A



Medical treatment for cholangiocarcinomaAuthors:?Jorge Adeva1, Bruno Sangro2, Maximiliano Salati3,4, Julien Edeline5, Adelaida La Casta6, Alessandro Bittoni7, Rosanna Berardi7, Jordi Bruix8 and Juan William Valle9,10Affiliations?1 Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain2 Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain3 Department of Oncology, University Hospital of Modena and Reggio Emilia, Modena, Italy 4 Division of Molecular Pathology, Institute of Cancer Research and Gastrointestinal Unit, Royal Marsden Hospital, London and Sutton, UK5 Department of Medical Oncology, Centre Eugene Marquis, Rennes, France6 Department of Medical Oncology, Hospital Universitario Donostia, Navarra, Spain7 Clinica Oncologica, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy8 Barcelona Clinic Liver Cancer (BCLC) group. Liver Unit. Hospital Clinic Barcelona. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)9 Division of Cancer Sciences, University of Manchester, Manchester, UK10 Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UKCorresponding authorJ Adeva, Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, SpainKey wordsCholangiocarcinoma, chemotherapy, targeted therapy, immunotherapyAbstractMost of patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially-curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention-to-treat analysis; however, a survival benefit was seen in a pre-planned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to uptake of adjuvant capecitabine by many clinicians.In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first-line treatment of patients with advanced disease; there is no established second-line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor [EGFR] and vascular endothelial growth factor [VEGF] pathways). An increasing number of genomic subtypes are being defined; for some of these on-target therapeutic options are under active investigation. The most developed are studies targeting IDH-1 (isocitrate dehydrogenase) mutations and FGFR-2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed. HighlightsThe standard of care in cholangiocarcinoma is based on Cisplatin – Gemcitabine combination in the first-line setting (ABC-02) and, for some authors, Capecitabine in the adjuvant setting (Bilcap).Due to a better tumor molecular profiling, IDH1 mutations and FGFR2 fusions have been positioned as the two main driver alterations in intrahepatic CCA and are being actively explored with specific antitargeted agents. However, many other alterations as NTRK rearrangements or BRAF mutations are also emerging as new potential targets. Immunotherapy is still looking for its niche in CCA. To date, MSI-H /dMMR is the only predictive marker for selecting antiPD1 therapy. Locoregional treatments like SIRT or SBRT are progressively testing its efficacy and safety and may represent a new therapeutic option in a near future. This article aims to briefly review past, present and exciting future of the medical treatment of cholangiocarcinoma. IntroductionCholangiocarcinoma (CCA), including the intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subtypes, represents the second commonest type of primary liver cancer and about 3% of all gastrointestinal malignancies. Even though CCA in Western countries is rare, incidence and mortality rates of this disease have risen in the past few decades, in particular with an increase of iCCA incidence ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1001/jamaoncol.2015.0735","ISBN":"2374-2445 (Electronic)","ISSN":"2374-2445","PMID":"26181261","abstract":"IMPORTANCE Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies. OBJECTIVE To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013. EVIDENCE REVIEW The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs. FINDINGS In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100 000 and age-standardized death rates (ASDRs) per 100 000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10% in 113 countries and decreased by more than 10% in 12 of 188 countries. CONCLUSIONS AND RELEVANCE Cancer poses a major threat to public health …","author":[{"dropping-particle":"","family":"Fitzmaurice C, Dicker D","given":"Pain A et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA oncology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2015"]]},"page":"505-527","title":"The Global Burden of Cancer 2013.","type":"article-journal","volume":"1"},"uris":[""]}],"mendeley":{"formattedCitation":"(1)","plainTextFormattedCitation":"(1)","previouslyFormattedCitation":"(1)"},"properties":{"noteIndex":0},"schema":""}(1). Radical surgical resection is the only potentially-curative treatment for CCA. However, CCA is usually asymptomatic in early stages and is often diagnosed when advanced (locally advanced/unresectable or metastatic). Furthermore, it has been shown that 10% to 45% of patients considered to have resectable disease at diagnosis are found to be unresectable during exploratory laparotomy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.surg.2007.10.010","ISBN":"1532-7361 (Electronic)\\r0039-6060 (Linking)","ISSN":"00396060","PMID":"18291258","abstract":"Background: Limited data exist regarding the role of extended liver resection for the management of intrahepatic cholangiocarcinoma (ICC), most of which derive from small single-center or larger multicenter series. In the current report, we present our experience with the surgical management of ICC, analyze operative results, and investigate prognostic factors in resected patients. Methods: A total of 72 patients underwent operative exploration for ICC between 1991 and 2005; 54 patients were resected, and 18 patients were deemed unresectable based on intraoperative findings. Demographics, pathology, anatomic characteristics, operative results, and survival were analyzed. Results: The resectability rate was 71%, with negative margins achieved in 78% of the resected patients. Extended liver resections were performed in 24 (44%) of the 72 patients. Perioperative mortality after resection was 7%, with 11% morbidity. The 1-, 3- and 5-year survival rates after resection were 80%, 49% and 25%, respectively, and were significantly greater than for patients with unresectable disease (P < .001). R1 liver resections conferred increased 5-year survival compared with patients deemed unresectable (P = .03). None of the factors evaluated proved to be independent prognostic factors on multivariate analysis. Conclusions: R0 resection of ICC provides the best chance for prolonged survival, whereas R1 resection appears to be superior to nonoperative treatment. Declining operative mortality as a result of improved intraoperative and perioperative care justifies the performance of extended liver resections in these patients, although benefit has to be evaluated with respect to nodal involvement. ? 2008 Mosby, Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Konstadoulakis","given":"Manousos M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roayaie","given":"Sasan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gomatos","given":"Ilias P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labow","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fiel","given":"Maria Isabell","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Charles M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"Myron E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Surgery","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2008"]]},"page":"366-374","title":"Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: Operative results and long-term outcome","type":"article-journal","volume":"143"},"uris":[""]}],"mendeley":{"formattedCitation":"(2)","plainTextFormattedCitation":"(2)","previouslyFormattedCitation":"(2)"},"properties":{"noteIndex":0},"schema":""}(2). Moreover, even though more aggressive surgical approaches and improved radiologic techniques have improved the chances of achieving a radical resection, recurrence rates after surgery are still high.Systemic therapy represents the mainstay of palliative treatment for patients with advanced or recurrent CCAs. Although CCA is traditionally considered a chemotherapy-resistant disease, clinical trials have demonstrated that systemic chemotherapy extends survival in patients with advanced biliary tract cancer (gallbladder cancer as well as CCA) compared with best supportive care ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/oxfordjournals.annonc.a010676","ISBN":"0923-7534","ISSN":"09237534","PMID":"8879373","abstract":"BACKGROUND: In certain patients with pancreatic and biliary cancer, chemotherapy may relieve tumour-related symptoms, improve quality of life and possibly prolong survival. The extent of these improvements is not completely known in spite of the extensive use of this treatment modality. The aim of this study was to estimate any gain in the quantity and quality of life produced by chemotherapy in patients with pancreatic and biliary cancer. PATIENTS AND METHODS: Between January 1991 and February 1995, 90 eligible patients with pancreatic or biliary cancer were randomized to either chemotherapy in addition to best supportive care or to best supportive care. Chemotherapy was allowed in the latter group if the supportive measures did not lead to palliation. Chemotherapy was either sequential 5-fluorouracil/leucovorin combined with etoposide (FELv) or, in elderly and poor performance patients, the same regimen without etoposide (FLv). Quality of life was evaluated with the EORTC-QLQ-C30 instrument. RESULTS: Mean scale scores in the QLQ-C30 improved more often/deteriorated less frequently in the chemotherapy group than in the best supportive care group. More patients in the chemotherapy group (36%, 17/49) had an improved or prolonged high quality of life for a minimum period of 4 months compared to those in the best supportive care group (10%, 4/41, P < 0.01). Overall survival was significantly longer in the chemotherapy group (median 6 vs. 2.5 months, P < 0.01). Also, the quality-adjusted survival time was longer for patients randomized to chemotherapy (median 4 vs. 1 months, P < 0.01). The effects were seen both in pancreatic and biliary cancer. CONCLUSIONS: The results show that chemotherapy can add to both quantity and quality of life in advanced pancreatic and biliary cancer. The number of patients who benefit from treatment is, however, still limited; for this reason careful selection before, and close monitoring during, treatment are necessary.","author":[{"dropping-particle":"","family":"Glimelius","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoffman","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sj?dén","given":"P. O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobsson","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sellstr?m","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Enander","given":"L. K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Linné","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svensson","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["1996"]]},"page":"593-600","title":"Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"(3)","plainTextFormattedCitation":"(3)","previouslyFormattedCitation":"(3)"},"properties":{"noteIndex":0},"schema":""}(3) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0732-183X","abstract":"Background: In a recently conducted study we have shown that combination of gemcitabine and oxaliplatin is superior to 5 fluorouracil and leucoverine or best supportive care. (Sharma A, Dwary AD, Mohanti BK,et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer:A randomized controlled study. J Clin Oncol. 2010; 28: 4581-4586.) In another recent publication from UK, gemcitabine and cisplatin combination was found superior to gemcitabine alone in biliary tract cancers (J W Valle, HS Wasan, DD Palmer, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Eng J Med. 2010;362:1273-1281.).The current study is being planned to see whether the combination of gemcitabine and oxaliplatin is equivalent (equivalence study) to gemcitabine and cisplatin in these patients. Methods: Primary end point of the study is overall survival in subjects receiving mGEMOX or GemCis regimen. Secondary end points are: a) Comparison of progression free survival in 2 groups; b) Response rates in two groups; c) Identification of genes predictive of responses in a subset of patients; d) To evaluate role of PET CT in GBC patients predicting disease activity. Sample size was calculated taking median survival of 9.5 months in our previous study with mGEMOX and 11.7 months with GemCis. For this total of 216 patients are required (108 in each arm); to make for major protocol violation and lost to follow up additional 22 patients in each arm will be enrolled. Thus in total 260 patients (130) in each arm will be recruited. This will have alpha and beta values of 0.05 and 0.20 respectively. So far 103 patients have been enrolled and interim analysis is being planned. Treatment protocol: Cycles will be repeated every 3 weeks. Arm A- mGEMOX. Inj Oxaliplatin 80 mg/m22 hours infusion in Dextrose 5% Day 1 and 8. Inj Gemcitabine 900 mg/m2IV 30 minutes infusion day 1 and 8 maximum of 6 cycles. Arm B- GEMCIS. Inj Cisplatin 25 mg/m2PO Days 1 and 8. Inj Gemcitabine 1000 mg/m2IV 30 minutes infusion day1and 8 maximum of 8 cycles.","author":[{"dropping-particle":"","family":"Sharma","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chaudhary","given":"S P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shukla","given":"N K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mohanti","given":"B K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deo","given":"S V S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pal","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raina","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thulkar","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vishnubhatla","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iyer","given":"V K","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2013"]]},"title":"A randomized controlled trial comparing modified gemcitabine plus oxaliplatin (mGEMOX) to gemcitabine plus cisplatin in the management of unresectable gall bladder cancer","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"(4)","plainTextFormattedCitation":"(4)","previouslyFormattedCitation":"(4)"},"properties":{"noteIndex":0},"schema":""}(4) and the cisplatin/gemcitabine combination represents the current standard of treatment, based on level 1 evidence ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1586/egh.10.45","ISSN":"1747-4132","PMID":"20678012","abstract":"Evaluation of: Valle J, Wasan H, Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362, 1273-1281 (2010). Biliary tract cancer is a rare disease and it is associated with a poor clinical outcome and survival. A standard therapy has not been established yet. The evaluated article reports on the first Phase III randomized controlled multicenter trial (ABC-02 trial) on palliative chemotherapy for biliary tract cancer. A total of 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer or ampullary cancer were included to receive either cisplatin followed by gemcitabine or gemcitabine alone for up to 24 weeks. The primary end point was overall survival and the secondary end point was progression-free survival. The median overall survival was 11.7 months in the cisplatin plus gemcitabine group and 8.1 months in the gemcitabine only group. The median progression-free survival was 8.0 months in the cisplatin plus gemcitabine group and 5.0 months in the gemcitabine-only group (p < 0.001). Adverse events were comparable in the two groups. Cisplatin plus gemcitabine, compared with gemcitabine alone, was associated with a significant survival advantage without an increase in substantial toxicity.","author":[{"dropping-particle":"al","family":"Valle J, Wasan H","given":"Palmer DH et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"page":"1273-1281","title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","type":"article-journal","volume":"362"},"uris":[""]}],"mendeley":{"formattedCitation":"(5)","plainTextFormattedCitation":"(5)","previouslyFormattedCitation":"(5)"},"properties":{"noteIndex":0},"schema":""}(5) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/sj.bjc.6605779","ISBN":"0007-0920","ISSN":"00070920","PMID":"20628385","abstract":"BACKGROUND: A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients.