). Further studies will determine the overall future efficacy of this therapy.

6.3 Palliative therapy

6.3.1 Chemoradiotherapy in locally advanced disease

A standard of treatment for locally advanced cholangiocarcinoma has not yet been defined. Hilar and perihilar cholangiocarcinoma can have benefit from concomitant chemoradiation, which demonstrated to improve OS in this subgroup (Foo 2006). Additionally, it is known that selected case of hilar cholangiocarcinoma can benefit from preoperative chemoradiation followed by liver transplantation, but these represent a minority of the cases (locally advanced, non nodal or distant metastases). It has been long time evaluated the role of concomitant chemoradiation in locally advanced disease, but a definite conclusion has not been reached yet. Kim et al. (Kim 2013) evaluated the activity of concomitant treatment in locally advanced intrahepatic cholangiocarcinoma in retrospective series. They considered 92 patients, receiving Capecitabine and cisplatin alone or in combination with radiation therapy. Concurrent treatment achieve a higher (but no statistically significant) disease control rate (46% vs. 41%; p=0.2), after a median follow-up of 5.3 months both overall survival and progression free survival were significantly longer in the chemoradiation group (PFS 4.3 vs. 1.9 months; p=0.001 – OS 9.3 vs. 6.2 months; p=0.048) (Kim 2013).
These results should be confirmed in prospective randomised trial, in order to define a standard of treatment.

6.3.2 Chemotherapy in advanced disease

The most part of cholangiocarcinoma is diagnosed at advanced unresectable stage, in this case symptoms palliation and disease control are the aims of treatment. Chemotherapy is the treatment of choice for patients with good performance status: it improves median survival time, even if overall survival remains dismal even in treated patient (median overall survival not exceeding 10 months).
The role of chemotherapy in improving patients outcome over best supportive care has been firstly define by Glimelius et al. (Glimelius 1996) in a randomised trial comparing best supportive care and chemotherapy (5fluorouracile/lederfolin with or without etoposide) in patients with pancreatic and biliary tract cancer. Chemotherapy significantly improved overall survival (6 months vs. 2.5 months) and was associated with a longer time to quality of life deterioration (4 months vs. 1.5 months) (Glimelius 1996). The greatest limit of this study is the contemporary enrolment of pancreatic and biliary tract cancer, which could interfere with the actual results for biliary tract cancer. Many following trials demonstrated gemcitabine-based chemotherapy to be an adequate alternative to 5fluoruracile-based treatment (Dingle 2005).
Retrospective study comparing gemcitabine- and fluoropirimidine-based treatment for cholangiocarcinoma, as no real standard existed until 2010, many combination have been used along time. Kim et al. (Kim 2008) analysed the outcome of 291 patients and did not find any statistical difference between gemcitabine- and fluoropirimidine-based chemotherapy in term of overall response rate, overall survival, and disease free survival; while the addition of platinum to both chemotherapeutic agent seamed to improve patients outcome, with a median overall survival of 10.6 vs. 8.1 months (p=0.257) (Kim 2008).
One of the first phase III clinical trial comparing chemotherapy with best supportive care specifically in cholangiocarcinoma has been published in 2010 (Sharma 2010). Eligible patient (unresectable gallbladder cancer) were randomised to receive chemotherapy with GEMOX (Gemcitabine and oxaliplatin), 5fluorouracile or best supportive care. The results confirmed the efficacy of chemotherapy, demonstrating a survival advantage in patients treated with GEMOX comparing with 5fluorouracil and best supportive care, with a median overall of 9.1 months vs. 4.9 and 4.5 months respectively (p=0.039); even response rate was higher in GEMOX arm.
Accordingly to these results, combination chemotherapy appeared to be more active than monotherapy in cholangiocarcinoma, and a number of phase II clinical trial investigating gemcitabine and platinum compound combination (both Oxaliplatin and Cisplatin combination) confirmed very promising results leading to further investigation in phase-III trial (Valle 2009; Lee 2006; André 2008; André 2004). A pooled meta-analysis confirmed that platinum compound and gemcitabine-based combination chemotherapy resulted to be more active than monotherapy (Eckel 2007; Yang 2013).
On the basis of such results, a phase III trial by Valle et al. (Valle 2010) finally defined gemcitabine and cisplatin (GEMCIS) combination as the standard of treatment for advanced cholangiocarcinoma (Valle 2010). It is a randomised phase III trial: 410 patients have been enrolled and received either gemcitabine alone (1,000 mg/m2 day 1, 8, and 15) every 28 days or gemcitabine (1,000 mg/m2 day 1 and 8) and cisplatin (25 mg/m2 day 1 and 8) every 21 days. The median overall survival was statistically longer for patients treated with GEMCIS (11.7 months) than those treated with gemcitabine alone (8.1 months; HR 0.64; 95%CI 0.52-0.80; p<0.001). This finding has been confirmed in similar phase III Japanese trial (Okusaka 2010), and from the pooled analysis of these trials, defining gemcitabine and cisplatin combination as the standard of treatment in advanced cholangiocarcinoma (Valle 2014).
French investigator compared oxaliplatin and cisplatin in combination with gemcitabine, reviewing all the available trials investigating GEMCIS and GEMOX combination (1,470 patients). The results suggested a longer survival in patients treated with GEMCIS (11.7 vs. 9.7 months), but with higher rate of toxicity (asthenia, liver toxicity, haematological, diarrhea) (Fiteni 2014).
Other therapeutic drug combination have been considered in the first line treatment of advanced/metastatic disease. One of the most promising is the combination of fluoropirimidine and platinum compound (FOLFOX, Capecitabine/Oxalipaltin and Capecitbiane/cisplatin) (Nehls 2008; Novarino 2013). Nowadays any randomized phase III trial has directly compared efficacy of gemcitabine-platinum and fluoropyrimidine-platinum combination chemotherapy. The only exception is a phase II trial (Lee 2015) comparing the activity of Capecitabine (XP) and gemcitabine (GP) in combination with cisplatin. Even though the small number of patients enrolled (49 treated with GP and 44 with XP), XP demonstrated to be more active than GP in term of response rate, while not significant difference have been observed in median OS (10.7 months and 8.6 months, for XP and GP respectively; p=0.365) (Lee 2015). Considering these results, further investigation should be considered, above all to draw and adequate treatment strategy. Indeed similar results were presented in a phase II trial comparing first line treatment with fluoropirimidine and cisplatin (FP) with Gemcitabine and cisplatin (GP). As for Lee’s trial, median overall survival was the same among treatment arms; but when considered patients receiving second line treatment a longer (even though not statistically significant) overall survival was achieved in the group treated with FP first line followed by GP second line than for the reverse sequence (19 vs. 13.2 months) (Croitoru 2012).
Other potentially active regimens are under evaluation, for example gemcitabine and Capecitabine combination (Iyer 2007; Knox 2005), or combination chemotherapy comprehending fluoropirimidine, gemcitabine and platinum compound with promising results (Yamashita 2010; Cereda 2010). Despite being promising, the results are not yet conclusive and further investigation should be performed.
Since the last decade, targeted therapies in association with standard have been investigated: cetuximab, panitumumab and erlotinib are the most promising drug in phase II trials (Philip 2006; Lubner 2010; Borbath 2013; Rubovszky 2013; Gruenberger 2010). Phase III trials failed to demonstrate enhanced activity from combination treatment with erlotinib, or cetuximab with GEMCIS and / or GEMOX, phase III trial (Lee 2012; Malka 2014).
In conclusion:

