Intrahepatic cholangiocarcinoma: Epidemiology, risk factors, diagnosis and surgical management

Accepted Manuscript Title: Intrahepatic cholangiocarcinoma: epidemiology, risk factors, diagnosis and surgical management Author: Han Zhang, Tian Yang, Mengchao Wu, Feng Shen PII: DOI: Reference:

S0304-3835(15)00588-1 http://dx.doi.org/doi: 10.1016/j.canlet.2015.09.008 CAN 12548

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Please cite this article as: Han Zhang, Tian Yang, Mengchao Wu, Feng Shen, Intrahepatic cholangiocarcinoma: epidemiology, risk factors, diagnosis and surgical management, Cancer Letters (2015), http://dx.doi.org/doi: 10.1016/j.canlet.2015.09.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Intrahepatic Cholangiocarcinoma: Epidemiology, Risk Factors, Diagnosis and Surgical Management

Han Zhang1, Tian Yang1, Mengchao Wu, Feng Shen* Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China

1

The authors contributed equally to this work.

*Corresponding author. Tel: +86 021 81875005; Fax: +86 021 65562400. E-mail address: [email protected] (F. Shen).

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Highlights ■ This review provides updated epidemiologic data on intrahepatic cholangiocarcinoma. ■ Various forms of biliary inflammations, as well as many metabolic factors, are identified as risk factors of ICC. ■ We assessed the role of surgical resection and other treatment modalities, as well as their short-term and long-term outcomes.

Abstract Intrahepatic cholangiocarcinoma (ICC), the least common form of cholangiocarcinomas, is a rare hepatobiliary malignancy that arising from the epithelial cells of the intrahepatic bile ducts. The incidence of ICC has been rising in the global scale over the last twenty years, which may reflect both a true increase and the trend of earlier detection of the disease. Other than some well recognized causative risk factors, the association between viral and metabolic factors and ICC pathogenesis has been increasingly identified recently. Surgical resection is currently the only feasible modality with a curative ability, but the resectability and curability remain low. The high invasiveness of ICC predisposes the tumors to multifocality, node metastasis and vascular invasions, leading to poor longterm survival after resection. The role of liver transplantation is controversial, while locoregional treatments and systematic therapies may provide survival benefits, especially in patients with unresectable and advanced tumors. The present review discussed the epidemiology, risk factors, surgical and multimodal management of ICCs, which mainly focused on the outcomes and factors associated with surgical treatment.

Keywords: Intrahepatic cholangiocarcinoma; epidemiology; risk factor; diagnosis; surgery

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1 Introduction Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with incidence only second to the hepatocellular carcinoma (HCC)[1] that arising from the epithelial cells of the intrahepatic bile ducts, either small intrahepatic ductules or large intrahepatic ducts proximal to the bifurcation of the hepatic ducts. It is the least common form of cholangiocarcinomas, compared to those located in the upper onethird of the biliary tract[2] and the two-thirds involving the bifurcation of the common hepatic duct (Klatskin tumors). Morphologically, ICC could be divided into three distinct subtypes (mass-forming, periductal-infiltrating, and intraductal-growth), each with different growth pattern and cross-sectional imaging characteristics[3]. Despite its rarity, it tends to be advanced or even lethal when diagnosed due to the challenges in the detection and treatment of the disease.

2 Epidemiology In the United States, there was about 35,660 patients with primary liver and intrahepatic bile duct cancers who were diagnosed each year[4]. Of which, approximately 15% are ICCs, with an overall incidence rate of 0.95 cases per 100,000 adults, suggested by the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) program database[1, 5]. The incidences of ICC worldwide, such as in Europe, North America, Asia, Japan, and Australia have been rising over the past two decades[6, 7], with the highest incidence of 96 cases per 100,000 men reported in Thailand[8]. Although some of these changes are attributable to the alterations in disease classification, or to the more advanced diagnostic modalities that could identify early lesions and biliary malignancies that are undiagnosed previously[9], the increasing incidence was found to be independent to the increased proportion of ICCs with early stage, smaller size or unclear stage[5], suggesting a true increase in incidence, which might be

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associated with some newly recognized risk factors such as viral hepatitis, nonviral chronic liver diseases and metabolic diseases[10, 11]. Of the 3 morphological subtypes, the mass-forming type is most common, which is found in over 85% of patients with ICC[3]. As other types of biliary tract cancers, the incidence of ICC increases with age, and most of the patients are aged between 55 and 75 years. The incidence of cholangiocarcinoma is slightly higher in males than females[12].

