Therapy For Cholangiocarcinoma Research Articles

834 - Monitoring circulating tumour DNA in patients receiving selective internal radiation therapy for liver metastases and intrahepatic cholangiocarcinoma

834 - Monitoring circulating tumour DNA in patients receiving selective internal radiation therapy for liver metastases and intrahepatic cholangiocarcinoma

Comparison of Choi criteria and Response Evaluation Criteria in Solid Tumors (RECIST) for intrahepatic cholangiocarcinoma treated with glass-microspheres Yttrium-90 selective internal radiation therapy (SIRT)

ObjectiveTo compare Choi criteria with Response Evaluation Criteria in Solid Tumors (RECIST) for the prediction of overall survival (OS) in patients treated with glass-microspheres, Yttrium‐90 selective internal radiation therapy (SIRT) for intrahepatic cholangiocarcinoma (ICC). MethodsBetween 2010 and 2014, 45 adult patients with locally advanced ICC treated with SIRT were retrospectively analyzed. Computed tomography scans performed before and after treatment were analyzed using both RECIST 1.1 and Choi criteria. Response was correlated with survival. ResultsPatients who achieved an objective response according to Choi had a longer OS than non-responders (median OS 19.9 months [95% CI, 1.1–38.7 months] vs. 7.5 months if stable disease [uncountable CI] and 3 months if progressive disease [95% CI, 0–6.2 months], log-rank test: p=0.003) whereas there was no significant survival difference according to the RECIST response (p=0.339). Among the 39 RECIST non-responding patients, those identified as responders by Choi (n=31) had significantly better OS than Choi non-responders (median OS 19.9 months (95% CI, 5.1–34.7 months) and 5.4 months (95% CI, 0–11.6 months), p=0.005). ConclusionsChoi criteria appear more appropriate than RECIST to identify responders with long survival among patients who received SIRT for ICC.

Genomic profiling and targeted therapy in cholangiocarcinoma to yield positive clinical outcomes.

e23162Background: Cholangiocarcinoma is an uncommon gastrointestinal malignancy that remains relatively understudied even as its worldwide incidence continues to climb. The treatment options for pa...

The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets.

Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets.

Role of adjuvant therapy after R0 resection for patients with distal cholangiocarcinoma.

The optimal treatment strategy for cholangiocarcinoma (CC) after curative resection remains controversial. The aim of this study was to analyze the role of adjuvant therapy in R0-resected distal CC. We retrospectively reviewed the medical records of patients who underwent R0 resection for distal CC at six cancer centers in Korea. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of the study were overall survival (OS) and recurrence-free survival (RFS). A total of 158 patients were included in the analysis; 47 patients (29.7%) had lymph node involvement. Fifty-six patients (35.4%) received adjuvant therapy (CT/CRT/RT: 27/20/9, respectively). Patients with advanced TNM stage (P<0.001), T3/T4 disease (P=0.009), positive lymph nodes (LN; P=0.052), and elevated baseline carbohydrate antigen 19-9 (P=0.071) were more likely to receive adjuvant therapy. The effect of adjuvant therapy varied according to treatment modality. A multivariable analysis showed a significant improvement in OS after CT [hazard ratio (HR) 0.21, 95% confidence interval (CI) 0.08-0.53, P=0.001] and CRT (HR 0.25, 95% CI 0.08-0.83, P=0.024). However, RT alone was associated with shorter OS (HR 2.38, P=0.040), along with T3/T4 disease (HR 2.12, P=0.012) and positive LN (HR 2.30, P=0.008). RFS benefited from adjuvant treatment with CT (HR 0.34, P=0.002) and CRT (HR 0.33, P=0.004), but not with RT alone (HR 1.42, P=0.361). In the subset analysis according to LN status, adjuvant therapy not including RT alone was associated with a significant OS and RFS advantage in both LN-negative and LN-positive patients. Our results show that patients receiving CT or CRT had significant improvements in OS and RFS. In addition, a benefit of adjuvant therapy (except RT alone) was observed even in LN-negative patients.

The role of adjuvant therapy after R0 resection for patients with intrahepatic and perihilar cholangiocarcinoma.