  • at the moment, the standard of treatment in advanced cholangiocarcinoma is Gemcitabine and Cisplatin combination;
  • meta-analysis and retrospective data supported GEMOX combination, but it did not resulted as effective as Gemcitabine and Cisplatin, even though maybe less toxic;
  • Fluoropirimidine/platinum compound can be possible alternative to GEM/CIS, but we have not enough strong evidences supporting its use in first line therapy;
  • Gemcitabine and fluoropirimidine can be another possible alternative treatment in patients who cannot receive combination chemotherapy;
  • no activity hs been described for targeted therapies (anti EGFR TKI and monoclonal antibody) in cholangiocarcinoma.
6.3.3 Second line chemotherapy

Second line chemotherapy cannot be considered as a standard of treatment in cholangiocarcinoma, although it can be discussed in selected cases. Due to the cholangiocarcinoma aggressive behaviour, failure of first line treatment is often associated with significant clinical deterioration that contraindicate further chemotherapy. In selected patients: with good performance status, long PFS after first line chemotherapy (>6 months), resected primary tumour and low CA 19.9 value, second line treatment can improve patients survival and quality of life (Fornaro 2014).
Considering the small percentage of patients able to undergo second line treatment, very limited literature data are available in this setting. Mainly retrospective studies showed a marginal survival advantage in second line chemotherapy, but with weak evidence of activity of second line treatment (Bridgewater 2013; Walter 2013; Lamarca 2014; Rogers 2014). Options for second-line systemic chemotherapy can include, if not used in first line, Gemcitabine and Fluoropirimidine monotherapy or in combination (GEM/5FU, GECP, FOLFOX, FOLFIRI, GEMOX).

6.3.4 Locoregional treatment

Intrahepatic cholangiocarcinoma local extension often controindicates surgical resection: in these cases, locoregional treatment option could be evaluated.
Potential treatment options, currently under investigation, are: transarterial chemoembolization (TACE), intra-arterial chemotherapy, radiofrequency ablation (RFA).
Intra-arterial chemotherapy administration (both TACE and hepatic arterial chemotherapy) has been evaluated in intrahepatic cholangiocarcinoma. Transarterial chemoembolisation is associated with a good disease control rate (20% of partial response and 60% of disease stabilisation, independently from chemotherapeutic agents), and a median overall survival of 13 to 20 months both in retrospective analysis and prospective analysis (Hyder 2013; Vogl 2012).
Other potential alternative locoregional approach is hepatic arterial chemotherapy infusion which, in retrospective data and phase I and II trial, guarantees a promising tumour control rate (with 16% of partial response and 65% of stable disease), achieving median overall survival of 13 months (Sinn 2013; Hayashi 2012).
Hilar cholangiocarcinoma, is mainly associated with locally advanced disease and biliary duct obstruction. Photodynamic therapy is a palliative option in hilar and perihilar cholangiocarcinoma, achieving a good locoregional tumour control. Biliary decompression, with endoscopic or percutaneous stenting reduces the risk of infectious cholangitis and improves quality of life, but it does not affect patients survival. Photodynamic therapy with the photosensitizer porfimer and endoscopic direct illumination of the tumour by laser light of 630 nm causes the generation of oxygen free radicals and induces tumour necrosis, with a tissue penetration to a depth of only 4-4.5 mm, which does not eradicate tumours but improves local control. Photodynamic therapy has a role in improve stent patency, biliary drainage, quality of life. Recent meta-analysis demonstrated that photodynamic therapy associated with biliary stenting is associated with improved survival if compared to biliary stenting alone, other than improved draingare and quality of life (Leggett 2012; Berr 2000). Even though the promising data regarding TACE, TAE and photodynamic therapy, low level of evidence supports their use in the clinical practice. These approach can be discussed in clinical trial setting and performed in highly specialized centres

7. LATE SEQUELAE

After surgery, complications consist of wound infections, sepsis, fistulae, cholangitis and, in cases of pancreaticoduodenectomy, delayed gastric empting (Nakeeb 1996). Hilar cholangiocarcinoma requires an aggressive resection (partial hepatectomy), but the risk is the development of postoperative liver remnant dysfunction or failure (encephalopathy, ascites, coagulopathy). This risk can be reduced with preoperative portal vein embolization, inducing controlateral liver hypertrophy. Preoperative bililiary decompressionwith biliary stenting is recommended in order to reduce the risk of postoperative complications. Metallic stent positioning does not contraindicate surgery, even though plastic stent is mainly used in the preoperative setting. It requires endoscopic procedure (ERCP), but percutaneous approach can be considered in case of endoscopic procedure failure. The procedures can lead to bacterial colonization and cholangitis in some series, which increased the risk of postoperative infection (Deviere 1988; Hochwald 1999; van der Gaag 2010).
Jaundice palliation is mandatory even in advanced disease in order to both improve quality of life and to allow palliative treatment (chemotherapy and /or radiotherapy) administration. Whether it is possible, endoscopic approach is preferable (ERCP) with plastic or metal stent positioning. In case of tumour localisation and growth preventing ERCP, percutaneous approach for biliary drainage is safe and equally effective as ERCP (Shah 2014). Jaundice drainage can be associated with early and late sequelae; ERCP can be complicated by bleeding, acute pancreatitis and cholangitis, while percutaneous approach has a lower incidence of compliations (Paik 2009). The most frequent late complication is biliary stent obstruction, which often requires stent replacement, other than medical treatment (antibiotics, iv hydration) (Inal 2003).
Common toxicities related to chemotherapy are nausea, vomiting, neutropenia, and anaemia

8. FOLLOW-UP

There are no standard guidelines for surveillance after surgery. The role of the tumour marker, CA 19-9, has not been established, although a persistently rising level is suspected to be an indicator of recurrence, often appearing several months earlier than radiological evidence. Based on the lack of clinical trials a rational postoperative surveillance should include a physical examination and laboratory tests every 3 or 4 months for the first 3 years after surgery, then every 6 months until year 5. CT scan of the abdomen should be performed every 6 months for 2 to 3 years after surgery to detect recurrence.