3 Risk Factors A number of pathologies affecting the biliary system that produce chronic biliary inflammation, bile stasis, and cirrhosis would all predispose the patients to the development of biliary malignancies [10]. Specifically, intrahepatic lithiasis, primary sclerosing cholangitits (PSC), congenital abnormalities of the bile ducts, parasite infection, and toxic exposures have all been associated with an increased risk of ICC[13]. It is worth to notice that chronic liver disease (viral infection and cirrhosis) and metabolic abnormalities are now recognized as risk factors for ICC[11]. In addition, ICC may also occur in some patients without exposure to known risk factors. 3.1 Intrahepatic lithiasis Intrahepatic stone disease, i.e. hepatolithiasis or recurrent pyogenic cholangitis is a strong risk factor for cholangiocarcinomas[14, 15]. Stone disease affecting only the intrahepatic bile ducts is rare in the west but is endemic in many areas of Southeast Asia. In Taiwan, for instance, an estimated 50 to 70 percent of patients undergoing resection for cholangiocarcinoma have concomitant hepatolithiasis[16]. The etiology of hepatolithiasis is largely unknown, but diet, congenital ductal abnormalities, and chronic inflammation from bacterial or parasitic infections have all been implicated. The calculi are usually brown pigment stones composed of calcium bilirubinate. Consequent bile stasis caused by the stones would predispose the patient to recurrent bacterial infections and chronic inflammation.

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3.2 Primary sclerosing cholangitits (PSC) There is a proven association between PSC and cholangiocarcinoma, especially perihilar disease. The annual incidence of cholangiocarcinoma in patients with PSC is approximately 0.6 to 1.5 percent per year[17, 18]. ICCs develop at a significantly younger age (between the ages of 30 and 50 years) in patients with PSC than in those without this condition[19]. Over one-third of cases are diagnosed within two years of the initial diagnosis of PSC, and the risk appears unrelated to the duration of the inflammatory disease[20]. Alcohol consumption has been suggested to be a risk factor for the development of cholangiocarcinoma in patients with PSC[21]. Certain genetic polymorphisms, such as natural killer cell receptor G2D (NKG2D), have been implicated as risk factors for these patients[22]. 3.3 Congenital abnormalities Congenital abnormalities of the biliary tree (Caroli's syndrome, congenital hepatic fibrosis, choledochal cysts) carry an approximately 15% risk of malignant change in the adult years (average age at diagnosis is 34 years)[23]. The overall incidence of cholangiocarcinoma in patients with untreated cysts is as high as 28%[24], while after proper treatment, the incidence could be as low as around 3%[25]. 3.4 Parasitic infection In some areas in Asia (particularly Thailand), infections with liver Clonorchis sinensis and Opistorchis viverrini are associated with ICC[26]. Patients are infected by having undercooked fish and ingesting the adult worms inhabiting and laying eggs in the biliary system. The organisms induce a chronic inflammatory state in the proximal biliary tree and may lead to malignant transformation of the lining epithelium[27]. 3.5 Toxic or occupational exposures Strong evidence has proved that exposure to the radiologic contrast agent Thorotrast and the development of subsequent cholangiocarcinoma; malignancy usually develops 30 to 35 years after