\\n\\nMETHODS: Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m(-2) plus gemcitabine 1000 mg m(-2) on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m(-2) on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks.\\n\\nRESULTS: A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and gamma-GTP increase (29.3%/35.7%).\\n\\nCONCLUSIONS: Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.","author":[{"dropping-particle":"","family":"Okusaka","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakachi","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fukutomi","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mizuno","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohkawa","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Funakoshi","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagino","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kondo","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagaoka","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Funai","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koshiji","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nambu","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furuse","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyazaki","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nimura","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2010"]]},"page":"469-474","title":"Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: A comparative multicentre study in Japan","type":"article-journal","volume":"103"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"(6)"},"properties":{"noteIndex":0},"schema":""}(6).Data from meta-analysis and recent clinical trials have shown a role for chemotherapy and chemoradiotherapy in the adjuvant setting with a survival benefit, especially in patients with node-positive disease or with microscopically-involved margins (R1 resections). The role of loco-regional treatments, such as transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT), has increasingly been investigated for patients with CCA over the last few years. A few studies have suggested a possible benefit of such therapies regarding tumor progression and survival, even if limited by their retrospective nature, small sample size and heterogeneity of chemotherapeutic agents. Radiofrequency ablation (RFA) and photodynamic therapy (PDT) have also been shown to be feasible in the treatment of CCA. Unfortunately, there is no level 1 evidence to date of the magnitude of benefit, if any, of these loco-regional treatments. Several clinical trials have evaluated the efficacy of specific molecular agents aimed at various potential targets in CCAs, such as epithelial growth factor receptor (EGFR) or vascular endothelial growth factor receptor (VEGFR) with discouraging results. Nevertheless, novel molecular alterations have been identified in CCA by recent genetic studies, which have shed new insights upon the pathogenic mechanisms of this disease and the signaling pathways that drive its progression. In particular, a large comprehensive molecular profiling study of biliary tract cancers demonstrated that nearly 40% of the patients harbor genetic alterations that are potentially targetable ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ng.3375","ISBN":"1546-1718 (Electronic)\\r1061-4036 (Linking)","ISSN":"15461718","PMID":"26258846","abstract":"The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.","author":[{"dropping-particle":"","family":"Nakamura","given":"Hiromi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arai","given":"Yasuhito","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Totoki","given":"Yasushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shirota","given":"Tomoki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Elzawahry","given":"Asmaa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kato","given":"Mamoru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hama","given":"Natsuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hosoda","given":"Fumie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Urushidate","given":"Tomoko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohashi","given":"Shoko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hiraoka","given":"Nobuyoshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ojima","given":"Hidenori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimada","given":"Kazuaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okusaka","given":"Takuji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kosuge","given":"Tomoo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Shinichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shibata","given":"Tatsuhiro","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Genetics","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2015"]]},"page":"1003-1010","title":"Genomic spectra of biliary tract cancer","type":"article-journal","volume":"47"},"uris":[""]}],"mendeley":{"formattedCitation":"(7)","plainTextFormattedCitation":"(7)","previouslyFormattedCitation":"(7)"},"properties":{"noteIndex":0},"schema":""}(7) also showing clear differences between intra and extra-hepatic CCAs.In this chapter, we discuss the current medical treatments for CCA in the adjuvant and advanced settings. In addition, we present data about loco-regional therapies and investigational treatments, such as new cytotoxic agents and combinations, targeted therapies and immunotherapeutic approaches under evaluation in CCA to show emerging new treatments and future directions of clinical and translational research.Adjuvant treatmentAs noted previously, surgical resection is the only potentially-curative approach in CCA. Nevertheless, recurrence rates of CCA remain high even after radical resection, and 5-years overall survival (OS) after surgery has been reported in the range of 25-35%. Recurrences are predominantly intrahepatic and usually occur within 2 to 3 years post-resection. Favorable prognosis after resection is associated with the presence of tumor-negative margins, absence of vascular invasion and lymph node metastasis, and adequate functional liver remnant ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/978-3-642-40558-7_9","ISBN":"9783642405570","abstract":"Liver transplantation and resection for hilar cholangiocarcinoma are mutually exclusive therapeutic pathways, without possibility of cross over. Interpretation of relevant imaging is essential for accurate preoperative diagnosis, operative planning, management of complications during neoadjuvant therapy, and post-transplant surveillance of patients with hilar cholangiocarcinoma. Preoperatively, careful and dynamic interpretation of both cross-sectional imaging and cholangiography is needed to appreciate tumor presence, location, and vascular involvement. While many post-transplant vascular complications can be managed with percutaneous endovascular techniques, a number of specific vascular complications are preferentially treated operatively. An experienced multidisciplinary team is required for successful treatment of hilar cholangiocarcinoma with liver transplantation.","author":[{"dropping-particle":"","family":"Zaydfudim","given":"Victor M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagorney","given":"David M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosen","given":"Charles B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biliary Tract and Gallbladder Cancer","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"page":"133-143","title":"Imaging of Hilar Cholangiocarcinoma for Liver Transplantation","type":"chapter"},"uris":[""]}],"mendeley":{"formattedCitation":"(8)","plainTextFormattedCitation":"(8)","previouslyFormattedCitation":"(8)"},"properties":{"noteIndex":0},"schema":""}(8).The high rates of loco-regional recurrence or distant metastases after resection provide the rationale for adjuvant treatment in CCA. Most of the published studies on adjuvant treatment in CCA are retrospective and include a small number of patients with a broad range of biliary tract cancer, gallbladder cancer or periampullary tumors. Two historical randomized controlled trials evaluated the efficacy of adjuvant chemotherapy after resection in CCA. An early study by Takada et al published in 2002 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/cncr.10831","ISBN":"0008-543X","ISSN":"0008543X","PMID":"12365016","abstract":"BACKGROUND: To the authors' knowledge, the significance of postoperative adjuvant chemotherapy in pancreaticobiliary carcinoma has not yet been clarified. A randomized controlled study evaluated the effect of postoperative adjuvant therapy with mitomycin C (MMC) and 5-fluorouracil (5-FU) (MF arm) versus surgery alone (control arm) on survival and disease-free survival (DFS) for each specific disease comprising resected pancreaticobiliary carcinoma (pancreatic, gallbladder, bile duct, or ampulla of Vater carcinoma) separately. METHODS: Between April 1986 and June 1992, a total of 508 patients with resected pancreatic (n = 173), bile duct (n = 139), gallbladder (n = 140), or ampulla of Vater (n = 56) carcinomas were allocated randomly to either the MF group or the control group. The MF group received MMC (6 mg/m(2) intravenously [i.v.]) at the time of surgery and 5-FU (310 mg/m(2) i.v.) in 2 courses of treatment for 5 consecutive days during postoperative Weeks 1 and 3, followed by 5-FU (100 mg/m(2)orally) daily from postoperative Week 5 until disease recurrence. All patients were followed for 5 years. RESULTS: After ineligible patients were excluded, 158 patients with pancreatic carcinoma (81 in the MF group and 77 in the control group), 118 patients with bile duct carcinoma (58 in the MF group and 60 in the control group), 112 patients with gallbladder carcinoma (69 in the MF group and 43 in the control group), and 48 patients with carcinoma of the ampulla of Vater (24 in the MF group and 24 in the control group) were evaluated. Good compliance (> 80%) was achieved with MF treatment. The 5-year survival rate in gallbladder carcinoma patients was significantly better in the MF group (26.0%) compared with the control group (14.4%) (P = 0.0367). Similarly, the 5-year DFS rate of patients with gallbladder carcinoma was 20.3% in the MF group, which was significantly higher than the 11.6% DFS rate reported in the control group (P = 0.0210). Significant improvement in body weight compared with the control was observed only in patients with gallbladder carcinoma. There were no apparent differences in 5-year survival and 5-year DFS rates between patients with pancreatic, bile duct, or ampulla of Vater carcinomas. Multivariate analyses demonstrated a tendency for the MF group to have a lower risk of mortality (risk ratio of 0.654; P = 0.0825) and recurrence (risk ratio of 0.626; P = 0.0589). The most commonly reported adverse drug reactions were anorexia, nausea/…","author":[{"dropping-particle":"","family":"Takada","given":"Tadahiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amano","given":"Hodaka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yasuda","given":"Hideki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nimura","given":"Yuji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushiro","given":"Takashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kato","given":"Hiroyuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagakawa","given":"Takukazu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakayama","given":"Toshimichi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2002"]]},"page":"1685-1695","title":"Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma","type":"article-journal","volume":"95"},"uris":[""]}],"mendeley":{"formattedCitation":"(9)","plainTextFormattedCitation":"(9)","previouslyFormattedCitation":"(9)"},"properties":{"noteIndex":0},"schema":""}(9) included 508 patients with pancreatic cancer, bile duct and periampullary cancer and gallbladder cancer (including 279 CCA patients) with stage II-IV disease that were randomized after surgery to observation or adjuvant chemotherapy with mitomycin-C and 5-fluorouracil (5-FU). Only patients with gallbladder cancer (n=112) were found to have a significant benefit at per protocol analysis from treatment in terms of 5-years overall survival (26% vs 14.4%, p= 0.037) and disease-free survival (20.3% vs 11.6%, p= 0.021). No significant difference was observed in the other subgroups of patients. A second randomized trial, the European Study Group for Pancreatic Cancer (ESPAC)-3 study, enrolled 428 patients with resected periampullary adenocarcinoma in stage I-IVa that were randomized to observation or chemotherapy with folinic acid 20 mg/m2 followed by 5-FU 425 mg/m2 administered 1 to 5 days every 28 days or gemcitabine 1000 mg/m2 once a week for 3 of every 4 weeks for 6 months. The study included 96 patients with biliary duct cancer. No significant difference was observed in terms of overall survival, primary endpoint of the study, between the observation group and the two chemotherapy groups. After adjusting for independent prognostic factors (secondary analysis), adjuvant chemotherapy was associated with significantly higher survival (HR: 0.75; 95% CI: 0.57-0.98;?p=0.03) among all patients included, with a better safety profile for gemcitabine compared to 5-fluorouracil ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1001/jama.2012.14657","ISBN":"0098-7484","abstract":"Context: Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas. Objective: To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection. Design, Setting, and Patients: The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial ( July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers. Interventions: One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months. Main Outcome Measures: The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life. Results: Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; chi2=1.33; P=.25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald chi2=4.53, P=.03). Conclusions: Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy. Trial Registration: clinica…","author":[{"dropping-particle":"","family":"Neoptolemos JP, Moore MJ, Cox JV","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA.","id":"ITEM-1","issued":{"date-parts":[["2012"]]},"page":"1861","title":"Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial.","type":"chapter"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"(10)"},"properties":{"noteIndex":0},"schema":""}(10); however, the study was underpowered to detect a survival benefit in patients with bile duct cancer with only 31-34 patients in each of the allocated treatment arms. A systematic review and meta-analysis of clinical trials on adjuvant treatment in biliary tract cancers by Horgan et al ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2011.40.5381","ISBN":"1527-7755 (Electronic)\\r0732-183X (Linking)","ISSN":"0732183X","PMID":"22529261","abstract":"PURPOSE: The benefit of adjuvant therapy (AT) for biliary tract cancer (BTC) is unclear, with conflicting results from nonrandomized studies. We report a systematic review and meta-analysis to determine the impact of AT on survival. METHODS: Studies published between 1960 and November 2010, which evaluated adjuvant chemotherapy (CT), radiotherapy (RT), or both (CRT) compared with curative-intent surgery alone for resected BTC were included. Only tumors of the gallbladder and bile ducts were assessed. Published data were extracted and computed into odds ratios (ORs) for death at 5 years. Subgroup analyses of benefit based on lymph node (LN) or resection margin positivity (R1) were prespecified. Data were weighted by generic inverse variance and pooled using random-effect modeling. RESULTS: Twenty studies involving 6,712 patients were analyzed. There was a nonsignificant improvement in overall survival with any AT compared with surgery alone (pooled OR, 0.74; P = .06). There was no difference between gallbladder and bile duct tumors (P = .68). The association was significant when the two registry analyses were excluded. Those receiving CT or CRT derived statistically greater benefit than RT alone (OR, 0.39, 0.61, and 0.98, respectively; P = .02). The greatest benefit for AT was in those with LN-positive disease (OR, 0.49; P = .004) and R1 disease (OR, 0.36; P = .002). CONCLUSION: This analysis supports AT for BTC. Prospective randomized trials are needed to provide better rationale for this commonly used strategy. On the basis of our data, such trials could involve two active comparators rather than a no-treatment arm among patients with LN-positive or R1 disease.","author":[{"dropping-particle":"","family":"Horgan","given":"Anne M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amir","given":"Eitan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walter","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Knox","given":"Jennifer J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"16","issued":{"date-parts":[["2012"]]},"page":"1934-1940","title":"Adjuvant therapy in the treatment of biliary tract cancer: A systematic review and meta-analysis","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(11)","plainTextFormattedCitation":"(11)","previouslyFormattedCitation":"(11)"},"properties":{"noteIndex":0},"schema":""}(11) evaluated data from 6712 patients in twenty studies published between 1960 and 2010. The authors found a non-significant improvement in overall survival with adjuvant therapy, including chemotherapy, radiotherapy or chemo-radiotherapy, compared with surgery alone (odds ratio [OR]: 0.74, 95% CI 0.55-1.01; p=0.06). However, after exclusion of two registry analyses, a significant benefit for adjuvant treatment over observation alone was demonstrated, especially for chemotherapy (OR 0.39, 95% CI 0.23-0.66; p<0.001) or chemoradiotherapy (OR 0.61, 95% CI 0.38-0.99; p=0.049) compared to radiotherapy alone. The greatest benefit was observed in patients with lymph node positive disease or R1 resection. However, the meta-analysis presented major limitations, including selection bias and heterogeneity of treatments performed, that precluded definitive conclusions.More recently, results of three phase III randomized clinical trials on adjuvant therapy have been presented. The French study (PRODIGE 12 - ACCORD 18) has been published in 2019 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Edeline J, Benabdelghani M","given":"Bertaut A et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Clin Oncol. 