INDEX

 

Abulwerdi FA, Liao C, Mady AS, Gavin J, Shen C, Cierpicki T et al. 3-Substituted-N-(4-hydroxynaphthalen-1yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: structure-based design, synthesis, SAR, and biological evaluation. J Med Chem 2014; 57(10): 4111-33. [Medline]

Adenugba A, Khan SA, Taylor-Robinson SD, Cox IJ, Toledano MB, Thillainayagam AV et al. Polychlorinated biphnyls in bile of patients with primary tract cancer. Chemosphere 2009; 76(6): 841-6. [Medline]

Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma, 1990-2009. World J Gastroenterol 2009; 15(34): 4240-62. [Medline]

Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 2012; 142(4): 1021-31. [Medline]

Anderson CD, Rice MH, Pinson CW, Chapman WC, Chari RS, Delbeke D. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg 2004; 8(1): 90-7. [Medline]

André T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F. Avenin D et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol 2004; 15(9): 1339-43. [Medline]

André T, Reyes-Vidal JM, Fartoux L, Ross P, Leslie M, Rosmorduc O et al. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J Cancer 2008; 99(6): 862-7. [Medline]

Appleman LJ. MET signaling pathway: a rational target for cancer therapy. J Clin Oncol 2011; 29(36): 4837-8. [Medline]

Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 2014; 59(4): 1427-34. [Medline]

Ben-Menachem T. Risk factors for cholangiocarcinoma. Eur J Gastroenterol Hepatol 2007; 19(8): 615-7. [Medline]

Bergquist A, Glaumann H, Persson B, Broomé U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 1998; 27(2): 311-6. [Medline]

Berr F, Wiedmann M, Tannapfel A, Halm U, Kohlhaw KR, Schmidt F et al. Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. Hepathology 2000; 31(2): 291-8. [Medline]

Birnbaum DL, Viganò L, Ferrero A, Langella S, Russolillo N, Capussotti L. Locally advanced gallbladder cancer: Which patients benefit from resection? Eur J Surg Oncol 2014; 40(8): 1008-15. [Medline]

Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992; 215(1): 31-8. [Medline]

Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2011; 8(9): 512-22. [Medline]

Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014; 60(6): 1268-89. [Medline]

Borad MJ, Champion MD2, Egan JB3, Liang WS4, Fonseca R1, Bryce AH et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet 2014; 10(2): e1004135. [Medline]

Borbath I, Ceratti A, Verslype C, Demols A, Delaunoit T, Laurent S et al. Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology. Ann Oncol 2013; 24(11): 2824-9. [Medline]

Borghero Y, Crane CH, Szklaruk J, Oyarzo M, Curley S, Pisters PW et al. 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 Oncol 2008; 15(11): 3147-56. [Medline]

Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014; 60(6): 1268-89. [Medline]

Bridgewater J, Palmer D, Cunningham D, Iveson T, Gillmore R, Waters J et al. Outcome of second-line chemotherapy for biliary tract cancer. Eur J Cancer 2013; 49(6): 1511. [Medline]

Brown KM, Gleller DA. Proximal biliary tract. Surg Clin N Am 2014; 94(2): 311-23. [Medline]

Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 2004; 99(3): 523-6. [Medline]

Butte JM, Kingham TP, Gönen M, D’Angelica MI, Allen PJ, Fong Y et al. Residual disease predicts outcomes after definitive resection for incidental gallbladder cancer. J Am Coll Surg 2014; 219(3): 416-29. [Medline]

Callea F, Sergi C, Fabbretti G, Brisigotti M, Cozzutto C, Medicina D. Precancerous lesions of the biliary tree. J Surg Oncol Suppl 1993; 3: 131-3. [Medline]

Cameron JL, Pitt HA, Zinner MJ, Kaufman SL, Coleman J. Management of proximal cholangiocarcinomas by surgical resection andradiotherapy. Am J Surg 1990; 159(1): 91-7; discussion 97-8. [Medline]

Cardinale V, Semeraro R, Torrice A, Gatto M, Napoli C, Bragazzi MC et al. Intra-hepatic and extra-hepatic cholangiocarcinoma: New insight into epidemiology and risk factors. World J Gastrointest Oncol 2010; 2(11): 407-16. [Medline]

Casavilla FA, Marsh JW, Iwatsuki S, Todo S, Lee RG, Madariaga JR et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 1997; 185(5): 429-36. [Medline]

Cereda S, Passoni P, Reni M, Viganò MG, Aldrighetti L, Nicoletti R et al. The cisplatin, epirubicin, 5-fluorouracil, gemcitabine (PEFG) regimen in advanced biliary tract adenocarcinoma. Cancer 2010; 116(9): 2208-14. [Medline]

Chan-On W, Nairismägi ML, Ong CK, Lim WK, Dima S, Pairojkul C et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet 2013; 45(12): 1474-8. [Medline]

Chartbotel B, Fervers B, Droz JP. Occupational exposure in rare cancers: a critical review of the literature. Crit Rev Oncol/Hematol 2013; 90(2): 99-134. [Medline]

Chen W, Ke K, Chen YL. Combined portal vein resection in the treatment of hilar cholangiocarcinoma: a systematic review and meta-analysis. Eur J Surg Oncol 2014; 40(5): 489-95. [Medline]

Cheng Q, Luo X, Zhang B, Jiang X, Yi B, Wu M. Predictive factors for prognosis of hilar cholangiocarcinoma: postresection radiotherapy improves survival. Eur J Surg Oncol 2007; 33(2): 202-7. [Medline]

Chua TC, Saxena A. Extended pancreaticoduodenectomy with vascular resection for pancreatic cancer: a systematic review. J Gastrointest Surg 2010; 14(9): 1442-52. [Medline]

Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol 2009; 50(1): 158-64. [Medline]

Clapéron A, Mergey M, Aoudjehane L, Ho-Bouldoires TH, Wendum D, Prignon A et al. Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor. Hepatology 2013; 58(6): 2001-11. [Medline]

Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 2008; 7(6): 504-16. [Medline]

Corvera CU, Blumgart LH, Akhurst T, DeMatteo RP, D’Angelica M, Fong Y et al. 18F- fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg 2008, 206(1): 57-65. [Medline]

Costello BA, Borad MJ, Qi Y, Kim GP, Northfelt DW, Erlichman C et al. Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. Invest New Drugs 2014; 32(4): 710-6. [Medline]

Croitoru A, Gramaticu I, Dinu I, Gheorghe L, Alexandrescu S, Buica F et al. Fluoropyrimidines plus Cisplatin versus gemcitabine/gemcitabine plus cisplatin in locally advanced and metastatic biliary tract carcinoma – a retrospective study. J Gastrointestin Liver Dis 2012; 21(3): 277-84. [Medline]

D’Hondt M, Lapointe R, Benamira Z, Pottel H, Plasse M, Letourneau R et al. Carcinoma of the gallbladder: patterns of presentation, prognostic factors and survival rate. An 11-year single center experience. Eur J Surg Oncol 2013; 39(6): 548-53. [Medline]

Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 2012; 143(1): 88-98. [Medline]

de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 1999; 341(18): 1368-78. [Medline]

de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011; 29(23): 1340-5. [Medline]

DeClerck YA. Desmoplasia: a response or a niche? Cancer Discov 2012; 2(9): 772-4. [Medline]

DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007; 245(5): 755-62. [Medline]

DeOliveira ML, Schulick RD, Nimura Y, Rosen C, Gores G, Neuhaus P et al. New staging system and a registry for perhilar cholangiocarcinoma. Hepatology 2011; 53(4): 1363-71. [Medline]