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exposure[28]. An increased incidence of cholangiocarcinoma has been less strongly associated with several occupations, including the auto, rubber and chemical industries[29]. 3.6 Chronic liver disease and cirrhosis Hepatitis B virus (HBV) and hepatitis C virus (HCV), as well as liver cirrhosis regardless of etiology, are proved to be potential risk factors for ICC[30-32]. The association between HCV infection and cholangiocarcinoma was first reported in 1991[33], followed by several studies which demonstrated a high rate of HCV-related cirrhosis in patients with ICC[5, 31]. A meta-analysis of 16 case-control studies identified a significantly increased risk of ICC (pooled odds ratio [OR] 3.38, 95% confidence interval [CI], 2.72 to 4.21) in patients with HCV infection[34]. An association between HBV infection and cholangiocarcinoma has also been reported, although the evidence is relatively weaker than the case of HCV[35, 36]. Chronic liver disease of nonviral causes would also contribute to an increased risk for ICC, such as nonalcoholic fatty liver disease (NAFLD)[37]. Cirrhosis is also strongly causative for ICC, including nonspecific cirrhosis (adjusted OR 27.2) and alcoholic liver disease (adjusted OR 7.4)[38]. A cohort study enrolling 11,605 persons with cirrhosis of any cause found a 10-fold increase in risk for ICC among these patients after a follow up of over six years. 3.7 Metabolic abnormalities and living habits Multiple recent studies have revealed the increasing links between metabolic abnormalities and the development of various cancers, including hepatobiliary malignancies. ICC shares some common risk factors as HCC, not only type II diabetes and obesity, but also living habits such as smoking and alcohol intake, as demonstrated in extrahepatic cholangiocarcinoma[39]. A meta-analysis of 11 casecontrol studies identified obesity (OR 1.56, 95% CI, 1.26-1.94), diabetes mellitus type II (1.89, 1.742.07), smoking (1.31, 0.95-1.82), and alcohol use (2.81, 1.52-5.21) as risk factors for ICC[40]. Another

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study based on the SEER database has confirmed the association between ICC and metabolic syndrome with an OR of 1.6[41]. Other metabolic conditions, such as thyrotoxicosis and chronic pancreatitis, were also found to be associated with ICC[31]. On the other hand, the correlation of diabetes and ICC is still uncertain with several studies showing controversial results[31, 42].

4 Diagnosis 4.1 Symptoms and signs Unlike those with cholangiocarcinoma of other sites, patients with ICC are less likely to have a history of jaundice. Instead, they may present with dull right upper quadrant pain, weight loss, and elevated alkaline phosphatase level, or rarely fever. While a considerable number of patients are asymptomatic, with the lesions detected incidentally during radiologic examinations[43]. Paraneoplastic syndromes are rare findings of patients with ICC, which may present with cutaneous findings such as Sweet syndrome[44] and acanthosis nigricans[45]. 4.2 Laboratory tests Patients with ICC usually have elevated levels of alkaline phosphatase, whereas serum bilirubin levels are usually normal or only slightly elevated[46]. Elevated levels of gamma-glutamyl transpeptidase and 5'-nucleotidase may be supportive to the diagnosis of hepatobiliary disease. Tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9) and alphafetoprotein (AFP) should be checked in all patients with suspected ICC. Although the findings are insufficient in specificity, multiple elevated tumor markers may aid in the setting of differential diagnosis, such as an elevated AFP would suggest HCC instead of ICC. A serum level of CA 19-9 greater than 100 U/mL (normal < 40 U/mL) has 75% sensitivity and 80% specificity in identifying

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cholangiocarcinoma in patients with PSC, and in those without PSC the sensitivity is 53%. Meanwhile, the combination of CEA and CA 19-9 has an accuracy of 86% in diagnosing cholangiocarcinoma[47]. Some investigators also found significantly higher CA19-9 levels in patients with unresectable cholangiocarcinomas[48], and that a high level (over 100 U/ml) was associated with worse recurrencefree survival (RFS) after resection[49]. 4.3 Imaging studies ICCs usually present as a malignant-appearing mass lesion in a non-cirrhotic liver. Cross-sectional imaging, such as contrast-enhanced computed tomography (CT) scan and magnetic resonance imaging (MRI) can be used to differentiate between ICC and HCC when intrahepatic metastatic diseases are ruled out[50]. Typical radiographic features of ICC include a hypodense hepatic lesion without a capsule, with distal biliary dilatation. Capsular retraction may be seen in a small part of patients due to fibrotic nature of the tumor. Rim enhancement would be seen in both arterial and venous phases after contrast administration[51]. Some ICCs small in size can have similar enhancement patterns to HCC[52]. CT scan is useful for detecting intrahepatic tumors, clarifying the level of biliary obstruction, and detecting the presence of liver atrophy. Multiphasic contrast-enhanced multidetector-row CT (MDCT) can also help distinguish benign from malignant lesions in the setting of intrahepatic bile duct strictures and aid with tumor staging and evaluation of resectability for ICC[51]. On MRI, ICCs appear as hypointense lesions on T1-weighted images and as heterogeneously hyperintense ones on T2-weighted images[53]. After gadoxetic acid enhancement, the tumor may present as a lobulated shape, weak rim, and a targetshaped mass. The most common sites for metastasis are the lymph nodes, the peritoneum, the lungs and pleura. CT and MRI may have some value in identifying metastatic tumors in these sites, while positron emission tomography with fluorodeoxyglucose (FDG-PET) scanning may play an important role in preoperative evaluation for detecting occult metastatic disease[54]. Similarly, Doppler ultrasound