302 Background: There is still debated regarding the optimal treatment strategy in cholangiocarcinoma (CC) after curative resection. The aim of this study was to analyze the role of adjuvant therapy in R0-resected intrahepatic and perihilar CC. Methods: We retrospectively reviewed the medical records of patients who underwent R0 resection for intrahepatic and perihilar CC between January 2001 and December 2013 at six cancer centers. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of our study were recurrence-free survival (RFS) and overall survival (OS). Multivariable Cox proportional hazards model was used to identify prognostic factors for survival. Results: A total of 137 patients were included in the analysis; 58.4% of patients had intrahepatic CC and 25.5% had lymph node involvement. Seventy-three patients (53.3%) received adjuvant therapy (CT/CRT/RT: 48/13/12, respectively). A greater percentage of patients receiving adjuvant therapy had stage III-IVA (P = 0.010), high histologic grade (P = 0.035), and positive lymph nodes (P = 0.088). Multivariable analysis identified positive nodes (hazard ratio (HR), 3.60; P &lt; 0.001), poor tumor differentiation (HR, 2.35, P = 0.048), and high baseline CA 19-9 level (HR, 1.97; P = 0.013) as predictors of decreased OS. The effect of adjuvant therapy varied according to the treatment modality. Adjuvant CRT was significantly associated with longer RFS (HR, 0.44; P = 0.036) but OS benefit was non-significant HR, 0.56; P = 0.245). In node-positive patients, CRT had a trend for longer OS (HR, 0.24; P = 0.097). In contrast, CT did not improve RFS (HR, 1.13; P = 0.617) or OS (HR, 1.70; P = 0.114). RT alone was associated shorter RFS (HR 3.08; P = 0.009) and OS (HR, 6.86, P &lt; 0.001). Conclusions: Adjuvant CT and RT were not associated with a survival advantage in R0-resected intrahepatic and perihilar CC. CRT appears to be appropriate treatment after complete resection especially in lymph node-positive patients.

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA- and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatin-remodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarker-driven trials are currently underway.

Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC. Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC. High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC.

Integrin β3 and LKB1 are independently involved in the inhibition of proliferation by lovastatin in human intrahepatic cholangiocarcinoma.

Human intrahepatic cholangiocarcinomas are one of the most difficult cancers to treat. In our study, Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme-CoA (HMG-CoA) reductase inhibitor, demonstrated anticancer properties by inhibiting cancer cell proliferation, cell migration and cell adhesion. Lovastatin inhibited the expressions of transforming growth factor (TGF)-β1, cyclooxygenase (COX)-2, and intercellular adhesion molecule (ICAM)-1. Furthermore, lovastatin inhibited the expressions of integrin β1 and integrin β3 but not integrin αv or integrin β5. While Lovastatin's inhibitory effects on TGFβ1, COX2, and ICAM-1 expression were independently controlled by the tumor suppressor LKB1, integrin β3 expression was not affected. Lovastatin's inhibitory effect on cell adhesion was associated with the decreased expression of integrin β3 and cell surface heterodimer integrin αvβ3. Quantitative real time PCR, fluorescent microscopy, and cell migration assays all confirmed that Lovastatin inhibits integrin αvβ3 downstream signaling including FAK activation, and β-catenin, vimentin, ZO-1, and β-actin. Overall, Lovastatin reduced tumor cell proliferation and migration by modifying the expression of genes involved in cell adhesion and other critical cellular processes. Our study highlights novel anti-cancer properties of Lovastatin and supports further exploration of statins in the context of cholangiocarcinoma therapy.

Role of Definitive Radiation Therapy of Intrahepatic Cholangiocarcinoma As Primary Treatment for Patients at High Risk

Role of Definitive Radiation Therapy of Intrahepatic Cholangiocarcinoma As Primary Treatment for Patients at High Risk

Nanoparticulate carriers for photodynamic therapy of cholangiocarcinoma: In vitro comparison of various polymer-based nanoparticles