Deviere J, Baize M, de Toeuf J, Cremer M. Long-term follow-up of patients with hilar malignant stricture treated by endoscopic internal biliary drainage. Gastrointest Endosc 1988; 34(2): 95-101. [Medline]

Dickson PV, Bhrman SW. Distal cholangiocarcinoma. Surg Clin N Am 2014; 94(2): 325-42. [Medline]

Dingle B, Rumble RB, Brouwers MC, Cancer Care Ontario’s Program in evidence-base care’s Gastrointetinal Cancer Disease Site Group. The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: a systematic review. Can J Gastreoenterol 2005; 19(12): 711-6. [Medline]

Dwyer JR, Sever N, Carlson M, Nelson SF, Beachy PA, Parhami F. Oxysterols are novel activators of the Hedgehog signaling pathway in pluripotent mesenchymal cells. J Biol Chem 2007; 282(12): 8959-68. [Medline]

Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y, Nagino M. Portal vein embolization before extended hepatectomy for biliary cancer: current technique and review of 494 consecutive embolizations. Dig Surg 2012; 29(1): 23-9. [Medline]

Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007; 96(6): 896-902. [Medline]

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds). AJCC Cancer Staging Manual. 7th edition. New York, Springer, 2010.

Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival and determinants of outcome after resection. Ann Surg 2008; 248(1): 84-96. [Medline]

Escudier B, Grünwald V, Ravaud A, Ou YC, Castellano D, Lin CC et al. Phase II results of Dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res 2014; 20(11): 3012-22. [Medline]

Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: liver, biliary tract and pancreas. Gastroenterology 2009; 136(4): 1134-44. [Medline]

Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest 2012; 122(8): 2911-5. [Medline]

Fava G, Marzioni M, Benedetti A, Glaser S, DeMorrow S, Francis H et al. Molecular pathology of biliary tract cancers. Cancer Lett 2007; 250(2): 155-67. [Medline]

Fingas CD, Bronk SF, Werneburg NW, Mott JL, Guicciardi ME, Cazanave SC et al. Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells. Hepatology 2011; 54(6): 2076-88. [Medline]

Fiteni F, Nguyen T, Vernerey D, Paillard MJ, Kim S, Demarchi M et al. Cisplatin/gemcitabine or oxaliplatin/gemcitabine in the treatment of advanced biliary tract cancer: a systematic review. Cancer Med 2014; 3(6): 1502-11. [Medline]

Foo ML, Gunderson LL, Bender CE, Buskirk SJ. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 1997; 39(4): 929-35. [Medline]

Fornaro L, Cereda S, Aprile G, Di Girolamo S, Santini D, Silvestris N et al. Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer. Br J Cancer 2014; 110(9): 2165-9. [Medline]

Foster JM, Hoshi H, Gibbs JF, Iyer R, Javle M, Chu Q et al. Gallbladder cancer: defining the indications for primary radical resection and radical re-resection. Ann Surg Oncol 2007; 14(2): 833-40. [Medline]

Fu BS, Zhang T, Li H, Yi SH, Wang GS, Xu C et al. The role of liver transplantation for intrahepatic cholangiocarcinoma: a single-center experience. Eur Surg Res 2011; 47(4): 218-21. [Medline]

Gao Q, Zhao YJ2, Wang XY1, Guo WJ3, Gao S4, Wei L et al. Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients. Gastroenterology 2014; 146(5): 1397-407. [Medline]

Gatta G, Ferrari A, Stiller CA, Pastore G, Bisogno G, Trama A et al; RARECARE Working Group. Embryonal cancers in Europe. Eur J Cancer 2012; 48(10): 1425-33. [Medline]

Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996; 7(6): 593-600. [Medline]

Gold DG1, Miller RC, Haddock MG, Gunderson LL, Quevedo F, Donohue JH et al. Adjuvant therapy for gallbladder carcinoma: the Mayo Clinic experience. Int J Radiat Oncol Biol Phys 2009; 75(1): 150-5. [Medline]

Gores GJ. Cholangiocarcinoma: current concepts and insight. Hepatology 2003; 37(5): 961-9. [Medline]

Graham RP, Barr Fritcher EG1, Pestova E2, Schulz J2, Sitailo LA2, Vasmatzis G et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol 2014; 45(8): 1630-8. [Medline]

Grassian AR, Pagliarini R, Chiang DY. Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 2014; 30(3): 295-302. [Medline]

Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D, Kaczirek K et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 2010; 11(12): 1142-8. [Medline]

Gu TL, Deng X, Huang F, Tucker M, Crosby K, Rimkunas V et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One 2011; 6(1): e15640. [Medline]

Guagnano V, Kauffmann A, Wöhrle S, Stamm C, Ito M, Barys L et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012; 2(12): 1118-33. [Medline]

Guglielmi A, Ruzzenente A, Campagnaro T, Valdegamberi A, Bagante F, Bertuzzo F et al. Patterns and prognostic significance of lymph node dissection for surgical treatment of perihilar and intrahepatic cholangiocarcinoma. J Gastrointest Surg 2013; 17(11): 1917-28. [Medline]

Haigh WG, Lee SP. Identification of oxysterols in human bile and pigment gallstones. Gastroenterology 2001; 121(1): 118-23. [Medline]

Hann LE, Greatrex KV, Bach AM, Fong Y, Blumgart LH. Cholangiocarcinoma at the hepatic hilus: sonographic findings. AJR Am J Roentgenol 1997; 168(4): 985-9. [Medline]

Haswell-Elkins MR, Sithithaworn P, Mairiang E, Elkins DB, Wongratanacheewin S, Kaewkes S et al. Immune responsiveness and parasite-specific antibody levels in human hepatobiliary disease associated with Opisthorchis veverrini infection. Clin Exp Immunol 1991; 84(2): 213-8. [Medline]

Hayashi T, Ishiwatari H, Yoshida M, Sato T, Miyanishi K, Sato Y et al. A phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable biliary tract cancer. Int J Clin Oncol 2012; 17(5): 491-7. [Medline]

He P, Shi JS, Chen WK, Wang ZR, Ren H, Li H. Multivariate statistical analysis of clinicopathologic factors influencing survival of patients with bile duct carcinoma. World J Gastroenterol 2002; 8(5): 943-6. [Medline]

Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Nyberg SL, Ishitani MB et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis 2004; 24(2): 201-7. [Medline]

Hemming AW, Reed AI, Fujita S, Foley DP, Howard RJ. Surgical management of hilar cholangiocarcinoma. Ann Surg 2005; 241(5): 693-9 ; discussione 699-702. [Medline]

Heron DE, Stein DE, Eschelman DJ, Topham AK, Waterman FM, Rosato EL et al. Cholangiocarcinoma: the impact of tumor location and treatment strategy on outcome. Am J Clin Oncol 2003; 26(4): 422-8. [Medline]

Hochwald SN, Burke EC, Jarnagin WR, Fong Y, Blumgart LH. Association of preoperative biliary stenting with increased postoperative infectious complications in proximal cholangiocarcinoma. Arch Surg 1999; 134(3): 261-6. [Medline]

Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 2010; 137(23): 4061-72. [Medline]

Holczbauer A, Factor VM, Andersen JB, Marquardt JU, Kleiner DE, Raggi C et al. Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 2013; 145(1): 221-31. [Medline]

Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 2012; 30(16): 1934-40. [Medline]

Hughes MA, Frassica DA, Yeo CJ, Riall TS, Lillemoe KD, Cameron JL et al. Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct. Int J Radiat Oncol Biol Phys 2007; 68(1): 178-82. [Medline]

Hyder O, Marsh JW, Salem R, Petre EN, Kalva S, Liapi E et al. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol 2013; 20(12): 3779-86. [Medline]

Hyder O, Marques H, Pulitano C, Marsh JW, Alexandrescu S, Bauer TW t al. A nomogram to predict long-term survival after resection for intrahepatic cholangiocarcinoma: an Eastern and Western experience. JAMA Surg 2014a; 149(5): 432-8. [Medline]

Hyder O, Dodson RM, Sachs T, Weiss M, Mayo SC, Choti MA et al. Surgery. Impact of adjuvant external beam radiotherapy on survival in surgically resected gallbladder adenocarcinoma: a propensity score-matched Surveillance, Epidemiology, and End Results analysis. Surgery 2014b; 155(1): 85-93. [Medline]

Inal M, Akgül E, Aksungur E, Demiryurek H, Yagmur O. Percutaneous self-expandable uncovered metallic stents in malignant biliary obstruction. Complications, follow-up and reintervention in 154 patients. Acta Radiol 2003; 44(2): 139-46. [Medline]

Isa T, Tomita S, Nakachi A, Miyazato H, Shimoji H, Kusano T et al. Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepatogastroenterology 2002; 49(45): 604-8. [Medline]

Ishimura N, Bronk SF, Gores GJ. Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes: implications for carcinogenesis. Gastroenterology 2005; 128(5): 1354-68. [Medline]

Isomoto H, Kobayashi S, Werneburg NW, Bronk SF, Guicciardi ME, Frank DA et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology 2005; 42(6): 1329-38. [Medline]

Iyer RV, Gibbs J, Kuvshinoff B, Fakih M, Kepner J, Soehnlein N et al. A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: a single-institution prospective study. Ann Surg Oncol 2007; 14(11): 3202-9. [Medline]

Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 2000; 60(1): 184-90. [Medline]

Jaiswal M, LaRusso NF, Shapiro RA, Billiar TR, Gores GJ. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes. Gastroenterology 2001; 120(1): 190-9. [Medline]

Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BS J et al. Staging, resecability and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001; 234(4): 507-17; discussion 517-9. [Medline]

Jarnagin WR, Shoup M. Surgical management of cholangiocarcinoma. Semin Liver Dis 2004; 24(2): 189-99. [Medline]

Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 2013; 45(12): 1470-3. [Medline]

Jonas S, Benckert C, Thelen A, Lopez-Hänninen E, Rösch T, Neuhaus P. Radical surgery for hilar cholangiocarcinoma. Eur J Surg Oncol 2008; 34(3): 263-71. [Medline]

Khan SA, Thomas HC, Toledano MB, Cox IJ, Taylor-Robinson SD. p53 Mutations in human cholangiocarcinoma: a review. Liver Int 2005; 25(4): 704-16. [Medline]

Kiguchi K, Carbajal S, Chan K, Beltrán L, Ruffino L, Shen J et al. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 2001; 61(19): 6971-6. [Medline]

Kim MJ, Oh DY, Lee SH, Kim DW, Im SA, Kim TY et al. Gemcitabine-based versus fluoropyrimidine-based chemotherapy with or without platinum in unresectable biliary tract cancer: a retrospective study. BMC Cancer 2008, 8: 374. [Medline]

Kim S, Kim SW, Bang YJ, Heo DS, Ha SW. Role of postoperative radiotherapy in the management of extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys 2002; 54(2): 414-9. [Medline]

Kim TH, Han SS, Park SJ, Lee WJ, Woo SM, Moon SH et al. Role of adjuvant chemoradiotherapy for resected extrahepatic biliary tractcancer. Int J Radiat Oncol Biol Phys 2011; 81(5): 853-9. [Medline]

Kim YI, Park JW, Kim BH, Woo SM, Kim TH, Koh YW et al. Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma. Radiat Oncol 2013, 8: 292. [Medline]

Kim YJ, Yun M, Lee WJ, Kim KS, Lee JD. Usefulness of 18FDG-PET in intrahepatic cholangiocarcinoma. Eur J Nucl Med Mol Imaging 2003; 30(11): 1467-72. [Medline]

Kipp BR, Voss JS, Kerr SE, Barr Fritcher EG, Graham RP, Zhang L et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol 2012; 43(10): 1552-8. [Medline]

Klempnauer J, Ridder GJ, von Wasielewski R, Werner M, Weimann A, Pichlmayr R. Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 1997; 15(3): 947-54. [Medline]

Knox JJ, Hedley D, Oza A, Feld R, Siu LL, Chen E et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 2005; 23(10): 2332-8. [Medline]

Kobayashi S, Werneburg NW, Bronk SF, Kaufmann SH, Gores GJ. Interleukine-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells. Gastroenterology 2005; 128(7): 2054-65. [Medline]

Konstadoulakis MM, Roayaie S, Gomatos IP, Labow D, Fiel MI, Miller CM et al. Aggressive surgical resection for hilar cholangiocarcinoma: is it justified? Audit of a single center’s experience. Am J Surg 2008; 196(2): 160-9. [Medline]

Kuver R. Mechanisms of oxysterol-induced disease: insights from the biliary system. Clin Lipidol 2012; 7(5): 537-48. [Medline]

Lafaro KJ, Cosgrove D, Geschwind JFH, Kamel I, Herman JM, Pawlik TM, Multidisciplinary care of patients with intrahepatic cholangiocarcinoma: updates in management. Gastroenterol Res Pract 2015;2015:860861. [Medline]

Lamarca A, Hubner RA, David Ryder, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol 2014; 25(12): 2328-38. [Medline]

Lee J, Hong TH, Lee IS, You YK, Lee MA. Comparison of the Efficacy between Gemcitabine-Cisplatin and Capecitabine-Cisplatin Combination Chemotherapy for Advanced Biliary Tract Cancer. Cancer Res Treat 2015; 47(2): 259-65. [Medline]

Lee J, Park SH, Chang HM, Kim JS, Choi Hj, Lee MA et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2012; 13(2): 181-8. [Medline]

Lee GW, Kang JH, Kim HG, Lee JS, Lee JS, Janf JS. Combination chemotherapy with gemcitabine and cisplatin as first-line treatment for immunohistochemically proven cholangiocarcinoma. Am J Clin Oncol 2006; 29(2): 127-31. [Medline]

Leggett CL, Gorospe EC, Murad MH, Montori VM, Baron TH, Wang KK. Photodynamic therapy for unresectable cholangiocarcinoma: a comparative effectiveness systematic review and meta-analyses. Photodiagnosis Photodyn Ther 2012; 9(3): 189-95. [Medline]