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can be useful in preoperative assessment to identify gross vascular invasions of the tumor to the portal vein and the hepatic artery with high sensitivity and specificity, which is comparable to angiography and CT arteriogram.

5 Tumor Staging In general, the staging starts with CT scan of the abdomen and pelvis. If distant metastatic disease, extraregional node involvement, or invasion of critical adjacent structures is not evident, a PET scan could be ordered to look for occult metastases. Unlike the past when ICC and HCC were regarded together as "primary liver cancer" for staging, the latest AJCC/UICC staging system (7th edition) separately assessed predictive factors for ICCs alone (Table 1). One of the updates is that the 7th edition no longer regard tumor size as a prognostic factor, instead, the number of lesions, vascular invasion, intrahepatic metastasis, and invasion of adjacent tissues were some important factors affecting the T stage of ICCs[55]. However, some authors believe that the system needs to be improved to increase the accuracy of prognostic stratification, and that tumor size, cancer cell differentiation and other prognostic predictors should be added to the current AJCC criteria[56].

6 Surgical Management Currently, surgical resection is the only well-established option for ICC which provides best possibility for disease cure[57]. However, compared with other hepatobiliary malignancies, ICC is generally associated with lower resectability and curability, as only a minority of patients are considered to be ideal candidates for curative resections and the post-operative long-term prognosis is still suboptimal. The invasiveness and relatively advanced stage of the tumor may be barriers for successful resections, which brings challenges to surgical approach and the possibility to achieve margin-negative (R0) resections.

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6.1 Staging laparoscopy

The role of staging laparoscopy has not been determined, although it is recommended in preventing unnecessary laparotomies and ruling out small peritoneal implants before proceeding with a laparotomy incision[58]. Studies have shown that approximately 36% of ICC is found to be unresectable due to laparoscopic detection of peritoneal or intrahepatic metastasis[59]. Some authors suggested that in patients with high-risk features of tumor metastasis such as node abnormality, multifocal nodules, or high serum level of CA 19-9, the routine use of diagnostic laparoscopy is recommended[57]. However, further studies are needed to determine the specific role of laparoscopic staging in the surgical management of ICC.

6.2 Preoperative portal vein embolization (PVE) PVE is a frequently used method to increase the safety for hepatic resection in patients with limited liver functions for the goal of achieving histologically negative resection margins[60, 61]. The aim of PVE is to induce lobar hypertrophy in patients who are predicted to have insufficient liver remnant after resection. Preoperative PVE may permit a margin-negative resection by increasing the future remnant liver volume. Despite some reports on hilar cholangiocarcinomas[62, 63], evaluations of safety and efficacy of PVE in ICC are pending. 6.3 Surgical resection When contraindications are precluded, ICC is usually treated by radical hepatic resection with the goal to achieve negative-margin (R0) resections[64]. In a recent multicenter study enrolling 584 patients who underwent resection for ICC, the overall probability of cure was 9.7% (95% CI, 6.1%-13.4%), which was higher (25.8%) in patients with single, well-differentiated small (≤ 5 cm) lesions and without vascular/periductal invasion and node metastases[65]. Even in selected candidates with younger