2019 Feb 1:JCO1800050","id":"ITEM-1","issued":{"date-parts":[["2019"]]},"title":"Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.","type":"article-journal","volume":"Feb 1:JCO1"},"uris":[""]}],"mendeley":{"formattedCitation":"(12)","plainTextFormattedCitation":"(12)","previouslyFormattedCitation":"(12)"},"properties":{"noteIndex":0},"schema":""}(12). This trial compared adjuvant treatment with gemcitabine and oxaliplatin for 12 cycles after surgery to observation alone in 193 patients with biliary tract cancer (following R0 or R1 resection). About one third of patients included presented N-positive disease while R1 resection was observed in 13% of patients. Unfortunately, after a median follow up of 46.5 months, no significant difference in terms of relapse free survival (RFS) was demonstrated between patients treated with chemotherapy and patients in the observation arm (median RFS 30.4 vs 18.5 months respectively; HR= 0.88, 95% CI 0.62.1.25; p=0.48) neither in the overall survival (median, 75.8 months in arm A?v?50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank?P?= 0.74).The BILCAP study was a phase III randomized clinical trial, presented at ASCO Annual Meeting 2017, compared surgery alone versus surgery followed by adjuvant chemotherapy with capecitabine (1250 mg/m2 bid days 1-14 every 21 days for 8 cycles) in patients with cholangiocarcinoma or gallbladder cancer ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2017.35.15_suppl.4006","ISSN":"0732-183X","abstract":"Background: Despite improvements in multidisciplinary management, BTC has a poor outcome. Approximately 20% of cases are suitable for surgical resection with a 5 year survival of < 10%. BILCAP aimed to determine whether capecitabine (Cape) improves overall survival (OS) compared to observation (Obs) following radical surgery. Methods: Patients with completely-resected cholangiocarcinoma (CCA) or gallbladder cancer (including liver and pancreatic resection, as appropriate), with adequate biliary drainage, no ongoing infection, adequate renal, haematological and liver function, and ECOG PS ≤2, were randomized 1:1 to Cape (1250 mg/m D1-14 every 21 days, for 8 cycles) or Obs. Randomization was minimized on tumor site, resection status, ECOG PS and surgical center. The primary outcome was OS in the intention to treat (ITT) population. 410 patients were needed to detect a hazard ratio (HR) of 0.69 (2- sided α = 0.05 and 80% power). HR was estimated by Cox survival model with adjustment for the minimization factors. Primary analysis performed with at least 24 months (m) follow-up. Results: 447 participants were randomized to Cape (n = 223) or Obs (n = 224) from 44 UK sites between 2006-2014. Median age was 63y (IQR 55, 69) and 201 (45%), 232 (52%), and 14 (3%) patients were ECOG PS 0, 1 and 2 respectively. Primary site: 84 (19%) intrahepatic, 128 (28%) hilar, 156 (35%) extrahepatic CCA and 79 (18%) muscle-invasive gallbladder cancers. Resection margins: R0 in 279 (62%) and R1 in 168 (38%); 207 (46%) were node-negative. Follow up was at least 36m in > 80% of surviving patients. By ITT analysis (n = 447), median OS was 51m (95%CI 35, 59) for Cape and 36m (95%CI 30, 45) for Obs, HR 0.80 (95%CI 0.63, 1.04; p = 0.097). Sensitivity analyses with adjustment for nodal status, grade of disease and gender indicated HR 0.71 (95%CI 0.55, 0.92 p < 0.01). In the per-protocol analysis (Cape n = 210, Obs n = 220) median OS was 53m (95%CI 40, NR) for Cape and 36m (95%CI 30, 44) for Obs, HR 0.75 (95%CI 0.58, 0.97; p = 0.028). Median RFS (ITT) was 25m (95%CI 19, 37) for Cape and 18m (95%CI 13, 28) for Obs. Grade 3-4 toxicity was less than anticipated. Conclusions: Cape improves OS in BTC when used as adjuvant and should become standard of care.","author":[{"dropping-particle":"","family":"Primrose JN, Fox R, Palmer DH, Prasad R, Mirza D, Anthoney DA","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"(15_suppl)","issued":{"date-parts":[["2017"]]},"page":"4006","title":"Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study.","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"(13)","plainTextFormattedCitation":"(13)","previouslyFormattedCitation":"(13)"},"properties":{"noteIndex":0},"schema":""}(13). The primary endpoint was overall survival. The study included 447 patients; 84 (19%) had intrahepatic CCA, 128 (28%) perihilar CCA, 156 (35%) extrahepatic CCA and 79 (18%) muscle-invasive gallbladder cancers. R1 resection was reported in 38% of patients while 54% had node-positive disease. By intention-to-treat (ITT) analysis, despite a notably prolonged OS from 36 to 52 months, the study did not meet its primary endpoint. Based on this statistical point, some authors do not accept this regimen as a new standard of care. However, in the prespecified sensitivity analyses adjusted by prognostic factors (nodal status, grade of disease and gender) the study showed a statistically significant benefit for treatment in OS (HR= 0.71, 95%CI 0.55-0.92, p<0.01). Based on these data, and after discussing with patients, some other authors have incorporated this regimen for their clinical practice.The third study (BCAT) evaluated adjuvant gemcitabine (vs. observation) in 225 Japanese patients with resected extrahepatic (perihilar and distal) CCA. There was no improvement in OS (median OS 62.3 vs. 63.8 months; HR=1.01, 95% CI 0.70 – 1.45; p=0.964) or RFS (median 36.0 vs. 39.9 months; HR=0.93, 95% CI 0.66 – 1.32; p=0?693); including no differences in the lymph node- and margin-positive subgroups ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/bjs.10776","ISSN":"13652168","abstract":"? 2018 BJS Society Ltd Published by John Wiley & Sons Ltd Background: Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. Methods: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m 2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. Results: Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse-free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare. Conclusion: The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 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Journal of Surgery","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"192-202","title":"Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer","type":"article-journal","volume":"105"},"uris":[""]}],"mendeley":{"formattedCitation":"(14)","plainTextFormattedCitation":"(14)","previouslyFormattedCitation":"(14)"},"properties":{"noteIndex":0},"schema":""}(14). The role of radiation in the adjuvant setting is also an area of active research. The SWOG0809 phase II study demonstrated that gemcitabine (1000 mg/m2 on days 1 and 8) and capecitabine (1500 mg/m2/day on days 1-14) every 21 days followed by concurrent capecitabine (1330 mg/m2/day) and radiotherapy (45 Gy to regional lymphatics and 54-59.4 Gy to tumor bed) was well-tolerated in patients with high-risk (defined as stage pT2-4 or N+ or positive resection margins) extrahepatic CCA or gallbladder cancer. The observed 2-year survival (65%) exceeded the pre-set threshold of efficacy (>45%). Studies are currently under development to evaluate the additional impact of radiotherapy over chemotherapy, particularly in patients at high risk of recurrence ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2014.60.2219","ISBN":"1527-7755 (Electronic)\\r0732-183X (Linking)","ISSN":"15277755","PMID":"25964250","abstract":"PURPOSE: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.\\n\\nPATIENTS AND METHODS: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.\\n\\nRESULTS: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.\\n\\nCONCLUSION: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.","author":[{"dropping-particle":"al","family":"Ben-Josef E, Guthrie K","given":"El-Khoueiry A et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"24","issued":{"date-parts":[["2015"]]},"page":"2617-2622","title":"SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"(15)","plainTextFormattedCitation":"(15)","previouslyFormattedCitation":"(15)"},"properties":{"noteIndex":0},"schema":""}(15). Historically, the perceived wisdom was that biliary tract cancer was too rare for the development of adequately-powered prospective randomized controlled trials (RCTs), particularly in the West. The three RCTs recently reported have, by necessity, combined anatomical subgroups (intrahepatic, perihilar and distal CCA) +/- gallbladder cancer to be feasible. Over the time that these studies have been performed, understanding has emerged that there are also molecular subgroups, for example intrahepatic CCAs harboring mutations in FGFR, which have a discrete natural behavior. This in turn may also be prognostic. Further analysis of tissue (where available) from these studies and new clinical trials are needed to determine the magnitude of benefit within discrete anatomical and molecular subgroups. However, as these are rare subgroups of a rare cancer, there may still be a need for future studies to include heterogeneous populations although subgroups carrying a known beneficial or detrimental prognosis, which would need to be stratified for. Advanced (unresectable and metastatic) disease treatmentFirst-line chemotherapyNearly two-thirds of patients with cholangiocarcinoma (CCA) present with advanced disease at diagnosis and 68-86% of resected cases eventually relapse either loco-regionally or at distance ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/cncr.11699","ISBN":"0008-543X (Print)\\r0008-543X (Linking)","ISSN":"0008543X","PMID":"14534886","abstract":"BACKGROUND: Current approaches to adjuvant treatment after resection of gallbladder carcinoma (GBCA) and hilar cholangiocarcinoma (HCCA) are based on an incomplete understanding of the recurrence patterns of these diseases. Through an in-depth analysis of the sites of initial recurrence after resection of GBCA and HCCA, the current study aimed to highlight differences in the biology of these tumors and to provide further insight for adjuvant therapeutic strategies.\\n\\nMETHODS: Patients with either GBCA or HCCA who underwent a potentially curative resection were identified prospectively from a maintained database. Specific sites of initial disease recurrence were identified retrospectively and categorized as locoregional (resection margin, porta hepatis, or retroperitoneal lymph nodes) or distant (peritoneal, extraabdominal, or discontiguous liver metastases). Differences in disease recurrence patterns, time to disease recurrence, and overall and site-specific survival were analyzed.\\n\\nRESULTS: Between May 1990 and August 2001, 177 patients underwent potentially curative resection, 97 for GBCA and 80 for HCCA. Disease recurrence and follow-up data were available for 156 patients (80 with GBCA and 76 with HCCA). The median time to disease recurrence was shorter for patients with GBCA compared with patients with HCCA (11.5 vs. 20.3 months; P = 0.007). Overall, 52 (68%) patients with HCCA and 53 (66%) patients with GBCA had disease recurrene at a median follow-up of 24 months. Of those who developed disease recurrence, isolated locoregional disease as the first site of failure occurred in 15% of patients with GBCA compared with 59% of patients with HCCA (P < 0.001). By contrast, an initial GBCA recurrence involving a distant site, with or without concomitant locoregional recurrence, occurred in 85% of patients compared with 41% of patients with HCCA (P < 0.001). This pattern of disease recurrence was diagnosis specific and did not change significantly when patients were stratified by several clinicopathologic factors, including disease stage and its component variables. Using multivariate analysis, diagnosis was an independent predictor of the site of disease recurrence. Among patients who experienced disease recurrence, survival was greater among the patients with HCCA compared with patients with GBCA (29 months vs. 20.6 months, respectively; P = 0.037). For both tumors, the site of initial disease recurrence had no apparent impact on survival time.