Li YY, Li H, Lv P, Liu G, Li XR, Tian BN et al. Prognostic value of chirrosis for intrahepatic cholangiocarcinoma after surgical treatment. J Gastrointest Surg 2011; 15(4): 608-13. [Medline]

Lim KH, Oh DY, Chie EK, Jang JY, Im SA, Kim TY et al. 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 Cancer 2009, 9: 345. [Medline]

Ling H, Roux E, Hempel D, Tao J, Smith M, Lonning S et al. Transforming growth factor β neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats. PLoS One 2013; 8(1): e54499. [Medline]

Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A changing pattern of presentation. Ann Surg 1994; 220(5): 644-52. [Medline]

Liu N, Rowley BR, Bull CO, Schneider C, Haegebarth A, Schatz CA et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol Cancer Ther 2013; 12(11): 2319-30. [Medline]

Lubner SJ, Mahoney MR, JKolesar JL, Loconte NK, Kim GP, Pitot HC et al. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol 2010; 28(21): 3491-7. [Medline]

Malka M, Cervera P, Foulon S, Trarbach T, de la Fouchardière C, Boucher E et al on behalf of the BINGO investigators. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol 2014; 15(8): 819-28. [Medline]

Martin RC, Klimstra DS, Schwartz L, Yilmaz A, Blumgart LH, Jarnagin W. Hepatic intraductal oncocytic papillary carcinoma. Cancer 2002; 95(10): 2180-7. [Medline]

Matsuo K, Rocha FG, Ito K, D’Angelica MI, Allen PJ, Fong Y et al. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resecability, and outcomes in 380 patients. J Am Coll Surg 2012; 215(3): 343-55. [Medline]

McMasters KM, Tuttle TM, Leach SD, Rich T, Cleary KR, Evans DB et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 1997; 174(6): 605-8. [Medline]

McNamara MG, Walter T, Horgan AM, Amir E, Cleary S, McKeever EL et al. Outcome of Adjuvant Therapy in Biliary Tract Cancers. Am J Clin Oncol 2013. [Epub ahead of print] [Medline]

Mertens JC, Fingas CD, Christensen JD, Smoot RL, Bronk SF, Werneburg NW et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 2013; 73(2): 897-907. [Medline]

Miyazaki M, Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Kato A et al. Recent advance in the treatment of hilar cholangiocarcinoma: hepatectomy with vascular resection. J Hepatobiliary Pancreat Surg 2007; 14(5): 463-8. [Medline]

Murakami Y, Uemura K, Hayashidani Y, Sudo T, Hashimoto Y, Ohge H et al. Prognostic significance of lymph node metastasis and surgical margin status for distal cholangiocarcinoma. J Surg Oncol 2007; 95(3): 207-12. [Medline]

Murakami Y, Uemura K, Sudo T, Hashimoto Y, Nakashima A, Kondo N et al. Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol 2011; 18(3): 651-8. [Medline]

Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakamura H et al. Adjuvant gemcitabine plus S-1 chemotherapy improves survival after aggressive surgical resection for advanced biliary carcinoma. Ann Surg 2009; 250(6): 950-6. [Medline]

Nachtergaele S, Mydock LK, Krishnan K, Rammohan J, Schlesinger PH, Covey DF et al. Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat Chem Biol 2012; 8(2): 211-20. [Medline]

Nagino M, Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y et al. Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Ann Surg 2013; 258(1): 129-40. [Medline]

Nagorney DM, Kendrick ML. Hepatic resection in the treatment of hilar cholangiocarcinoma. Adv Surg 2006; 40: 159-71. [Medline]

Nakanuma Y, Kida T, Minato H, Terada T. Pathology of cholangiocellular carcinoma. In: Tobe T, Kameda H, Okudaira M, Ohto M, Endo Y, Mito M et al (eds). Primary liver cancer in Japan. Tokyo, Springer-Verlag, 1992; pp. 39-50.

Nakeeb A, Lillemoe KD, Grosfeld JL. Surgical techniques for pancreatic cancer. Minerva Chir 2004; 59(2): 151-63. [Medline]

Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224(4): 463-73; discussion 473-5. [Medline]

Nakeeb A, Tran KQ, Black MJ, Erickson BA, Ritch PS, Quebbeman EJ et al. Improved survival in resected biliary malignancies. Surgery 2002; 132(4): 555-63; discussion 563-4. [Medline]

Nathan H, Aloia TA, Vauthey JN, Abdalla EK, Zhu AX, Schulick RD et al. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2009; 16(1): 14-22. [Medline]

Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastroint Surg 2007; 11(11): 1488-96; discussion 1496-7. [Medline]

Nehls O, Oettle H, Hartmann JT, Hofheinz RD, Hass HG, Horger MS et al. Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer 2008; 98(2): 309-15. [Medline]

Niu GC, Shen CM, Cui W, Li Q. Surgical treatment of advanced gallbladder cancer. Am J Clin Oncol 2015; 38(1): 5-10. [Medline]

Novarino AM, Satolli MA, Chiappino I, Giacobino A, Napoletano R, Ceccarelli M et al. FOLFOX-4 regimen or single-agent gemcitabine as first-line chemotherapy in advanced biliary tract cancer. Am J Clin Oncol 2013; 36(5): 466-71. [Medline]

Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 1: epidemiology and etiology. J Gastroenterol Hepatol 2002; 17(10): 1049-55. [Medline]

Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi 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(4): 469-74. [Medline]

Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324(5933): 1457-61. [Medline]

Ong CK, Subimerb C, Pairojkul C, Wongkham S, Cutcutache I, Yu W et al. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat Genet 2012; 44(6): 690-3. [Medline]

Paik WH, ParkYS, Hwang J-H, Lee SH, Yoon CJ, Kang SG et al. Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach. Gastrointest Endosc 2009; 69(1): 55-62. [Medline]

Park BK, Paik YH, Park JY, Park KH, Bang S, Park SW et al. The clinicopathologic significance of the expression of vascular endothelial growth factor-C in intrahepatic cholangiocarcinoma. Am J Clin Oncol 2006; 29(2): 138-42. [Medline]

Park J, Tadlock L, Gores GJ, Patel T. Inhibition of interleukine 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatolgy 1999; 30(5): 1128-33. [Medline]

Park JH, Choi EK, Ahn SD, Lee SW, Song SY, Yoon SM et al. Postoperative chemoradiotherapy for extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys 2011; 79(3): 696-704. [Medline]

Pawlik TM, Gleisner AL, Vigano L, Kooby DA, Bauer TW, Frilling A et al. Incidence of finding residual disease for incidental gallbladder carcinoma: implications for re-resection. J Gastrointest Surg 2007; 11(11): 1478-86; discussion 1486-7. [Medline]

Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 2006; 24(19): 3069-74. [Medline]

Pitt HA, Nakeeb A, Abrams RA, Coleman J, Piantadosi S, Yeo CJ et al. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 1995; 221(6): 788-97. [Medline]

Qin XL, Wang ZR, Shi JS, Lu M, Wang L, He QR. Utility of serum CA19-9 in diagnosis of cholangiocarcinoma: in comparison with CEA. World J Gastroenterol 2004; 10(3): 427-32. [Medline]

Raggi C, Invernizzi P, Andersen JB. Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts. J Hepatol 2015; 62(1): 198-207. [Medline]

RARECARE project – Surveillance of Rare Cancers in Europe. Incidence (1995-2002) in Europe by sex, age, and EU region with expected new case in EU (27) in 2008.