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age and earlier-stage lesions, R0 resection can only be achieved in less than 30% of patients[66]. Compared to peri-hilar and distal cholangiocarcinomas, R0 resection is more likely to be achieved in ICC, although microvascular invasion occurs more frequently[67]. Therefore, large-volume liver resections, such as hemi-hepatectomy or more extensive hepatic resection (≥ 5 liver segment resections), as well as resections and reconstruction of extrahepatic bile duct system may be needed in a considerable proportion of patients (over 70% for hemi-hepatectomy or extended hepatic resection[68] and over 20% for biliary resection and reconstruction[69]). It should also be noted that these approaches might be more risky because the extended hepatic resection has been demonstrated as an independent risk factor for major postoperative complications (OR, 6.2; 95% CI, 2.11-19.62)[70]. Moreover, R0 resection is very challenging in patients with locally advanced tumors or tumors large in size[68]. ICC is considered unresectable if intrahepatic or distant metastases, invasion or encasement of major vessels, or extensive node metastasis are present based on staging studies. In these cases, resection should not be attempted. 6.4 Lymphadenectomy during surgery Few study has reported the benefits of lymphadenectomy during surgical resection for ICC[71]. Despite the fact that node involvement is an important predictive factor for poorer prognosis, evidence of the therapeutic benefit from lymphadenectomy does not seem strong enough, and there is a lack of consensus about whether or not it should be routinely performed[69, 72]. Nevertheless, recent multicentic studies have emphasized the potential importance of lymphadenectomy during the surgical resection for ICC based on the fact that over one third of patients (as many as 40%) undergoing node evaluation had pathological metastasis[68, 71, 73], and that node status has been demonstrated to be strongly associated with surgical prognosis (median survival: 30 vs. 24 months for without or with node metastasis)[68]. They believe that routine node evaluation should be performed in the resection of ICC.

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Similarly, the 2015 expert consensus of ICC recommended regional lymphadenectomy to be considered as a standard part of surgical therapy because of the prognostic importance and high incidence of node metastasis, as well as the potential therapeutic benefit in decreasing locoregional recurrence[57]. 6.5 Outcomes after resection Long-term outcomes vary among patients who receive R0 resection for ICC, which is dependent on the location and extent of the primary lesion, margin status of the surgery, node status and incidence of surgical complications. The commonly recognized prognostic factors after resection are completeness of resection, number of tumors, presence of vascular invasion and node metastases. Some authors had reported an improved survival over time for the past few years, however, this might be attributed to improved non-surgical therapy or more careful selection of candidates for surgical resection[74]. Postoperative complications were found to be independent predictors of worse long-term outcomes (hazard ratio [HR], 1.64; 95% CI, 1.30-2.08), and the outcome worsens with increased severity of the complications[75]. Outcomes of ICC depend on disease stage (especially the presence or absence of node involvements and vascular invasion) and status of surgical margins, rather than size[72]. Postoperative 5-year overall survival are generally up to 40%[50, 76], but better survival can be achieved in patients with negative margins (R0 resections) and negative node involvement, among which the 5year survival could be as high as 63%[77-79]. Patients who had a positive-margin (R1) resection had higher risk of recurrence (HR, 1.61; 95% CI, 1.15-2.27) and shorter overall survival (OS) (1.54; 1.122.11) than those with R0 resection[80]. Stage-stratified 5-year survivals according to the 7th edition of the AJCC staging system were 32% for all patients enrolled, 62% for stage I (T1N0), 27% for stage II (T2N0) and 14% for stage III (T3N0, T1-3, N1) in a French study of 163 patients undergoing potentially curative surgery[73].

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After R0 resection, local recurrence is the most common pattern[81], and the other patterns such as intrahepatic, nodal, or extrahepatic distant (intraperitoneal) recurrences/metastases were also observed[82]. A study utilizing an international database identified 563 patients undergoing curativeintent resection for ICC and found a recurrence rate of 71% with a median follow-up of 19 months. First recurrence site was intrahepatic only (59.8%), extrahepatic only (14.5%), or both intra- and extrahepatic (25.7%)[83]. The demonstrated risk factors for recurrence included histologically-positive margins and node involvement. Recurrent ICCs are associated with worse outcome, among those patients, median survival from the time of the recurrence was 11.1 months with the treatment of different modalities, the median survival of patients undergoing resection of recurrent tumor was 26.7 months[83]. A nomogram is a good tool to predict survival after resection. One nomogram has been developed for ICC that includes tumor (T) and nodal (N) classifications, tumor size, the number of tumor nodules, preoperative serum tumor marker levels and vascular invasion[84] (Figure 1). 6.6 Liver transplantation (LT) LT is not recommended as a routine procedure for ICCs due to the lack of standard indications and highly controversial outcomes[84]. In fact, due to unsatisfactory long-term survival and high recurrence rates, many centers are no longer conducting LT for ICC. Without concomitant anti-cancer chemotherapies, the 3-year survival of patients with ICC who underwent LT ranged between 50% and 65%[85, 86]. Meanwhile, patients undergoing systematic adjuvant or neoadjuvant therapy achieved better long-term survival[87]. Commonly reported adverse prognostic factors for LT were perineural invasion, multifocality, infiltrative tumor growth pattern, lymphovascular invasion, and a history of PSC. Meanwhile, recent studies found that certain ICC patients, particularly those with small solitary tumors, enjoyed more favorable long-term survival after LT, despite the limited number of participants who

