Cholangiocarcinoma (CCA) is rare malignant tumors composed of cells that resemble those of the biliary tract. It is notoriously difficult to diagnose, and is associated with a high mortality. Traditionally, CC is divided into intrahepatic and extraheaptic disease according to its location within the biliary tree. Intrahepatic cholangiocarcinoma (ICCA) or peripheral cholangiocellular carcinoma (PCCA) appears within the second bifurcation of hepatic bile duct, and is the second most common primary liver cancer following hepatocellular carcinoma (HCC), ICCA or peripheral CCA often presents with advanced clinical features, and the cause for this cancer rise is still unclear (Shimoda & Kubota, 2007).
Worldwide, cholangiocarcinoma (ICCA and extra-hepatic cholangiocarcinoma) accounts for 3% of all gastrointestinal cancer. As ICCA accounts for approximately 10% to 20% of all primary liver cancer. The incidence rates of ICCA are extensive, varying among different parts of the world. The incidence of ICCA appears to be higher among men in different areas of the world. The incidence ratios of male to female vary between 1.3 among white Americans to 3.3 among the French. In general, male preponderance is less pronounced in ICCA than in HCC (Dodson et al., 2013).
Several risk factors have been associated with the development of ICCA; however, the cause is still unknown for most ICCA cases. The association between ICCA and chronic biliary tract inflammation, such as primary sclerosing cholangitis (PSC), liver fluke infestation, or hepatolithiasis, is well recognized. Especially, PSC is a definite risk factor for ICCA, and the risk for developing ICCA after the diagnosis of cholestatic liver disease is 1.5% per year. Approximately 30% of the patients with PSC who are likely to develop ICCA will be diagnosed with malignancy of the bile duct within two years after diagnosis of the PSC. Bile stenosis and recurrence of biliary inflammation might predispose individuals with these conditions to cancer (Bergquist et al., 2002).
Routine imaging, such as ultrasonography, abdominal and chest computed tomography and cholangiography [magnetic resonance cholangio-pancreatography (MRCP), percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiography (ERC), are useful for evaluating metastasis, tumor location, and extent of tumor. Angiography or 3-dimensional vascular imaging is helpful for evaluating vascular invasion (Knox et al., 2005).
The curative treatment strategy for ICCA, most patients present with advanced disease and cannot be applicable for surgical management. The selection of performable curative surgical resection depends on location of the tumors. Surgery for ICCA is similar to that of other liver malignancies, and includes hepatic lobectomy, segementectomy or subsegmentectomy with or without resection of the common bile duct. For hilar lesions, preoperative evaluation of tumor location and involvement of intra- or extra-hepatic biliary tree are extremely important for obtaining tumor-free margin (Denys et al., 2002).
If the patient requires extended hepatic resection, preoperative portal vein embolization (PE) is effective for inducing lobar hypertrophy, and decreasing risk of operative morbidity and mortality, such as remnant liver failure. In case with involvement of distal common bile duct tumors are resected via Whipple procedure; periampullary region tumors have a uniformly better prognosis, with a long-term survival rate of 30-40% (Shen et al., 2011).
Orthotopic liver transplantation is considered for some patients with proximal tumors who are not candidates for resection because of the extent of tumor spread in the liver. The largest series reports a 53% 5-year survival rate and a 38% complete pathologic response rate with preoperative radiation therapy and chemotherapy. Liver transplantation may have a survival benefit over palliative treatments, especially for patients with tumors in the initial stages. One study has demonstrated a 5-year survival rate greater than 80% in select patients (Heimbach et al., 2004).
The role of systemic chemotherapy in the unresectable ICCA is undefined. While no single agent or combination therapy has achieved significant response rates, most promising approaches involve the use of single agent gemcitabine (GEM). Combination regimens of GEM with agents, such as 5-FU, docetaxel, oxaliplatin, cisplatin, and capecitabine, have been limited by toxicity without good effective response for unresectable ICCA patients (Dingle et al., 2005).
The value of adjuvant radiotherapy has been to improve local control, with variable effect on overall survival after complete resection. Several series have shown an increase in median survival duration with postoperative radiation, from 8 months with surgery alone to more than 19 months. Special radiation techniques have been used, such as intraluminal brachytherapy and external-beam therapy during surgery (ie, intraoperative radiotherapy [IORT]) (Darwin, 2015).
Transarterial chemoembolization (TACE), which increases the local concentration of chemotherapeutic agents and reduces systemic exposure (Liapi and Geschwind, 2007), has shown promising results in increasing survival (Kiefer et al., 2011), and radioembolization also seems to increase survival. Thus, these regional therapies are considered as an option for treating small tumors when the general health condition of the patient does not permit a more aggressive treatment. (Hoffmann et al., 2012).
Recently, several preclinical studies have shown the therapeutic potential of targeting molecular pathways in CCA. The EGFR pathway has been identified as a promising molecular target for CCA (Andersen JB et al., 2012). The addition of erlotinib was found to increase the complete and partial response and increased progression-free survival f(Lee J., 2012). Other promising, druggable molecular targets for CCA include vascular endothelial growth factor receptor, Januskinase-1/2, STAT3, MET and IDH 1 and 2 (Takahashi H et al., 2014). An interesting approach targets the microenvironment, such as cancer associated fibroblasts (CAF) (Mertens JC et al., 2013). CAF have been shown to promote tumor progression and CCA. Navitoclax, a BH3 mimetic, selectively induced apoptosis of CAFs resulting in inhibiton of tumor progression and prolongation of survival a preclinical in vivo model (Razumilava N et al., 2014).
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