RARECAREnet project (visit website)

Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383(9935): 2168-79. [Medline]

Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005; 242(3): 451-8; discussion 458-61. [Medline]

Rea DJ, Rosen CB, Nagorney DM, Heimbach JK, Gores GJ. Transplantation for cholangiocarcinoma: when and for whom? Surg Oncol Clin N Am 2009; 18(2): 325-37, ix. [Medline]

Riediger H, Makowiec F, Fischer E, Adam U, Hopt UT. Postoperative morbidity and long-term survival after ancreaticoduodenectomy with superior mesenterico-portal vein resection. J Gastrointest Surg 2006; 10(8): 1106-15. [Medline]

Rizvi S, Gores JG. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013; 145(6): 1215-29. [Medline]

Rizvi S, Borad MJ, Patel T, Gores GJ. Cholangiocarcinoma: molecular pathways and therapeutic opportunities. Sem Liver Dis 2014; 34(4): 456-64. [Medline]

Rogers JE, Law L, Nguyen VD, Qiao W, Javle MM, Kaseb A et al. Second-line systemic treatment for advanced cholangiocarcinoma. J Gastrointest Oncol 2014; 5(6): 408-13. [Medline]

Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 2013; 340(6132): 626-30. [Medline]

Rosen CB, Heimbach JK, Gores GJ. Liver transplantation for cholangiocarcinoma. Transpl Int 2010; 23(7): 692-7. [Medline]

Ross JS, Wang K, Gay L, Al-Rohil R, Rand JV, Jones DM et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 2014; 19(3): 235-42. [Medline]

Rubovszky G, Láng I, Ganofszky E, Horváth Z, Juhos E, Nagy T et al. Cetuximab, gemcitabine and capecitabine in patients with inoperable biliary tract cancer: a phase 2 study. Eur J Cancer 2013; 49(18): 3806-12. [Medline]

Saborowski A, Saborowski M, Davare MA, Druker BJ, Klimstra DS, Lowe SW. Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target. Proc Natl Acad Sci U S A 2013; 110(48): 19513-8. [Medline]

Sagawa N, Kondo S, Morikawa T, Okushiba S, Katoh H. Effectiveness of radiation therapy after surgery for hilar cholangiocarcinoma. Surg Today 2005; 35(7): 548-52. [Medline]

Sekiya S, Suzuki A. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J Clin Invest 2012; 122(11): 3914-8. [Medline]

Serafini FM, Sachs D, Bloomston M, Carey LC, Karl RC, Murr MM et al. Location, not staging, of cholangiocarcinoma determines the role for adjuvant chemoradiation therapy. Am Surg 2001; 67(9): 839-43; discussion 843-4. [Medline]

Shah KN, Clary BM. Endoscopic and percutaneous approaches to the treatment of biliary tract and primary liver tumors: controversies and advances. Surg Oncol Clin N Am 2014; 23(2): 207-30. [Medline]

Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004; 24(2): 115-25. [Medline]

Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA. Risk factors for intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005; 128(3): 620-6. [Medline]

Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal P, Sreenivas V et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol 2010; 28(30): 4581-6. [Medline]

Sharma MP, Ahuja V. Aetiological spectrum of obstructive jaundice and diagnostic ability of ultrasonography: a clinician’s perspective. Trop Gastroenterol 1999; 20(4): 167-9. [Medline]

Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit Rev Oncog 2012; 17(1): 69-95. [Medline]

Shih SP, Schulick RD, Cameron JL, Lillemoe KD, Pitt HA, Choti MA et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg 2007; 245(6): 893-901. [Medline]

Shimoda M, Farmer DG, Colquhoun SD, Rosove M, Ghobrial RM, Yersiz H et al. Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature. Liver Transpl 2001; 7(12): 1023-33. [Medline]

Shinoara ET, Mitra N, Guo M, Metz JM. Radiation therapy is associate with improved survival in the adjuvant and definitive treatment of intrahepatice cholangiocarcinoma. Int J Radiation Oncology Biol Phys 2008; 72(5): 1495-501. [Medline]

Sia D, Hoshida Y, Villanueva A, Roayaie S, Ferrer J, Tabak B et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 2013; 144(4): 829-40. [Medline]

Sinn M, Nicolau A, Gebauer B, Podrabsky P, Seehofer D, Ricke J et al. Hepatic arterial infusion with oxaliplatin and 5-FU/folinic acid for advanced biliary tract cancer: a phase II study. Dig Dis Sci 2013; 58(8): 2399-405. [Medline]

Siqueira E, et al. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Gastrointest Endosc 2002; 56: 40-47. [Medline]
Erratum in: Gastrointest Endosc 2002 Oct;56(4):612.

Sirica AE. Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy. Hepatology 2005; 41(1): 5-15. [Medline]

Sirica AE. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol. 2008; 14(46): 7033-58. [Medline]

Sirica AE. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2012; 9(1): 44-54. [Medline]

Slattery JM, Sahani DV. What is the current state-of-the-art imaging for detection and staging of cholangiocarcinoma? Oncologist 2006; 11(8): 913-22. [Medline]

Sobin LH, Gospodarowicz M, Wittekind C (eds). TNM classification of malignant tumours. Sixth edition. Hoboken, Wiley-Blackwell, 2002.

Sotiropoulos GC, Kaiser GM, Lang H, Molmenti EP, Beckebaum S, Fouzas I et al. Liver transplantation as a primary indication for intrahepatic cholangiocarcinoma: a single-center experience. Transplant Proc 2008; 40(9): 3194-5. [Medline]

Sugiyama H, Onuki K, Ishige K, Baba N, Ueda T, Matsuda S et al. Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells. J Gastroenterol 2011; 46(6): 779-89. [Medline]

Swierczynski SL, Maitra A, Abraham SC, Iacobuzio-Donahue CA, Ashfaq R, Cameron JL et al. Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays. Hum Pathol 2004; 35(3): 357-66. [Medline]

Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res 2007; 5(3): 203-20. [Medline]

Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H et al; Study Group of Surgical Adjuvant Therapy for Carcinomas of the Pancreas and Biliary Tract. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002; 95(8): 1685-95. [Medline]

Takahashi Y, Ebata T, Yokoyama Y, Igami T, Sugawara G, Mizuno T et al. Surgery for recurrent biliary tract cancer: a single-center experience with 74 consecutive resections. Ann Surg 2014. [Epub ahead of print] [Medline]