\\n\\nCO…","author":[{"dropping-particle":"","family":"Jarnagin","given":"William R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruo","given":"Leyo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Little","given":"Sarah A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klimstra","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Angelica","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"DeMatteo","given":"Ronald P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wagman","given":"Raquel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blumgart","given":"Leslie H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fong","given":"Yuman","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2003"]]},"page":"1689-1700","title":"Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: Implications for adjuvant therapeutic strategies","type":"article-journal","volume":"98"},"uris":[""]}],"mendeley":{"formattedCitation":"(16)","plainTextFormattedCitation":"(16)","previouslyFormattedCitation":"(16)"},"properties":{"noteIndex":0},"schema":""}(16) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000339695","ISSN":"00302414","PMID":"22777276","abstract":"This study aimed to provide further insights into the indications for adjuvant therapeutic strategies via analysis of the sites of initial recurrence after resection of gallbladder cancer (GBC) and intrahepatic (IHC) and extrahepatic cholangiocarcinoma (EHC).","author":[{"dropping-particle":"","family":"Jung","given":"Se Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Woo","given":"Sang Myung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Hyung Ki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Woo Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Han","given":"Mi Ah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Han","given":"Sung Sik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Seong Hoon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Sang Jae","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Tae Hyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koh","given":"Young Hwan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hong","given":"Eun Kyung","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Oncology (Switzerland)","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"83-90","title":"Patterns of initial disease recurrence after resection of biliary tract cancer","type":"article-journal","volume":"83"},"uris":[""]}],"mendeley":{"formattedCitation":"(17)","plainTextFormattedCitation":"(17)","previouslyFormattedCitation":"(17)"},"properties":{"noteIndex":0},"schema":""}(17). Chemotherapy is still the cornerstone of standard treatment for unresectable, metastatic or recurrent disease with several classes of active cytotoxic agents, including gemcitabine, platinum compounds and fluoropyrimidines ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdq420","ISBN":"1569-8041 (Electronic); 0923-7534 (Linking)","ISSN":"09237534","PMID":"20943640","abstract":"The prognosis for advanced/inoperable biliary tract cancer is poor and the management of biliary obstruction and sepsis remains the cornerstone of best supportive care (BSC). Many phase II studies have reported some activity of chemotherapy, usually involving one or more of a fluoropyrimidine, a platinum agent and gemcitabine. No adequately powered study has shown conclusively a benefit for chemotherapy compared with BSC alone although three small randomized studies have suggested an improved survival. Results from the randomized phase III ABC-02 study demonstrated a survival advantage of cisplatin and gemcitabine doublet-chemotherapy over gemcitabine monotherapy {median survival of 11.7 compared with 8.1 months, hazard ratio (HR), 0.64 [95% confidence interval (CI) 0.52 to 0.80]; log rank P < 0.001} as well as a significantly longer progression-free survival [median 8 compared with 5 months; HR 0.63 (95% CI 0.51 to 0.77); log rank P < 0.001]. A similar magnitude of benefit was seen in Japanese patients in a second study using the same treatment regimens (the BT-22 study). Ongoing studies are underway evaluating other chemotherapy regimens in first-line although attention is turning to the addition of targeted therapies; these will be reviewed. Pivotal to success in this process is both the identification of appropriate targets across this heterogeneous group of malignancies (e.g. EGFR, VEGF, MEK inhibition, amongst others) and collaboration between investigators to deliver relevant, timely and adequately powered studies. ? The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.","author":[{"dropping-particle":"","family":"Valle","given":"J. W.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"page":"21(SUPPL. 7)","title":"Advances in the treatment of metastatic or unresectable biliary tract cancer","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(18)","plainTextFormattedCitation":"(18)","previouslyFormattedCitation":"(18)"},"properties":{"noteIndex":0},"schema":""}(18). Despite the well-known clinical and biological heterogeneity across tumors arising from different locations of the biliary tree (intrahepatic, perihilar, distal), CCAs have been historically grouped together in clinical trials as biliary cancers, with the inclusion also of gallbladder and ampullary carcinoma. This makes the interpretation and generalizability of results challenging.In the late ’90, a study first demonstrated an improvement in overall survival (OS) and quality of life for bilio-pancreatic patients treated with chemotherapy compared with best supportive care (BSC) (median OS 6 versus 2.5 months; p<0.01) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/oxfordjournals.annonc.a010676","ISBN":"0923-7534","ISSN":"09237534","PMID":"8879373","abstract":"BACKGROUND: In certain patients with pancreatic and biliary cancer, chemotherapy may relieve tumour-related symptoms, improve quality of life and possibly prolong survival. The extent of these improvements is not completely known in spite of the extensive use of this treatment modality. The aim of this study was to estimate any gain in the quantity and quality of life produced by chemotherapy in patients with pancreatic and biliary cancer. PATIENTS AND METHODS: Between January 1991 and February 1995, 90 eligible patients with pancreatic or biliary cancer were randomized to either chemotherapy in addition to best supportive care or to best supportive care. Chemotherapy was allowed in the latter group if the supportive measures did not lead to palliation. Chemotherapy was either sequential 5-fluorouracil/leucovorin combined with etoposide (FELv) or, in elderly and poor performance patients, the same regimen without etoposide (FLv). Quality of life was evaluated with the EORTC-QLQ-C30 instrument. RESULTS: Mean scale scores in the QLQ-C30 improved more often/deteriorated less frequently in the chemotherapy group than in the best supportive care group. More patients in the chemotherapy group (36%, 17/49) had an improved or prolonged high quality of life for a minimum period of 4 months compared to those in the best supportive care group (10%, 4/41, P < 0.01). Overall survival was significantly longer in the chemotherapy group (median 6 vs. 2.5 months, P < 0.01). Also, the quality-adjusted survival time was longer for patients randomized to chemotherapy (median 4 vs. 1 months, P < 0.01). The effects were seen both in pancreatic and biliary cancer. CONCLUSIONS: The results show that chemotherapy can add to both quantity and quality of life in advanced pancreatic and biliary cancer. The number of patients who benefit from treatment is, however, still limited; for this reason careful selection before, and close monitoring during, treatment are necessary.","author":[{"dropping-particle":"","family":"Glimelius","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoffman","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sj?dén","given":"P. O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobsson","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sellstr?m","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Enander","given":"L. K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Linné","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svensson","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["1996"]]},"page":"593-600","title":"Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"(3)","plainTextFormattedCitation":"(3)","previouslyFormattedCitation":"(3)"},"properties":{"noteIndex":0},"schema":""}(3). Subsequently, various chemotherapeutic agents have been tested either alone or in combination in numerous studies that were mainly small-sized, uncontrolled and nonrandomized phase II trials (see Table 1 and 2). In 2007, a pooled analysis of 104 clinical trials, including 2810 treated patients, showed better response rate (RR, 28% vs. 15.3%, p=0.000), disease control rate (DCR, 61% vs. 50.4%, p=0.000), time to progression (4.4 vs. 3.4 months, P=0.015) and a trend for improved OS (median 9.3 vs. 7.5 months, p=0.061) for doublet chemotherapy compared with monotherapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000365781","ISBN":"0007-0920 (Print)\\r0007-0920","ISSN":"14219794","PMID":"17325704","abstract":"Owing to the lack of randomised controlled trials no standard of chemotherapy exists in the treatment of advanced biliary tract carcinoma. 5-fluorouracil or gemcitabine is recommended based on small and predominately phase II trials. The aim of this analysis was to analyse existing trials, even small and nonrandomised, and identify superior regimens. Chemotherapy trials published in English from 1985 to July 2006 were analysed as well as ASCO abstracts from 1999 to 2006. Response rate (RR=CR+PR), tumour control rate (TCR=CR+PR+SD), time to tumour progression (TTP), overall survival (OS), and toxicity were analysed. One hundred and four trials comprising 112 trial arms and 2810 patients, thereof 634 responders and 1368 patients with tumour control were analysed. Pooled RR and TCR were 22.6 and 57.3%, respectively. Significant correlations of RR and TCR with survival times were found. Subgroup analysis showed superior RRs for gallbladder carcinoma (GBC) compared with cholangiocarcinoma, but shorter OS for GBC. Furthermore, superior RRs and TCRs of gemcitabine and platinum containing regimens were found with highest RRs and TCRs in the combination subgroup. Based on published results of predominately phase II trials, gemcitabine combined with platinum compounds represents the provisional standard of chemotherapy in advanced biliary tract cancer, unless a new evidence-based standard has been defined.","author":[{"dropping-particle":"","family":"Eckel","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmid","given":"Roland M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Chemotherapy","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014"]]},"page":"13-23","title":"Chemotherapy and targeted therapy in advanced biliary tract carcinoma: A pooled analysis of clinical trials","type":"article-journal","volume":"60"},"uris":[""]}],"mendeley":{"formattedCitation":"(19)","plainTextFormattedCitation":"(19)","previouslyFormattedCitation":"(19)"},"properties":{"noteIndex":0},"schema":""}(19). Interestingly, the same study suggested gemcitabine combined with cisplatin or oxaliplatin as the most active regimen based on increased RR and DCR as compared with other combinations. In 2010, the landmark UK ABC-02 trial established the doublet cisplatin and gemcitabine as first-line standard of care for advanced CCA ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1586/egh.10.45","ISSN":"1747-4132","PMID":"20678012","abstract":"Evaluation of: Valle J, Wasan H, Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362, 1273-1281 (2010). Biliary tract cancer is a rare disease and it is associated with a poor clinical outcome and survival. A standard therapy has not been established yet. The evaluated article reports on the first Phase III randomized controlled multicenter trial (ABC-02 trial) on palliative chemotherapy for biliary tract cancer. A total of 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer or ampullary cancer were included to receive either cisplatin followed by gemcitabine or gemcitabine alone for up to 24 weeks. The primary end point was overall survival and the secondary end point was progression-free survival. The median overall survival was 11.7 months in the cisplatin plus gemcitabine group and 8.1 months in the gemcitabine only group. The median progression-free survival was 8.0 months in the cisplatin plus gemcitabine group and 5.0 months in the gemcitabine-only group (p < 0.001). Adverse events were comparable in the two groups. Cisplatin plus gemcitabine, compared with gemcitabine alone, was associated with a significant survival advantage without an increase in substantial toxicity.","author":[{"dropping-particle":"al","family":"Valle J, Wasan H","given":"Palmer DH et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"page":"1273-1281","title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","type":"article-journal","volume":"362"},"uris":[""]}],"mendeley":{"formattedCitation":"(5)","plainTextFormattedCitation":"(5)","previouslyFormattedCitation":"(5)"},"properties":{"noteIndex":0},"schema":""}(5). In this randomized phase III study, 410 patients, among which were 241 CCAs, were randomly allocated to receive gemcitabine alone or gemcitabine combined with cisplatin. The doublet conferred a statistically significant OS advantage over single-agent gemcitabine (11.7 vs. 8.1 months; HR, 0.64; 95% CI, 0.52–0.80; p<0.001). In addition, cisplatin plus gemcitabine was well tolerated and adverse events were similar between treatment arms. A nonsignificant increase in neutropenia was noted in the cisplatin plus gemcitabine arm, though this did not translate into a higher infection rate. Of note, grade 3-4 liver function test derangements were more frequently observed in the gemcitabine-only group (27.1% vs. 16.7%, p=0.01), probably reflecting an inferior disease control. Interestingly, the magnitude of benefit of combination chemotherapy was consistent across the anatomical subgroups. Similar results were mirrored for the Asian population in the Japanese randomized phase II BT22 study (median OS 11.2 vs 7.7 months, HR, 0.69) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/sj.bjc.6605779","ISBN":"0007-0920","ISSN":"00070920","PMID":"20628385","abstract":"BACKGROUND: A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients.\\n\\nMETHODS: Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m(-2) plus gemcitabine 1000 mg m(-2) on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m(-2) on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks.\\n\\nRESULTS: A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and gamma-GTP increase (29.3%/35.7%).\\n\\nCONCLUSIONS: Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.","author":[{"dropping-particle":"","family":"Okusaka","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakachi","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fukutomi","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mizuno","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohkawa","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Funakoshi","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagino","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kondo","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagaoka","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Funai","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koshiji","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nambu","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furuse","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyazaki","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nimura","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2010"]]},"page":"469-474","title":"Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: A comparative multicentre study in Japan","type":"article-journal","volume":"103"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"(6)"},"properties":{"noteIndex":0},"schema":""}(6). Of note, retrospective feasibility and safety data are available that support the combination of cisplatin and gemcitabine also in fit patients with persistent jaundice related to biliary tract obstruction from luminal disease (but not in those with jaundice secondary to extensive metastatic replacement of the liver) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejca.2015.05.018","ISSN":"18790852","PMID":"26066735","abstract":"Abstract Introduction The advanced biliary tract cancer (ABC)-02 study established cisplatin and gemcitabine (CisGem) as a reference 1st-line regimen for patients with advanced/metastatic biliary tract cancer; patients with bilirubin ≥1.5 × upper limit of normal (ULN) were excluded and there are few extant data for systemic treatment in the context of elevated bilirubin. Methods Patients with ABC, receiving CisGem with a baseline bilirubin of ≥1.5×ULN were eligible for this retrospective analysis; response, toxicity and survival data were collected. Results Thirty-three patients of 545 screened; median age 59 years, range 23-79; 58% male, 58% with metastases (79% in the liver) of performance status (PS) 0 (33%), 1 (64%) or 2 (3%) were eligible. The median baseline bilirubin was 55 μmol/L (range 32-286); due to biliary tract obstruction (BTO, 76%) or liver metastases (LM, 24%). Toxicity was comparable to the ABC-02 study; bilirubin normalised in 64% during chemotherapy/follow-up. The median progression-free survival (PFS) was 6.9 months (95% confidence interval (CI): 4.4-9.0) and median overall survival (OS) 9.5 months (95% CI: 5.7-12.8). Patients with BTO had a longer PFS and OS than those with LM (7.0 versus 2.6 months; p = 0.1633 and 9.8 versus 4.4 months, hazard ratio (HR) 0.74; p = 0.465, respectively); not statistically significant (due to small sample size). Normalisation of bilirubin and completion of eight CisGem cycles were associated with longer OS (11.4 versus 2.9 months, HR 0.49; p = 0.08 and 15.2 versus 5.4 months, HR 0.12 p < 0.001, respectively). No difference in OS was shown between the bilirubin percentiles (for either PFS or OS). Conclusion For PS 0-1 patients with ABC and high bilirubin due to luminal disease despite optimal stenting CisGem can be used safely with results similar to those in patients with normal bilirubin.","author":[{"dropping-particle":"","family":"Lamarca","given":"Angela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benafif","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ross","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bridgewater","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valle","given":"Juan W.