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underwent LT. In summary, LT is not completely ineffective, but its controversial indications and costeffectiveness may limit its use in the treatment of ICC. 6.7 Locoregional treatments Hepatic artery based therapies, including hepatic arterial infusion (HAI), transarterial chemoembolization (TACE), drug-eluting bead TACE (DEB-TACE), and Yttrium radioembolization (Y-90), are potentially beneficial therapeutic choices for patients with unresectable ICCs. A metaanalysis comparing these modalities has identified HAI as the one with the best survival outcomes (median OS, 22.8 months, 95% CI, 9.8-35.8 months) and response to therapy (56.9%, 95% CI, 41.072.8%) compared to Y-90 and TACE in patients with unresectable ICCs[90]. TACE, which was first described in the treatment of HCC[91], may be beneficial to some patients with advanced disease, both in the therapeutic and surgical adjuvant settings. A retrospective study of 273 patients found TACE to be comparable to surgical resection in terms of RFS in node positive patients or patients with positive resection margin[92]. Another Chinese study on 114 patients who underwent R0 resection identified the ability of adjuvant TACE to improve survival in those patients with poor prognostic factors (tumor size ≥ 5 cm or advanced TNM stage), while it failed to significantly change the survival in patients without these factors[93]. There is a clear evidence that TACE provides better survival benefits compared with supportive therapy in patients with unresectable ICC[94]. DEB-TACE with specific drug-eluting beads is believed to be able to enhance drug concentrations within the tumor with fewer systemic side-effects as compared to conventional TACE. Some reports also demonstrated the potential survival benefits of DEB-TACE compared with TACE or systemic chemotherapy[95, 96].

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Radiofrequency ablation (RFA) and microwave ablation (MWA) are locoregional treatment options that could prolong survival in ICC patients who are not candidates for surgery. They are generally recommended for the local control of small and localized lesions without extrahepatic spread[97]. A meta-analysis of 84 patients data from seven observational studies revealed that the pooled 1-, 3-, and 5-year survival rates were 82% (95% CI, 72%-90%), 47% (28%-65%), and 24% (11%-40%), respectively, in patients with unresectable ICC undergoing RFA[98]. Meanwhile, MWA could be another choice when facilitates are available. A Chinese cohort consisting of 26 patients treated with MWA combined with simultaneous TACE produced a complete ablation rate of 92.3% and median PFS and OS of 6.2 and 19.5 months. Nevertheless, the exact role of these procedures for unresectable ICCs remains to be determined due to a lack of prospective randomized trials.

7 Systematic Therapy Definitive recommendations for systematic therapy are insufficient due to the lack of evidence from prospective randomized phase III trials[57]. Most the available data currently are from phase II trials and retrospective studies evaluating the role of chemotherapy on biliary cancers with multiple tumor types. Cisplatin-, gemcitabine- or fluorouracil-based regimens represent the mainstay of therapeutic treatment in most studies. For the adjuvant use, the exact role of systematic therapy after resection of ICC has not been established due to data insufficiency. For node-negative and margin-negative patients, no difference in survival outcomes between systematic adjuvant therapy (with fluorouracil or gemcitabine) versus surgery alone was found in postoperative patients with bile duct cancers in two randomized studies involving patients with pancreas, gallbladder, bile duct, and ampullary cancers[99, 100]. Results of more undergoing trials which are specific for ICC are to be reported over the next few years.