Tan JC, Coburn NG, Baxter NN, Kiss A, Law CH. Surgical management of intrahepatic cholangiocarcinoma – a population-based study. Ann Surg Oncol 2008; 15(2): 600-8. [Medline]

Tanaka Y, Martin Mola E. IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab. Ann Rheum Dis 2014; 73(9): 1595-7. [Medline]

Taniai M, Grambihler A, Higuchi H, Werneburg N, Bronk SF, Farrugia DJ et al. Mcl-1 mediates tumor necrosis factor-related apoptosis inducing ligand resistance in human cholangiocarcinoma cells. Cancer Res 2004; 64(10): 3517-24. [Medline]

Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 2003; 52(5): 706-12. [Medline]

Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H et al. Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma. Int J Radiat Oncol Biol Phys 2000; 46(3): 581-7. [Medline]

Toyoda M, Ajiki T, Fujiwara Y, Nagano H, Kobayashi S, Sakai D et al. Phase I study of adjuvant chemotherapy with gemcitabine plus cisplatin in patients with biliary tract cancer undergoing curative resection without major hepatectomy (KHBO1004). Cancer Chemother Pharmacol 2014; 73(6): 1295-301. [Medline]

Tsuzuki T, Ogata Y, Iida S, Nakanishi I, Takenaka Y, Yoshii H. Carcinoma of the bifurcation of the hepatic ducts. Arch Surg 1983; 118(19): 1147-51. [Medline]

Tyson GL, El-Serag HB. Risk factors for choalngiocarcinoma. Hepatology 2011; 54(1): 173-84. [Medline]

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A et al; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362(14): 1273-81. [Medline]

Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol 2014; 25(2): 391-8. [Medline]

Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study – The UK ABC-01 Study. Br J Cancer 2009; 101(4): 621-7. [Medline]

van der Gaag NA, Rauws EA, van Eijck CH, Bruno MJ, van der Harst E, Kubben FJ et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010; 362(2): 129-37. [Medline]

Vogl TJ, Naguibi NN, Nour-Eldin NE, Bechstein WO, Zeuzem S, Trojan J et al. Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma: results and prognostic factors governing treatment success. Int J Cancer 2012; 131(3): 733-40. [Medline]

Voss JS, Holtegaard LM, Kerr SE, Fritcher EG, Roberts LR, Gores GJ et al. Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum Pathol 2013; 44(7): 1216-22. [Medline]

Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011; 10(12): 2426-36. [Medline]

Walter T, Horgan AM, McNamara M, McKeever L, Min T, Hedley D et al. Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: a large retrospective study. Eur J Cancer 2013; 49(2): 329-35. [Medline]

Wang P, Dong Q, Zhang C, Kuan PF, Liu Y, Jeck WR et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 2013a; 32(25): 3091-100. [Medline]

Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013b; 340(6132): 622-6. [Medline]

Weinbren K, Mutum SS. Pathological aspects of cholangiocarcinoma. J Pathol 1983; 139(2): 217-38. [Medline]

Welling TH, Feng M, Wan S, Hwang SY, Volk ML, Lawrence TS et al. Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma. Liver Transpl 2014; 20(1): 81-8. [Medline]

Welzel TM, Mellemkjaer L, Gloria G, Sakoda LC, Hsing AW, El Ghormli L et al. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer 2007; 120(3): 638-41. [Medline]

Wernberg JA, Lucarelli DD. Gallbladder Cancer. Surg Clin North Am 2014; 94(2): 343-60. [Medline]

Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 2013; 3(6): 636-47. [Medline]

Yamamoto S, Kubo S, Hai S, Uenishi T, Yamamoto T, Shuto T et al. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci 2004; 95(7): 592-5. [Medline]

Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and staging classification. J Hepatobiliary Pancreat Surg 2003; 10(4): 288-91. [Medline]

Yamashita Y, Taketomi A, Itoh S, Harimoto N, Tsujita E, Sugimachi K et al. Phase II trial of gemcitabine combined with 5-fluorouracil and cisplatin (GFP) chemotherapy in patients with advanced biliary tree cancers. Jpn J Clin Oncol 2010; 40(1): 24-8. [Medline]

Yang R, Wang B, Chen YJ, Li HB, Hu JB, Zou SQ. Efficacy of gemcitabine plus platinum agents for biliary tract cancers: a meta-analysis. Anticancer Drugs 2013; 24(8): 871-7. [Medline]

Yeh CN, Jan YY, Chen MF. Influence of age on surgical treatment of peripheral cholangiocarcinoma. Am J Surg 2004; 187(4): 559-63. [Medline]

Yeh TS, Jan YY, Tseng JH, Chiu CT, Chen TC, Hwang TL et al. Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings. Am J Gastroenterol 2000; 95(2): 432-40. [Medline]

Yoon JH, Higuchi H, Werneburg NW, Kaufmann SH, Gores GJ. Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line. Gastroenterology 2002; 122(4): 985-93. [Medline]

Yoon JH, Canbay AE, Werneburg NW, Lee SP, Gores GJ. Oxysterols induce cyclooxygenase-2 expression in cholangiocytes: implications for biliary tract carcinogenesis. Hepatology 2004; 39(3): 732-8. [Medline]

Yu C, Bruzek LM, Meng XW, Gores GJ, Carter CA, Kaufmann SH et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 2005; 24(46): 6861-9. [Medline]

Zaydfudim VM, Rosen CB, Nagorney DM. Hilar cholangiocarcinoma. Surg Oncol Clin N Am 2014; 23(2): 247-63. [Medline]

Zender S, Nickeleit I, Wuestefeld T, Sörensen I, Dauch D, Bozko P et al. A critical role for notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell 2013; 23(6): 784-95. [Medline]

Zhang Y, Uchida M, Abe T, Nishimura H, Hayabuchi N, Nakashima Y. Intrahepatic peripheral cholangiocarcinoma: comparison of dynamic CT and dynamic MRI. J Comput Assist Tomogr 1999; 23(5): 670-7. [Medline]

Zhu GQ, Shi KQ, You J, Zou H, Wang LR, Braddock M et al. Systematic review with network meta-analysis: adjuvant therapy for resected biliary tract cancer. Aliment Pharmacol Ther 2014; 40(7): 759-70. [Medline]

 

Dr. Giordano Beretta (Associate Editor)
Medical Oncology Unit, Humanitas Gavazzeni – Bergamo (Italy)
mail: beregd@iol.it

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gatta@istitutotumoti.mi.it

Dr. Roberto Labianca (Editor)
Medical Oncology Unit, Giovanni XXIII Hospital – Bergamo (Italy)
mail: rlabian@tin.it

Dr. Stefania Mosconi (Author)
Medical Oncology Unit, Giovanni XXIII Hospital – Bergamo (Italy)
mail: s.mosconi@tin.it

Dr. Michela Squadroni (Author)
Medical Oncology Unit, Humanitas Gavazzeni – Bergamo (Italy)
mail: michela.squadroni@gavazzeni.it

Dr. Luca Tondulli (Author)
MEdical Oncology Unit, Borgo Roma Hospital – Verona (Italy)
mail: luca.tondulli@alice.it