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Cancer","id":"ITEM-1","issue":"13","issued":{"date-parts":[["2015"]]},"page":"1694-1703","title":"Cisplatin and gemcitabine in patients with advanced biliary tract cancer (ABC) and persistent jaundice despite optimal stenting: Effective intervention in patients with luminal disease","type":"article-journal","volume":"51"},"uris":[""]}],"mendeley":{"formattedCitation":"(20)","plainTextFormattedCitation":"(20)","previouslyFormattedCitation":"(20)"},"properties":{"noteIndex":0},"schema":""}(20).Several attempts have been made over time to improve the efficacy of chemotherapy by using new cytotoxics or adding of a third drug to the reference doublet. Regimens containing taxanes (docetaxel and paclitaxel) and irinotecan displayed significantly lower RR and DCR and were therefore dismissed ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Eckel F","given":"Schmid RM","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Br J Cancer","id":"ITEM-1","issued":{"date-parts":[["2007"]]},"page":"896–902","title":"Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials","type":"article-journal","volume":"96"},"uris":[""]}],"mendeley":{"formattedCitation":"(21)","plainTextFormattedCitation":"(21)","previouslyFormattedCitation":"(21)"},"properties":{"noteIndex":0},"schema":""}(21). The GEMOX regimen, with the substitution of cisplatin by oxaliplatin, can represent a valuable alternative as first-line option in patient unfit or unwilling to cisplatin based on promising results from a non-randomized phase II study ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/sj.bjc.6604628","ISBN":"0007-0920 (Print)\\n0007-0920 (Linking)","ISSN":"15321827","PMID":"19238628","abstract":"Advanced biliary tract carcinomas (BTCs) are often diagnosed at an advanced/metastatic stage and have a poor prognosis. The combination of gemcitabine and oxaliplatin (GEMOX) has shown promising activity in this setting. This international phase II study evaluated the efficacy and safety of GEMOX as first-line therapy in patients with advanced BTCs. Eligible patients with previously untreated locally advanced or metastatic BTC received gemcitabine 1000 mg m(-2) (day 1) and oxaliplatin 100 mg m-2 (day 2), every 2 weeks. Seventy patients were enroled; 72.9% had metastatic disease. Sixty-seven patients were treated. There were 10 confirmed partial responses (14.9%; 95% confidence interval (CI), 7.4-25.7%) in the treated population (RECIST). Twenty-four patients (35.8%) had stable disease. The objective response rate was 20.5% in patients with non-gallbladder cancers (9/44 patients) and 4.3% in patients with gallbladder cancers (1/23). Median overall survival for the intent-to-treat population was 8.8 months (95% CI, 6.9-11.1%) and progression-free survival was 3.4 months (95% CI, 2.5-4.6%). Grade 3/4 toxicities included thrombocytopenia (14.9% of patients), alanine aminotransferase elevation (13.4%), anaemia (10.4%), neutropenia (11.9%) and pain (1 1.9%). In this study, GEMOX demonstrated activity in non-gallbladder carcinoma, but poor activity in gallbladder carcinoma. GEMOX is well tolerated in advanced BTCs.","author":[{"dropping-particle":"","family":"André T, Reyes-Vidal J","given":"Fartoux L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2008"]]},"page":"862-867","title":"Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: A phase II study","type":"article-journal","volume":"99"},"uris":[""]}],"mendeley":{"formattedCitation":"(22)","plainTextFormattedCitation":"(22)","previouslyFormattedCitation":"(22)"},"properties":{"noteIndex":0},"schema":""}(22). The limited survival gain provided by first-line chemotherapy and its palliative intent highlights the need for factors aiding in treatment selection. Several parameters have been suggested to have prognostic value in advanced CCA treated with first-line chemotherapy. Clinical factors such as Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), gender, disease status, liver metastasis, and number of metastatic sites together with biochemical parameters (i.e. hemoglobin, bilirubin, white blood count, neutrophils, alkaline phosphatase, neutrophil/lymphocyte ratio and derived neutrophil/lymphocyte ratio) have been identified as independent risk factors for OS ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdv483","ISBN":"4420767960","ISSN":"15698041","PMID":"26483051","abstract":"BACKGROUND: Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease. METHODS: Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset. RESULTS: A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]. CONCLUSION: These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.","author":[{"dropping-particle":"al","family":"Bridgewater J, Lopes A","given":"Wasan H et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"134-140","title":"Prognostic factors for progression-free and overall survival in advanced biliary tract cancer","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(23)","plainTextFormattedCitation":"(23)","previouslyFormattedCitation":"(23)"},"properties":{"noteIndex":0},"schema":""}(23) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejca.2014.02.015","ISSN":"18790852","PMID":"24630393","abstract":"Background Biliary tract cancers (BTCs) include intrahepatic (IHC), hilar, distal bile duct (DBD) and gallbladder carcinoma (GBC). Neutrophil/lymphocyte ratio (NLR), a marker of host inflammation, is prognostic in several cancers but has not been reviewed in large BTC series, or advanced BTC (ABTC) at diagnosis. Patients and methods Baseline demographics and NLR at diagnosis were retrospectively evaluated in 864 consecutive patients with BTC treated from January 1987 to December 2012. The association between NLR and overall survival (OS) was determined using a multivariable Cox proportional hazards model. Results Eight hundred and sixty-four patients were included in the analysis, of which 62% had ABTC and 38% had surgery with curative intent. Median age was 65 years, 444 (51%) were male and 727 (84%) had performance status (PS) ≤2. A NLR ≥3.0, PS >2, IHC primary, stage, lack of surgery, haemoglobin <110 g/L and albumin <40 g/L were associated with significantly worse OS on multivariable analysis. A NLR ≥3.0 was an independent prognostic factor for OS for the entire cohort; median OS was 21.6 months versus 12.0 months for patients with NLR <3.0 versus NLR ≥3.0 respectively (adjusted hazard ratio (HR)-1.26, 95% confidence interval (CI); 1.06-1.50, P = 0.01). NLR was also prognostic in patients with ABTC (HR-1.26, 95% CI; 1.02-1.56, P = 0.035) and hilar cancer: overall group (N = 149) (HR-1.70, 95% CI; 1.10-2.50, P = 0.01) and advanced group (N = 111) (HR-1.57, 95% CI; 1.04-2.44, P = 0.048). Conclusion Baseline NLR is a readily available and inexpensive prognostic biomarker in patients with BTC and likely warrants validation in large prospective clinical trials. ? 2014 Elsevier Ltd. All rights reserved.","author":[{"dropping-particle":"","family":"McNamara","given":"M. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Templeton","given":"A. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maganti","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walter","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horgan","given":"A. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McKeever","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Min","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amir","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Knox","given":"J. J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Cancer","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2014"]]},"page":"1581-1589","title":"Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer","type":"article-journal","volume":"50"},"uris":[""]}],"mendeley":{"formattedCitation":"(24)","plainTextFormattedCitation":"(24)","previouslyFormattedCitation":"(24)"},"properties":{"noteIndex":0},"schema":""}(24) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"2219-679X","abstract":"Background: Data regarding prognostic factors in advanced biliary tract cancer (BTC) remains scarce. The aim of this study was to review our institutional experience with cisplatin and gemcitabine in advanced BTC as well as to evaluate potential prognostic factors for overall survival (OS). Material and methods: Consecutive patients with advanced BTC who initiated palliative chemotherapy with cisplatin and gemcitabine from 2009 to 2012 at the BC Cancer Agency were identified using the pharmacy database. Clinicopathologic variables and treatment outcome were retrospectively collected. Potential prognostic factors were assessed by univariate and multivariate analyses. Results: A total of 106 patients were included in the analysis. Median OS was 8.5 months (95% CI: 6.5-10.5). On univariate analysis, poor ECOG performance status (ECOG PS) at diagnosis, primary tumor location (extra-hepatic cholangiocarcinoma, and unknown biliary cancer), and sites of advanced disease (extra-hepatic metastasis) were significantly associated with worse OS (P<0.001, 0.036 and 0.034, respectively). Age, gender, CA19-9, CEA, hemoglobin, neutrophil count, and prior stent were not significantly associated with OS. On multivariate analysis, ECOG PS 2/3 was the only predictor of poor OS (P<0.001), while primary location (P=0.089) and sites of advanced disease (P=0.079) had a non-significant trend towards prognostic significance. Conclusions: In this population based analysis, a poorer performance status was significantly prognostic of worse OS. Although not significant in our analysis, primary tumor location and sites of advanced disease may also have prognostic relevance.","author":[{"dropping-particle":"","family":"R.D.","given":"Peixoto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D.","given":"Renouf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"H.","given":"Lim","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Gastrointestinal Oncology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2014"]]},"page":"428-432","title":"A population based analysis of prognostic factors in advanced biliary tract cancer","type":"article-journal","volume":"5"},"uris":[""]}],"mendeley":{"formattedCitation":"(25)","plainTextFormattedCitation":"(25)","previouslyFormattedCitation":"(25)"},"properties":{"noteIndex":0},"schema":""}(25) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdv253","ISBN":"4420767960","ISSN":"15698041","PMID":"26037798","abstract":"BACKGROUND The superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone in patients with advanced biliary tract cancer (ABC) has been demonstrated in two randomised trials; ABC02 and the Biliary Tract (BT) 22 study. We used a combined dataset from these two trials to investigate the derived neutrophil-to-lymphocyte ratio (dNLR), which is thought to be a prognostic factor associated with clinical outcomes in several solid tumours, including ABC. METHODS White blood cell (WBC) and absolute neutrophil count (ANC) were available for 379 of 410 patients from ABC-02 and all 83 patients in BT-22. The dNLR was calculated as ANC/(WBC-ANC), as previously specified. We examined the association between dNLR and overall survival (OS) and progression-free survival (PFS), as well as comparing the treatment effect in two patient groups defined by their dNLR level. A high dNLR was defined as ≥3.0, which was approximately the upper tertile value. RESULTS A total of 462 individual patient records were analysed, 328 with baseline dNLR <3 and 134 with dNLR ≥3. There were 443 deaths in the cohort, and all surviving patients had a dNLR <3. There was strong evidence that dNLR was closely associated with both OS [hazard ratio (HR), 1.62; 95% confidence interval (CI) 1.32-2.01] and PFS (HR, 1.40; 95% CI 1.13-1.72). There was limited evidence (P = 0.10) of a differential effect of CisGem on OS between the two dNLR groups, but this was clearest in the ABC-02 dataset (P = 0.06). There was good evidence (P = 0.008) of an association between low baseline dNLR and long-term survival on a CisGem regimen. There was also good evidence of an association between ECOG performance status (split at 0 and 1 versus 2) on both OS (P < 0.001) and PFS (P = 0.01), but no evidence of a differential treatment effect, with both groups receiving benefit from the addition of cisplatin. CONCLUSIONS These data confirm that high dNLR is associated with worse OS and PFS, and suggests it may also be predictive of benefit for the addition of cisplatin to gemcitabine in European patients with ABC. Incorporating dNLR into the clinical context may better inform prognosis and chemotherapy decisions in ABC patients.","author":[{"dropping-particle":"","family":"Grenader","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nash","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Plotkin","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furuse","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mizuno","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okusaka","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wasan","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valle","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bridgewater","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2015"]]},"page":"1910-1916","title":"Derived neutrophil lymphocyte ratio may predict benefit from cisplatin in the advanced biliary cancer: The ABC-02 and BT-22 studies","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"(26)","plainTextFormattedCitation":"(26)","previouslyFormattedCitation":"(26)"},"properties":{"noteIndex":0},"schema":""}(26). Although these represent potentially useful tools to improve patients’ risk stratification both in daily practice and clinical trials, they have limited accuracy in predicting prognosis and no role as predictive factors thus highlighting the urgent need for novel molecular biomarkers.Beyond first-lineCurrently, no second-line treatment has shown superiority over BSC in a prospective randomized clinical trial, thus the role of chemotherapy for patients failing first-line is still unclear. Moreover, the rapid deterioration of patients’ PS on progression usually precludes further lines of treatment. Nonetheless, 20-40% of patients are offered second-line chemotherapy in daily practice based on a small number of prospective phase II studies and retrospective analyses suggesting a benefit for selected patient populations. A systematic literature review of these studies reported a mean OS of 7.2 months, mean PFS of 3.2 months, RR of 7.7 %, and DCR of 49.5%, for patients receiving second-line chemotherapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdu162","ISBN":"4201300420","ISSN":"15698041","PMID":"24769639","abstract":"The randomized NCRN phase III ABC-02 trial provided level-A evidence for first-line chemotherapy with cisplatin and gemcitabine combination in advanced biliary cancer (ABC). This systematic literature review aims to evaluate the level of evidence for the use of second-line chemotherapy for patients with ABC in terms of overall survival (OS), response, toxicity and quality of life. Eligible studies were identified using Medline, ASCO, ESMO and the World Gastrointestinal Congress databases. Searches were last updated on 15 December 2013. Eligible studies reported survival and/or response data for patients with ABC receiving second-line systemic chemotherapy. This systematic review was registered in the PROSPERO database (No. CRD42013004205). Five hundred and fifty-eight studies were identified from the searches in Medline (n = 342), ASCO (n = 160), ESMO (n = 27) and World Gastrointestinal Congress (n = 29). Twenty-five studies were eligible: 14 phase II clinical trials, 9 retrospective analyses and 2 case reports. In total, data from 761 patients were reported with median number of patients included in each study of 22 (range 9-96). The mean OS was 7.2 months [95% confidence interval (CI) 6.2-8.2] [phase II: 6.6 (95% CI 5.1-8.1); retrospective analysis: 7.7 (95% CI 6.5-8.9)]. The mean progression-free survival (PFS), response rate (RR) and disease control rate were 3.2 months (95% CI 2.7-3.7), 7.7% (95% CI 4.6-10.9) and 49.5% (95% CI 41.4-57.7), respectively. The best correlations were between OS and PFS for all studies (r = 0.54; P = 0.01) and between OS and PFS (r = 0.61; P = 0.04) and OS and RR (r = 0.62; P = 0.03) for phase II studies, respectively. Biliary tract cancer is known to be a chemo-responsive disease. There is insufficient evidence (level C) to recommend a second-line chemotherapy schedule in ABC, although the available data suggest that a cohort of patients may benefit. Further prospective and randomized studies are needed to clarify the relative value of second-line chemotherapy in this setting.","author":[{"dropping-particle":"","family":"Lamarca","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hubner","given":"R. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"David Ryder","given":"W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valle","given":"Juan W.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"page":"2328–2338","title":"Second-line chemotherapy in advanced biliary cancer: A systematic review","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(27)","plainTextFormattedCitation":"(27)","previouslyFormattedCitation":"(27)"},"properties":{"noteIndex":0},"schema":""}(27) . Patients with good ECOG PS (0-1), PFS to first-line >6 months, CA19.9 <152 U/ml and those who underwent previous surgery were more likely to benefit from salvage chemotherapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/bjc.2014.190","ISSN":"15321827","PMID":"24714745","abstract":"Background:The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model.Methods:Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models.Results:The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215-0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370-0.891), progression-free survival after first-line CT 6 months (P=0.027; HR, 0.633; 95% CI 0.422-0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392-0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001).Conclusions:Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.British Journal of Cancer advance online publication, 8 April 2014; doi:10.1038/bjc.2014.190 .","author":[{"dropping-particle":"","family":"Fornaro","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cereda","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aprile","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Girolamo","given":"S.","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santini","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silvestris","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lonardi","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leone","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milella","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vivaldi","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Belli","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergamo","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lutrino","given":"S. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Filippi","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Russano","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vaccaro","given":"V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brunetti","given":"A. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rotella","given":"V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Falcone","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barbera","given":"M. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Corbelli","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fasola","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aglietta","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zagonel","given":"V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reni","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vasile","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brandi","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2014"]]},"page":"2165-2169","title":"Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer","type":"article-journal","volume":"110"},"uris":[""]}],"mendeley":{"formattedCitation":"(28)","plainTextFormattedCitation":"(28)","previouslyFormattedCitation":"(28)"},"properties":{"noteIndex":0},"schema":""}(28). Regarding the most appropriate regimen in this setting, a fluoropyrimidine-based schedule is considered a reasonable choice after cisplatin plus gemcitabine first-line treatment. It is noteworthy mentioning that the poor level of evidence and the marked heterogeneity across studies are important drawbacks and well-designed prospective trials are needed. Recently, a randomized phase II study reported improved 9-month PFS for the XELIRI regimen (capecitabine and irinotecan) over single agent irinotecan (60.9% vs. 32.0%, P=0.045)) with an acceptable safety profile ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3892/mco.2017.1206","ISBN":"2049-9450 (Print) 2049-9450","ISSN":"2049-9450","PMID":"29556385","abstract":"The prognosis of patients with unresectable and recurrent biliary tract cancer (BTC) is very poor. Although gemcitabine (GEM) plus cisplatin therapy is useful for unresectable cases, the median overall survival (OS) of the patients is <1 year, and third-line chemotherapy following failure of 5-fluorouracil (5-FU) and GEM plus cisplatin is currently unavailable. The clinical efficacy and basic effects of low-dose paclitaxel (PTX) therapy for patients with BTC was previously reported. We herein present the results of a phase I clinical trial of weekly low-dose PTX as third-line palliative chemotherapy. PTX was administered on days 1, 8, 15 and 22 of each cycle and repeated twice as follows: Level 1, 40 mg/m(2); level 2, 50 mg/m(2) (n=3). During the two cycles, grade 1 or 2 adverse events were observed in 3 patients, whereas dose-limiting adverse events (grade 3 or 4) were not observed. The disease control rate was 83.3% (partial response, n=3; stable disease, n=2). The OS and median survival were 15.4 and 9.0 months, respectively. In conclusion, palliative chemotherapy with low-dose PTX following failure of GEM and 5-FU was well-tolerated, safe and effective for patients with unresectable or recurrent BTCs, and the optimal dose was 50 mg/m(2).","author":[{"dropping-particle":"","family":"Tajima","given":"Hidehiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohta","given":"Tetsuo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shinbashi","given":"Hiroyuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirose","given":"Atsushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okazaki","given":"Mitsuyoshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamaguchi","given":"Takahisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohbatake","given":"Yoshinao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamoto","given":"Koichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakanuma","given":"Shinichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sakai","given":"Seisho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kinoshita","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Makino","given":"Isamu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakamura","given":"Keishi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayashi","given":"Hironori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oyama","given":"Katsunobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inokuchi","given":"Masafumi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyashita","given":"Tomoharu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takamura","given":"Hiroyuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ninomiya","given":"Itasu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fushida","given":"Sachio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakamura","given":"Hiroyuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Molecular and Clinical Oncology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2017"]]},"page":"753-757","title":"Phase I study of weekly palliative chemotherapy with low-dose third-line paclitaxel for biliary tract cancer","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"(29)","plainTextFormattedCitation":"(29)","previouslyFormattedCitation":"(29)"},"properties":{"noteIndex":0},"schema":""}(29).The ABC-06 ( Identifier: NCT01926236) is an ongoing randomized phase III trial aimed at ascertaining the value of second-line chemotherapy in BTC, including CCA. In this study, the combination of 5-FU, folinic acid and oxaliplatin (mFOLFOX) is compared to active symptom control after failure of first-line cisplatin and gemcitabine treatment. The study met its recruitment target of 162 patients at the beginning of 2018 and its results are highly anticipated. Beyond second-line, data so far available are even more scarce regarding safety and efficacy of chemotherapy. Although some reports from small studies suggest activity of agents such irinotecan and nab-paclitaxel in heavily pretreated patients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"33/6/2619 [pii]","ISBN":"0250-7005","ISSN":"02507005","PMID":"23749917","abstract":"AIM: To evaluate the treatment outcomes of irinotecan monotherapy for patients with advanced biliary tract cancer refractory to gemcitabine, cisplatin, and oral fluoropyrimidine. PATIENTS AND METHODS: Irinotecan (100 mg/m(2)) was administered intravenously on days 1, 8, and 15, repeated every four weeks. RESULTS: Thirteen patients were enrolled. The dose intensity was only 55.0%. The response rate and disease control rate were 1/13 (7.7%) and 3/13 (23.1%), respectively. The median overall survival and time-to-progression were 6.7 months (95% confidence interval=3.0-10.4 months) and 1.8 months (95% confidence interval=1.6-3.9 months), respectively. Grade 3/4 adverse events included leukopenia (7/13), neutropenia (8/13), anemia (6/13), nausea (1/13), vomiting (1/13), anorexia (2/13), diarrhea (1/13), and constipation (1/13). CONCLUSION: Irinotecan monotherapy had a modest antitumor effect even for patients who were refractory to gemcitabine, cisplatin, and oral fluoropyrimidine. However, this regimen was not fully tolerated as third-line or fourth-line therapy. Therefore, further evaluation of a modified irinotecan regimen is necessary.","author":[{"dropping-particle":"","family":"Sasaki","given":"Takashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Isayama","given":"Hiroyuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakai","given":"Yousuke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takahara","given":"Naminatsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Satoh","given":"Yumiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takai","given":"Daiya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kogure","given":"Hirofumi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamamoto","given":"Natsuyo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirano","given":"Kenji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tada","given":"Minoru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yatomi","given":"Yutaka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koike","given":"Kazuhiko","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Anticancer Research","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2013"]]},"page":"2619-2622","title":"A pilot study of salvage irinotecan monotherapy for advanced biliary tract cancer","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"(30)","plainTextFormattedCitation":"(30)","previouslyFormattedCitation":"(30)"},"properties":{"noteIndex":0},"schema":""}(30)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/sj.bjc.6602576","ISBN":"0007-0920 LA - eng PT - Clinical Trial PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial","ISSN":"00070920","PMID":"15856037","abstract":"The purpose of this study was to determine whether epirubicin, cisplatin and infused 5FU (ECF) improves overall survival (OS) compared to 5FU, etoposide and leucovorin (FELV) in patients with previously untreated advanced biliary cancer in a prospective randomised study. Patients were randomly assigned to receive epirubicin, cisplatin and infused 5FU ECF or bolus 5FU etoposide and leucovorin (FELV). The primary end point was OS with secondary end points of objective response rate (ORR), failure-free survival (FFS), quality of life (QOL) and toxicity. In all, 54 patients were recruited with 27 randomly assigned to each arm. The median OS for ECF was 9.02 months (95% confidence interval (CI): 6.46-11.51) and FELV 12.03 months (95% CI: 9.3-14.7), P=0.2059. Objective response rates were similar for both arms: ECF 19.2% (95% CI: 6.55-39.3); FELV 15% (95% CI: 3.2-37.9), P=0.72. There was significantly increased grade 3/4 neutropenia with FELV vs ECF (53.8 vs 29.5%, respectively, P=0.020). Symptom resolution was impressive for both regimens. This is the largest reported randomised study to date in this setting. ECF did not improve OS compared to FELV, but was associated with less acute toxicity. These data suggest that chemotherapy can prolong OS and achieve good symptomatic relief in advanced biliary cancer.","author":[{"dropping-particle":"","family":"Rao","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cunningham","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hawkins","given":"R. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hill","given":"M. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Daniel","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ross","given":"P. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oates","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Norman","given":"A. R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2005"]]},"page":"1650-1654","title":"Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"(31)","plainTextFormattedCitation":"(31)","previouslyFormattedCitation":"(31)"},"properties":{"noteIndex":0},"schema":""}(31), there is no evidence base for recommending routine use of later lines in CCA.Investigational treatmentsa. New cytotoxics agents and combinations The modest survival benefits observed with currently-available treatment options highlight the need for new effective agents and combinations for patients with CCA. Acelarin is a first-in-class nucleotide analogue; in contrast to gemcitabine, through phosphoramidation, it is independent of the membrane transporter (human equilibrative transporter-1 (hENT-1) and is not subject to metabolism by cytidine deaminase, thereby achieving reduced toxic metabolites. In a phase I study, the recommended dose for phase II was determined at 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle; levels of the active intracellular metabolite, difluoro-deoxycytidine triphosphate (dFdCTP), were 217-times greater than those seen with equimolar doses of gemcitabine ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41416-018-0244-1","ISBN":"4141601802","ISSN":"15321827","PMID":"30206366","abstract":"Gemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms. Sixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed. Sixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle. NUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive.","author":[{"dropping-particle":"al","family":"Blagden S, Rizzuto I","given":"Suppiah P et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2018"]]},"page":"815-822","title":"Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study","type":"article-journal","volume":"119"},"uris":[""]}],"mendeley":{"formattedCitation":"(32)","plainTextFormattedCitation":"(32)","previouslyFormattedCitation":"(32)"},"properties":{"noteIndex":0},"schema":""}(32). A phase Ib study of Acelarin in combination with cisplatin (ABC-08, NCT02351765) has completed accrual; the recommended dose was 625 mg/m2 with cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle. Preliminary results show acceptable toxicity and, with the limitation of a small sample size, an encouraging response rate of 50% (7/14 patients) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"al","family":"McNamara