The photodynamic therapy with porphyrin derivatives is an established approach to targeted tumor therapy, but is still afflicted with disadvantages of the physicochemical characteristics of the photosensitizer. To overcome drug-related restrictions in photodynamic therapy, three 5,10,15,20-tetrakis(m-hydroxyphenyl) porphyrin (mTHPP)-loaded nanoparticulate formulations based on poly(dl-lactide-co-glycolide) (PLGA), poly(d,l-lactide) (PLA), and Eudragit® E were prepared in a consistent diameter range and compared with free mTHPP in vitro. Formulation behavior was investigated in two different cholangiocellular cell lines, EGI-1 and TFK-1.High cytotoxicity was shown for all photosensitizer loaded nanoparticle (NP) formulations and free mTHPP, with EC50 values ranging from 0.2 to 1.3μM. PLA based NP were not as effective in all performed tests as other formulations. Nanoparticulate embedded mTHPP remained photodynamically active and resulted in caspase-3 activation even at low concentrations of 250nM. PLGA based NP exhibited highest caspase-3 activation.For all formulations an effective intracellular accumulation of mTHPP was observed, whereby for mTHPP-Eudragit® E-NP a 200-fold drug accumulation was shown.Polymer based nanoparticles were shown to be an effective and highly active transport vehicle for the photosensitizer mTHPP in vitro. Problems like low solubility of free drug can be circumvented by successful embedding into nanoparticulate carrier systems, maintaining therapeutic effects of the photosensitizer.

Impact of intravenous contrast enhancement phase on target definition for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC): Observations from patients enrolled on a prospective phase 2 trial

BackgroundThe safety and efficacy of radiation therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC) depend on accurate definition of gross tumor volume (GTV), but GTV often varies between phases of multiphasic computed tomography (CT) imaging. MethodsWe contoured GTVs on arterial, portal venous, and delayed phases of multiphasic CT scans for 32 patients treated on an institutional review board–approved prospective trial of proton therapy for primary liver tumors and determined which phase provided optimal GTV visualization. We assessed agreement between individual phase GTVs to determine if GTV for each phase was encompassed in a 5-mm expansion of either the smallest or the best-visualized GTV. ResultsThere were 19 HCC lesions and 14 IHC lesions. HCC lesions were best identified on the arterial phase in 42% (n = 8), portal venous phase in 32% (n = 6), and delayed phase in 26% (n = 5). IHC lesions were best identified on portal venous phase in 64% (n = 9) and the arterial phase in 29% (n = 4), with 1 case equally visualized on arterial and portal venous phases. In all 33 lesions, a 5-mm expansion around the smallest GTV failed to cover GTVs defined on other available phases. A 5-mm expansion around the best-visualized GTV provided satisfactory coverage of all available phases’ GTVs in 6/18 HCC cases and 2/9 IHC cases. ConclusionsVariability between GTVs on multiphasic CT scans could not be overcome with a 5-mm expansion of either the smallest GTV or the best-visualized GTV. Assessment of all available intravenous contrast phases is essential to accurately define the GTV.

Significance of S100P as a biomarker in diagnosis, prognosis and therapy of opisthorchiasis-associated cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a malignancy of bile duct with the difficulty in early diagnosis, poor prognosis and less alternation in therapy. S100P is a member of S100 family proteins and plays important roles in cancers. We investigated the S100P expression and its correlation with clinicopathology in 78 cases of opisthorchiasis-associated CCA, and the effects of S100P knockdown with shRNA interference on the proliferation, cell cycle, migration, apoptosis and sensitivity to anti-cancer drug. Extremely high expression of S100P mRNA was detected in the CCA tumor tissues. The increased S100P protein expression was immunohistochemically confirmed and localized in the CCA cytoplasm and/or nuclei as well as in the hyperneoplasia and dysplasia bile ducts, but not in normal bile ducts. The intensity of immunostaining was correlated with survival, tumor stage and metastasis, and the high expression could be an independent prognostic factor. High levels of S100P were detected in the serum and bile fluid of CCA patients. The shRNA-mediated knockdown of S100P expression inhibited the proliferation in vitro and in vivo, and migration of CCA cells, arrested cell cycle with the up-regulated expression of cell cycle arrest related factors, p21, p27, GADD45A, and 14-3-3 zeta. S100P knockdown also promoted CCA cell apoptosis by up-regulating expression of apoptosis related factors, DR5, TRADD, caspase 3 and BAX, and increased the sensitivity of CCA cells to the chemotherapeutic agents sunitinib and apigenin. Taken together, this study indicates that S100P might be a promising biomarker for the diagnosis, prognosis and therapy of CCA.