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The role of systematic therapy in patients with unresectable ICC is more clearly demonstrated. For patients with node metastasis or undergoing R1 resection, systemic therapy with either gemcitabine or fluorouracil should be considered. A systematic review and meta-analysis involving over 6,000 patients of 20 studies proved the benefit of adjuvant chemotherapy or chemoradiotherapy in R1 resection (OR 0.36, 95% CI 0.19–0.68) and patients with LN metastasis (0.49, 0.3–0.8). Moreover, for metastatic ICC, cisplatin plus gemcitabine is recommended as the standard-of-care. Data from the Advanced Biliary Cancers (ABC)-02, with an improvement in median survival of 3.6 months (11.7 months versus 8.1 months) and progression-free survival of 3 months (8.0 months versus 5 months), compared with gemcitabine alone[101]. Other studies, including a pooled analysis of 3,000 patients from 104 trials, have also demonstrated the role of other cytotoxic agents such has gemcitabine-based combinations and 5-FU based combinations[102, 103]. Multiple targeted therapies for ICC have been identified, based on the discovery of various mutations (most commonly IDH1 and KRAS)[104, 105]. The primary targets of these therapies are angiogenesis and the epidermal growth factor receptor (EGFR) pathway[104, 106]. Erlotinib, an EGFR inhibitor specifically targeting the EGFR tyrosine kinase, is potentially beneficial when given in combination with cytotoxic agents in patients with advanced cholangiocarcinoma, demonstrated by a randomized phase III study. In this study, the addition of erlotinib to chemotherapy (gemcitabine/oxaliplatin) prolonged the median progression-free survival of 2.9 months (5.9 months [95% CI, 4.7-7.1] for chemotherapy plus erlotinib vs 3.0 months [95% CI, 1.1-4.9] for chemotherapy alone; HR 0.73, 95% CI, 0.53-1.00)[107]. Potential roles of other molecular targeting agents, such as anti-EGFR monoclonal antibodies (panitumumab and cetuximab) and anti-angiogenic agents (sorafenib and bevacizumab), are being evaluated by various undergoing trials.

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In summary, ICC is the second most common hepatic malignancy with an increasing incidence and multiple risk factors of infectious, environmental and metabolic origin. Surgical resection provides the only cure in selected patients while other treatment modalities, such as locoregional and systemic therapies, can serve as adjuvant procedures after liver resection, or may be beneficial to the patients who have unresectable ICC.

Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 81472284, 81372262, and 81172020), Program for Excellent Young Scholars of SMMU, Charitable Project on Cancer Research of Shanghai and State Key Project on Infectious Diseases of China (No. 2012ZX10002-016).

Conflict of interest The authors declare no conflict of interest.

Conflict of interest statement None

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Tables and Figure legends:

Figure 1. A nomogram for predicting survival outcome after liver resection for ICC. (To use the nomogram, an individual patient's value is located on each variable axis, and a line is drawn upward to determine the number of points received for each variable value. The sum of these numbers is located on the total points axis, and a line is drawn downward to the survival axes to determine the likelihood of 3- or 5-year survival). CA 19-9, preoperative serum level of CA 19-9; CEA, preoperative serum level of carcinoembryonic antigen; Direct invasion and local metastasis, direct invasion of adjacent

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structures and local extrahepatic metastasis; LN metastasis, regional lymph node metastasis; PI, periductal infiltrating type.

Primary tumor (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ (intraductal tumor)

T1

Solitary tumor without vascular invasion

T2a

Solitary tumor with vascular invasion

T2b

Multiple tumors, with or without vascular invasion

T3

Tumor perforating the visceral peritoneum or involving the

Local extra hepatic structures by direct invasion T4 Tumor with periductal invasion

Regional lymph nodes (N)

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NX

Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis

N1

Regional lymph node metastasis present

Distant metastasis (M)

M0

No distant metastasis

M1

Distant metastasis present

Anatomic stage groupings

Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T3

N0

M0

Stage IVA

T4

N0

M0

Any T

N1

M0

Any T

Any N

M1

Stage IVB

Table 1. The seventh edition of AJCC/TNM staging system for intrahepatic bile duct tumors.

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