MG, Bridgewater J, Palmer D","given":"et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"ESMO Congress","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"Annals of Oncology (2018) 29 (suppl_8): viii205-vi","title":"A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08)","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(33)","plainTextFormattedCitation":"(33)","previouslyFormattedCitation":"(33)"},"properties":{"noteIndex":0},"schema":""}(33). A phase III study is in development to evaluate this combination against cisplatin and gemcitabine. Given the favorable results of intensification of chemotherapy seen in pancreatic cancer with FOLFIRINOX ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa1011923","ISBN":"1533-4406 (Electronic)\\r0028-4793 (Linking)","ISSN":"0028-4793","PMID":"21561347","abstract":"BACKGROUND: Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. RESULTS: The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). CONCLUSIONS: As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; number, NCT00112658.).","author":[{"dropping-particle":"al","family":"Conroy T, Desseigne F","given":"Ychou M et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"19","issued":{"date-parts":[["2011"]]},"page":"1817-1825","title":"FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer","type":"article-journal","volume":"364"},"uris":[""]}],"mendeley":{"formattedCitation":"(34)","plainTextFormattedCitation":"(34)","previouslyFormattedCitation":"(34)"},"properties":{"noteIndex":0},"schema":""}(34), a number of investigators have studied triple chemotherapy combinations. An initial phase I study with modified (m)FOLFIRINOX in patients with gastrointestinal malignancies concluded that this regimen was too toxic, even when making irinotecan dose adjustments for UGT1A1 polymorphisms. Six of 28 (21%) patients with biliary tract cancer had a partial response, which did not appear to incrementally improve on historical data with cisplatin and gemcitabine ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Sharma M, Catenacci D, Karrison T","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"ASCO GI","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"Journal of Clinical Oncology 35, no. 4_suppl (Febr","title":"A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX (mFOLFIRINOX) in previously untreated patients (pts) with advanced gastrointestinal malignancies","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(35)","plainTextFormattedCitation":"(35)","previouslyFormattedCitation":"(35)"},"properties":{"noteIndex":0},"schema":""}(35). A phase III French study (AMEBICA) is ongoing comparing mFOLFIRINOX vs. cisplatin and gemcitabine ( NCT02591030). An early parallel phase II study reported in 2009 did not find an appreciable improvement in response rate (19% and 23%) or overall survival (10.0 months and 9.9 months, for cholangiocarcinoma and gallbladder cancer, respectively) from the triplet of oxaliplatin, gemcitabine and 5-FU; there was, as anticipated, a marked increase in toxicity ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/sj.bjc.6605377","ISBN":"1532-1827 (Electronic)\\r0007-0920 (Linking)","ISSN":"00070920","PMID":"19904267","abstract":"BACKGROUND: Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy.\\n\\nMETHODS: Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m(-2) over 30 min), oxaliplatin (65 mg m(-2)) and 5-FU (1500 mg m(-2) over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure.\\n\\nRESULTS: Response rates were 19% (95% CI: 6-32%) and 23% (95% CI: 9-37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6-12.4) and 9.9 months (95% CI: 7.5-12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia.\\n\\nCONCLUSION: Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.","author":[{"dropping-particle":"","family":"Wagner","given":"A. D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buechner-Steudel","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moehler","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmalenberg","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Behrens","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fahlke","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wein","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Behl","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuss","given":"O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kleber","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fleig","given":"W. E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2009"]]},"page":"1846-1852","title":"Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: Two parallel, multicentre phase-II trials","type":"article-journal","volume":"101"},"uris":[""]}],"mendeley":{"formattedCitation":"(36)","plainTextFormattedCitation":"(36)","previouslyFormattedCitation":"(36)"},"properties":{"noteIndex":0},"schema":""}(36). Conversely, a more recent phase II study of cisplatin 35 mg/m2, gemcitabine 100 mg/m2 and 5-FU 2400 mg/m2 48-hour infusion, every 14 days, was associated with a response rate of 37.5% and median OS of 15.6 months among the 8 (of 39) patients with biliary tract cancer ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Davis EJ, Griffith KA, Kim E","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Am J Clin Oncol","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2018"]]},"page":"128-132","title":"A Phase II Study of Biweekly Cisplatin, Fixed-Dose-Rate Gemcitabine and Infusional 5-Fluorouracil in Patients With Metastatic Pancreatic and Biliary Cancers","type":"article-journal","volume":"41"},"uris":[""]}],"mendeley":{"formattedCitation":"(37)","plainTextFormattedCitation":"(37)","previouslyFormattedCitation":"(37)"},"properties":{"noteIndex":0},"schema":""}(37), although this improvement would need to be confirmed in a prospective randomized study. Based on a promising median overall survival (16.2 months) seen in a phase II Japanese study with cisplatin, gemcitabine and the oral fluoropyrimidine, S1 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00280-014-2648-9","ISSN":"14320843","PMID":"25477010","abstract":"PURPOSE: Gemcitabine/cisplatin combination therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). We aimed to evaluate the efficacy and safety of adding S-1 to gemcitabine/cisplatin combination therapy for patients with advanced BTC. METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent BTC were eligible for inclusion. The primary end point was overall survival. Based on the results of our preceding phase I study, gemcitabine and cisplatin were administered intravenously at doses of 1,000 or 25 mg/m(2), respectively, on day 1, and oral S-1 was administered daily at a dose of 80 mg/m(2) on days 1-7 every 2 weeks. This study was registered with (NCT01284413) and the UMIN Clinical Trials Registry (ID 000004468). RESULTS: Fifty patients enrolled between October 2011 and August 2012 were evaluated. After a median follow-up of 15.1 months (range 2.4-24.4 months), the median overall survival time was 16.2 months [95 % confidence interval (CI) 10.2-22.2 months], and the one-year overall survival rate was 59.9 % (95 % CI 46.2-73.5 %). The grade 3-4 hematological toxicities were as follows: neutropenia (32 %), anemia (32 %), thrombocytopenia (10 %), and febrile neutropenia (4 %). The common grade 3-4 non-hematological toxicities were biliary tract infection (14 %), anorexia/nausea (10 %), and fatigue (8 %). CONCLUSIONS: Gemcitabine/cisplatin/S-1 combination chemotherapy offered a promising survival benefit with manageable toxicity in patients with advanced BTC. A randomized phase III trial to investigate the efficacy of this regimen compared to gemcitabine/cisplatin combination therapy in patients with advanced BTC is now underway (UMIN000014371/NCT02182778).","author":[{"dropping-particle":"","family":"Kanai","given":"Masashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hatano","given":"Etsuro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kobayashi","given":"Shogo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fujiwara","given":"Yutaka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marubashi","given":"Shigeru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyamoto","given":"Atsushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shiomi","given":"Hisanori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kubo","given":"Shoji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ikuta","given":"Shinichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yanagimoto","given":"Hiroaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Terajima","given":"Hiroaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ikoma","given":"Hisashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sakai","given":"Daisuke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kodama","given":"Yuzo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seo","given":"Satoru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morita","given":"Satoshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ajiki","given":"Tetsuo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagano","given":"Hiroaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ioka","given":"Tatsuya","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer Chemotherapy and Pharmacology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2015"]]},"page":"293-300","title":"A multi-institution phase II study of gemcitabine/cisplatin/S-1 (GCS) combination chemotherapy for patients with advanced biliary tract cancer (KHBO 1002)","type":"article-journal","volume":"75"},"uris":[""]}],"mendeley":{"formattedCitation":"(38)","plainTextFormattedCitation":"(38)","previouslyFormattedCitation":"(38)"},"properties":{"noteIndex":0},"schema":""}(38), a phase III study was performed of this combination vs. cisplatin and gemcitabine. The study, presented at ASCO 2018, met its primary end-point with a hazard ratio of 0.791 (stratified log-rank one-sided p-value 0.046, 95% CI 0.628 – 0.996), although the improvement in median OS was small (12.6 to 13.5 months) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Sakai D, Kanai M, Kobayashi S","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"ESMO Congress","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"Annals of Oncology, Volume 29, Issue suppl_8, 1 Oc","title":"Randomized phase III study of gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401-MITSUBA)","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(39)","plainTextFormattedCitation":"(39)","previouslyFormattedCitation":"(39)"},"properties":{"noteIndex":0},"schema":""}(39) and the clinical significance is, therefore, questionable. Promising preliminary data have been reported on the safety and efficacy of cisplatin, gemcitabine and nab-paclitaxel combination: this triplet produced a RR of 32.2% and a DCR of 82.3% in a phase II trial. Moreover, mPFS and 1-year OS were 11.4 months and 66.7%, while the mOS was not reached (estimated to be superior to 20 months). Dose reductions to the schedule were required due to grade 3-4 hematological toxicities; this regimen is undergoing prospective evaluation in a randomized controlled study. In the development of novel combinations, particularly with dose-intensification, the trade-off between enhanced efficacy, toxicity and impact on quality of life needs careful evaluation. For example, in patients with disease which could be rendered resectable, a toxic regimen of short duration aiming to achieve maximum response may be appropriate. In patients with widespread metastatic disease, a sequenced approach of active agents may be preferable, although this is subject to prospective evaluation in clinical trials with a focus on impact on quality of life. b.??????Targeting angiogenesisAngiogenesis and lymphangiogenesis are crucial in the carcinogenesis of BTCs. Several studies have confirmed an overexpression of molecules involved in the formation of new vessels on tumor samples and a correlation with worse prognosis. Alterations of genes involved in the angiogenic process, such as FGFR2, characterize these tumors and could interfere with the interplay between VEGF, TSP-1 (trombospondin) and Ang-1/2 (angiopoietin). Based on these data there have been preclinical and phase I and II trials targeting VEFG pathway with antibodies (bevacizumab, ramucirumab, aflibercept), TKIs (vandetanib, sorafenib, sunitinib, cediranib, regorafenib, selumetinib) and others (curcumin, tymoquinone), alone or in combination with chemotherapy or other drugs. Results have been contrasting due to unknown drug resistance mechanisms. Moreover, phase I and II trials did not lead to encouraging results (see table 3) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Zhu AX, Meyerhardt JA","given":"Blaszkowsky LS et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet Oncology","id":"ITEM-1","issue":"(1)","issued":{"date-parts":[["2010"]]},"page":"48-54","title":"Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study.","type":"article-journal","volume":"Jan;11"},"uris":[""]}],"mendeley":{"formattedCitation":"(40)","plainTextFormattedCitation":"(40)","previouslyFormattedCitation":"(40)"},"properties":{"noteIndex":0},"schema":""}(40) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2010.28.4075","ISSN":"0732-183X","abstract":"Purpose: Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Patients and Methods: Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Results: Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Conclusion: Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer. 2010 by American Society of Clinical Oncology.","author":[{"dropping-particle":"","family":"S.J.","given":"Lubner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"M.R.","given":"Mahoney","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J.L.","given":"Kolesar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"N.K.","given":"LoConte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"G.P.","given":"Kim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"H.C.","given":"Pitot","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"P.A.","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J.","given":"Picus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"W.-P.","given":"Yong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"L.","given":"Horvath","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"G.","given":"Van Hazel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"C.E.","given":"Erlichman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"K.D.","given":"Holen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"title":"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","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(41)","plainTextFormattedCitation":"(41)","previouslyFormattedCitation":"(41)"},"properties":{"noteIndex":0},"schema":""}(41) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Iyer RV, Pokuri VK","given":"Groman A et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Am J Clin Oncol.","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2018"]]},"page":"649-655.","title":"A Multicenter Phase II Study of Gemcitabine, Capecitabine, and Bevacizumab for Locally Advanced or Metastatic Biliary Tract Cancer","type":"article-journal","volume":"Jul;41"},"uris":[""]}],"mendeley":{"formattedCitation":"(42)","plainTextFormattedCitation":"(42)","previouslyFormattedCitation":"(42)"},"properties":{"noteIndex":0},"schema":""}(42) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000479970","ISSN":"14230232","abstract":"OBJECTIVE: Since 2010, gemcitabine and cisplatin have been considered standard first-line treatment in patients with advanced biliary tract cancer. Many centers have replaced cisplatin with oxaliplatin, which seems to obtain similar results. While first-line treatment has been well established, there are no phase III trials supporting second-line treatment, and the phase II trials with chemotherapy do not show any clear benefit. In this study, we investigated the effect of adding bevacizumab to chemotherapy in second-line treatment., METHODS: From November 2013 to January 2016, 50 patients with advanced biliary tract cancer were enrolled in this prospective phase II trial. All patients had received a gemcitabine-platinum combination as first-line treatment. The patients received capecitabine, irinotecan, gemcitabine, and bevacizumab in a 2-week schedule as second-line treatment., RESULTS: The combination was well tolerated with a median progression-free survival of 3.6 months, a median overall survival of 6.4 months, and a response rate of 6%., CONCLUSION: The combination of capecitabine, irinotecan, gemcitabine, and bevacizumab as a second-line treatment for advanced biliary tract cancer is well tolerated but with a modest, if any, benefit. Copyright ? 