Efficacy and safety of photodynamic therapy for unresectable cholangiocarcinoma: A meta-analysis

Photodynamic therapy with the placement of a biliary stent may improve the prognosis in patients with unresectable cholangiocarcinoma. The aim of this research is to determine the hazard ratio of photodynamic therapy with stent compared to biliary stenting alone or other therapies for the treatment of cholangiocarcinoma. Several databases were searched from inception to December 31 2013 for trials comparing photodynamic therapy+stent vs. stent-only or other treatments for cholangiocarcinoma. The outcomes of interest included patient survival, the changes of serum bilirubin levels, the quality of life (Karnofsky performance status), and adverse events. The hazard ratios (HR) were extracted from the survival curves using Tierney's Method. LnHR and its variance were pooled using an inverse variance-weighted average. Inconsistency was quantified using I(2) statistics. In all, 8 trials comparing PDT+stent with other therapeutic methods were selected. We made a meta-analysis based on the 7 trials, which compared the result of PDT+stent and the stent-only group. HR summarizes the survival for the two groups. Overall survival was significantly better in patients who received photodynamic therapy than those who did not [HR=0.49, 95% confidence interval (CI), 0.33∼0.73, P=0.0005]. Among the 8 trials (642 subjects), 5 assessed the changes of serum bilirubin levels, and/or Karnofsky performance status, as other indications for improvement. In all, the incidence for phototoxic reaction is 11.11%. The incidence for other events in photodynamic therapy and the stent-only group was 13.64% and 12.79%, respectively. The palliative treatment of cholangiocarcinoma, with photodynamic therapy, is associated with an increased survival benefit, an improved biliary drainage, and a better quality of life. However, the quality of this evidence is low.

Endoscopically inserted nasobiliary catheters for high dose-rate brachytherapy as part of neoadjuvant therapy for perihilar cholangiocarcinoma.

Selected patients with unresectable perihilar cholangiocarcinoma can undergo neoadjuvant chemoradiotherapy followed by liver transplantation, which has been shown to improve survival. The aim of this study was to determine the feasibility and safety of endoscopic transpapillary insertion of nasobiliary tubes (NBTs) and brachytherapy catheters for high dose-rate (HDR) brachytherapy as part of this neoadjuvant chemoradiotherapy. Medical records of patients undergoing biliary brachytherapy for hilar cholangiocarcinoma at the Mayo Clinic, Rochester were reviewed. Patients were treated with curative intent using external beam radiotherapy (4500 cGy), chemotherapy (5-FU or capecitabine), and HDR brachytherapy (930 - 1600 cGy in one to four fractions delivered over 1 - 2 days) prior to planned liver transplantation. Between 2009 and 2013, 40 patients underwent biliary HDR brachytherapy via endoscopically placed NBTs (8.5 - 10 Fr). Patients had a median age of 55 years (range 28 - 68); 25 patients (62.5 %) had primary sclerosing cholangitis. Prior to therapy, 29 patients (72.5 %) had plastic stents, two (5 %) had metal stents, and nine (22.5 %) had no stents. Bilateral NBTs were placed in five patients (12.5 %). NBT/brachytherapy catheter displacement was seen in eight patients (20 %) - five intraprocedure and three post-procedure. A radiotherapy error and NBT kinking each occurred once. Post-procedure adverse events included: cholangitis (n = 5; 12.5 %), severe abdominal pain (n = 3; 7.5 %), duodenopathy (n = 3; 7.5 %), gastropathy (n = 3; 7.5 %), and both duodenopathy and gastropathy (n = 2; 5 %). HDR biliary brachytherapy administered via endoscopically placed NBTs and brachytherapy catheters is technically feasible and appears reasonably safe in selected patients with unresectable perihilar cholangiocarcinoma.

SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma

The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen. Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m(2) intravenously on days 1 and 8) and capecitabine (1,500 mg/m(2) per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m(2) per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively. A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage. This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.

The Efficacy of Intraluminal Brachytherapy as Palliative Therapy of Hilar Cholangiocarcinoma

Background/Aims: The aim of this study is to assess the therapeutic benefits of a combination of external beam radiation therapy (EBRT) and intraluminal brachytherapy (ILBT) in hilar cholangiocarcinoma as palliative therapy. Methods: A total of 21 patients with hilar cholangiocarcinoma were included. Only 12 patients were treated with EBRT (group 1), and only nine patients were treated with EBRT and ILBT (group 2). The survival data and stent patency period were measured in both groups and the results were compared. Results: No statistically significant difference in patient survival was observed between the two groups. The median survival period of group 1 was 353 days and that of group 2 was 224 days. Also, stent patency did not differ significantly between groups. The period for group 1 was 250 days, and that of group 2 was 133 days. In addition, there were no other factors influencing patient survival and stent patency period. However, patient survival tended to increase with increase in the amount of irradiation dose (Spearman’s correlation coefficient=0.65, p =0.065). Conclusions: EBRT with ILBT did not have a benefit when compared with the treatment effect of EBRT alone as palliative therapy for hilar cholangiocarcinoma. Korean J Pancreatobiliary 2015;20(2):71-77

Progression of targeted therapy in advanced cholangiocarcinoma.

It is necessary to establish an effective therapy to improve the survival of patients with advanced cholangiocarcinoma (CCA). Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.

Neoadjuvant chemoradiation therapy for cholangiocarcinoma to improve R0 resection rate: The first report of phase II study.

402 Background: With the much-improved surgical techniques of hepatic lobectomy, but the long-term survival of patients undergoing such surgery remains far from satisfactory. Then, to improve the prognosis of cholangiocarcinoma patients, we have applied neoadjuvant chemoradiation therapy followed by conventional resection for possibly resectable cholangiocarcinoma, named NACRAC. Here, we analyzed and evaluated the Phase II (P-2) study. Methods: Patients with histologically or cytologically confirmed adenocarcinoma of the extra- and hilar cholangiocarcinoma were enrolled from 2008 to 2013 at Department Surgery, Tohoku University Hospital. The dose of gemcitabine was determined 600mg/m2 of gemcitabine with external beam radiation therapy (1.8-Gy daily fractions to a total dose of 45 Gy) ( Hepatogastroenterology. 2011;58(112):1866-72.). The primary endpoint of P-2 is R0-resection rate. We hypothesized that R0-resection rate become from 60% to 80%. Results: Total numbers of enrolled patients were 25 cases. 22 cases were operated, and 20 cases were resected. After chemoradiation, 3 cases were not operated by liver metastases, tumor progression, and heart failure. 2 cases were not resected by peritoneal carcinomatosis. One case was diagnosed as pancreatic cancer at the final pathological diagnosis. R0-resectinn cases were 17 cases. R0 resection rate was 89.6% (17/19) among operated cases. In recruited 24 cases (A pancreatic cancer was not included), R0 resection rate was 70.8% (17/24). Grade 3 and 4 adverse events (AE) were neutropenia, leukocytopenia, and Thrombocytopenia. No grade 5 AE and no fatal AE in this P-2 study. Conclusions: Neoadjuvant chemoradiation therapy with conventional resections appears to be effective and well tolerated. After both disease free survival and overall survival are going to be fixed, we will decide a proper indication of neoadjuvant therapy for cholangiocarcinoma. Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN UMIN000000992 and UMIN000001754 Clinical trial information: 000001754.

Cholangiocarcinoma and malignant bile duct obstruction: A review of last decades advances in therapeutic endoscopy.

In the last decades many advances have been achieved in endoscopy, in the diagnosis and therapy of cholangiocarcinoma, however blood test, magnetic resonance imaging, computed tomography scan may fail to detect neoplastic disease at early stage, thus the diagnosis of cholangiocarcinoma is achieved usually at unresectable stage. In the last decades the role of endoscopy has moved from a diagnostic role to an invaluable therapeutic tool for patients affected by malignant bile duct obstruction. One of the major issues for cholangiocarcinoma is bile ducts occlusion, leading to jaundice, cholangitis and hepatic failure. Currently, endoscopy has a key role in the work up of cholangiocarcinoma, both in patients amenable to surgical intervention as well as in those unfit for surgery or not amenable to immediate surgical curative resection owing to locally advanced or advanced disease, with palliative intention. Endoscopy allows successful biliary drainage and stenting in more than 90% of patients with malignant bile duct obstruction, and allows rapid reduction of jaundice decreasing the risk of biliary sepsis. When biliary drainage and stenting cannot be achieved with endoscopy alone, endoscopic ultrasound-guided biliary drainage represents an effective alternative method affording successful biliary drainage in more than 80% of cases. The purpose of this review is to focus on the currently available endoscopic management options in patients with cholangiocarcinoma.