2017 S. Karger AG, Basel.","author":[{"dropping-particle":"","family":"Larsen","given":"Finn Ole","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Markussen","given":"Alice","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Diness","given":"Laura","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nielsen","given":"Dorte","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Oncology (Switzerland)","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"title":"Efficacy and Safety of Capecitabine, Irinotecan, Gemcitabine, and Bevacizumab as Second-Line Treatment in Advanced Biliary Tract Cancer: A Phase II Study","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(43)","plainTextFormattedCitation":"(43)","previouslyFormattedCitation":"(43)"},"properties":{"noteIndex":0},"schema":""}(43) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/bjc.2013.801","ISSN":"00070920","abstract":"BACKGROUND: Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers.\\n\\nMETHODS: Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively.\\n\\nRESULTS: Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1-20%), with a median progression-free survival of 2 months (95% CI: 2-3), and median overall survival of 6 months (95% CI: 3-8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash.\\n\\nCONCLUSIONS: Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.","author":[{"dropping-particle":"","family":"El-Khoueiry","given":"A. B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rankin","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegel","given":"A. B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iqbal","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gong","given":"I. Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Micetich","given":"K. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kayaleh","given":"O. R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lenz","given":"H. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanke","given":"C. D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"title":"S0941: A phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(44)","plainTextFormattedCitation":"(44)","previouslyFormattedCitation":"(44)"},"properties":{"noteIndex":0},"schema":""}(44) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejca.2014.09.013","ISBN":"1879-0852\\r0959-8049","ISSN":"18790852","PMID":"25446376","abstract":"Background Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. Patients and methods 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0-2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA). Results Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS. Conclusion The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.","author":[{"dropping-particle":"","family":"Moehler","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maderer","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schimanski","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanzler","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Denzer","given":"U.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolligs","given":"F. T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ebert","given":"M. P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Distelrath","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geissler","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trojan","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schütz","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berie","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sauvigny","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lammert","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lohse","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dollinger","given":"M. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindig","given":"U.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Duerr","given":"E. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lubomierski","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zimmermann","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wachtlin","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaiser","given":"A. K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schadmand-Fischer","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galle","given":"P. R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Woerns","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Cancer","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"title":"Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: A double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(45)","plainTextFormattedCitation":"(45)","previouslyFormattedCitation":"(45)"},"properties":{"noteIndex":0},"schema":""}(45) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/bjc.2013.432","ISSN":"00070920","abstract":"BACKGROUND: This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy. METHODS: Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m(-2) and cisplatin 25 mg m(-2) on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand-foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m(-2), cisplatin 20 mg m(-2) and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57-77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome. RESULTS: A total of 39 patients were accrued. The most common grade 3-4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34-66%). Median PFS and overall survival were 6.5 (95% CI: 3.5-8.3) and 14.4 months (95% CI: 11.6-19.2 months), respectively. No correlation was observed between pERK and outcomes. CONCLUSION: The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.","author":[{"dropping-particle":"","family":"Lee","given":"J. K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Capanu","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Reilly","given":"E. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chou","given":"J. F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shia","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"S. S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gansukh","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reidy-Lagunes","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Segal","given":"N. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"K. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"K. Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saltz","given":"L. B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abou-Alfa","given":"G. K.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"title":"A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(46)","plainTextFormattedCitation":"(46)","previouslyFormattedCitation":"(46)"},"properties":{"noteIndex":0},"schema":""}(46) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(15)00139-4","abstract":"Background: Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival. Methods: In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0-1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine [on days 1 and 8 every 21 days, for up to eight cycles]) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with , number NCT00939848, and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented. Findings: Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 122 months (IQR 73-185), median progression-free survival was 80 months (95% CI 65-93) in the cediranib group and 74 months (57-85) in the placebo group (HR 093, 80% CI 074-119, 95% CI 065-135; p=072). Patients who received cediranib had more grade 3-4 toxic effects than did patients who received placebo: hypertension (23 [37%] vs 13 [21%]; p=005), diarrhoea (eight [13%] vs two [3%]; p=005); platelet count decreased (ten [16%] vs four [6%]; p=009), white blood cell decreased (15 [24%] vs seven [11%]; p=006) and fatigue (16 [24%] vs seven [11%]; p=004). Interpretation: Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of 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Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.","author":[{"dropping-particle":"","family":"Beatty","given":"Gregory L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chiorean","given":"Elena G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fishman","given":"Matthew P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saboury","given":"Babak","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teitelbaum","given":"Ursina R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"Weijing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huhn","given":"Richard D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Wenru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Dongguang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharp","given":"Leslie L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Torigian","given":"Drew A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Dwyer","given":"Peter J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vonderheide","given":"Robert H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Science","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"title":"CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(49)","plainTextFormattedCitation":"(49)","previouslyFormattedCitation":"(49)"},"properties":{"noteIndex":0},"schema":""}(49) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Sun W, Patel A","given":"Normolle D et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer.","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"title":"A phase 2 trial of regorafenib as a single agent in patients with chemotherapy-refractory, advanced, and metastatic biliary tract adenocarcinoma","type":"article-journal","volume":"Dec 18. do"},"uris":[""]}],"mendeley":{"formattedCitation":"(50)","plainTextFormattedCitation":"(50)","previouslyFormattedCitation":"(50)"},"properties":{"noteIndex":0},"schema":""}(50) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Neuzillet C, Seitz JF, Fartoux L","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"ASCO GI. Journal of Clinical Oncology","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"33, no. 3_suppl (January 20 2015) 343-343.","title":"Sunitinib as second-line treatment in patients with advanced intrahepatic cholangiocarcinoma (SUN-CK phase II trial): Safety, efficacy, and updated translational results","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(51)","plainTextFormattedCitation":"(51)","previouslyFormattedCitation":"(51)"},"properties":{"noteIndex":0},"schema":""}(51). Clinical trials on selected subgroups identified by predictive factors are strongly needed to define setting of patients who might benefit more from antiangiogenic agents. ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3390/ijms18020418","ISSN":"14220067","PMID":"28212293","abstract":"Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2), are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.","author":[{"dropping-particle":"","family":"Simone","given":"Valeria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brunetti","given":"Oronzo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lupo","given":"Luigi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Testini","given":"Mario","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maiorano","given":"Eugenio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simone","given":"Michele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Longo","given":"Vito","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rolfo","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peeters","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scarpa","given":"Aldo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Azzariti","given":"Amalia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Russo","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ribatti","given":"Domenico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silvestris","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Molecular Sciences","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"title":"Targeting angiogenesis in biliary tract cancers: An open option","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(52)","plainTextFormattedCitation":"(52)","previouslyFormattedCitation":"(52)"},"properties":{"noteIndex":0},"schema":""}(52)c.?EGFR / HER2i EGFR family receptor plays a key role in cell cycle, migration and angiogenesis ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1158/0008-5472.CAN-06-2130","ISBN":"0008-5472 (Print)\\n0008-5472 (Linking)","ISSN":"00085472","PMID":"17079474","abstract":"The association between chronic inflammation and the development and progression of malignancy is exemplified in the biliary tract where persistent inflammation strongly predisposes to cholangiocarcinoma. The inflammatory cytokine interleukin-6 (IL-6) enhances tumor growth in cholangiocarcinoma by altered gene expression via autocrine mechanisms. IL-6 can regulate the activity of DNA methyltransferases, and moreover, aberrant DNA methylation can contribute to carcinogenesis. We therefore investigated the effect of chronic exposure to IL-6 on methylation-dependent gene expression and transformed cell growth in human cholangiocarcinoma. The relationship between autocrine IL-6 pathways, DNA methylation, and transformed cell growth was assessed using malignant cholangiocytes stably transfected to overexpress IL-6. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine decreased cell proliferation, growth in soft agar, and methylcytosine content of malignant cholangiocytes. However, this effect was not observed in IL-6-overexpressing cells. IL-6 overexpression resulted in the altered expression and promoter methylation of several genes, including the epidermal growth factor receptor (EGFR). EGFR promoter methylation was decreased and gene and protein expression was increased by IL-6. Thus, epigenetic regulation of gene expression by IL-6 can contribute to tumor progression by altering promoter methylation and gene expression of growth-regulatory pathways, such as those involving EGFR. Moreover, enhanced IL-6 expression may decrease the sensitivity of tumor cells to therapeutic treatments using methylation inhibitors. These observations have important implications for cancer treatment and provide a mechanism by which persistent cytokine stimulation can promote tumor growth.","author":[{"dropping-particle":"","family":"Wehbe","given":"Hania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henson","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meng","given":"Fanyin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mize-Berge","given":"Janna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Tushar","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer Research","id":"ITEM-1","issue":"21","issued":{"date-parts":[["2006"]]},"page":"10517-10524","title":"Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression","type":"article-journal","volume":"66"},"uris":[""]}],"mendeley":{"formattedCitation":"(53)","plainTextFormattedCitation":"(53)","previouslyFormattedCitation":"(53)"},"properties":{"noteIndex":0},"schema":""}(53) and the overexpression has been implicated in the carcinogenesis of cholangiocarcinoma. High levels of expression have been documented in many cases of cholangiocarcinoma, particularly in the intrahepatic type (38-100 %) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"al","family":"Pignochino Y, Sarotto I, Peraldo- Neia C","given":"et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMC","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"page":"631","title":"Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(54)","plainTextFormattedCitation":"(54)","previouslyFormattedCitation":"(54)"},"properties":{"noteIndex":0},"schema":""}(54).Several combinations of drugs have been tested to evaluate the effectiveness of target therapy, but unfortunately, both the EGFR inhibitor and the combination of anti-EGFR antibody with chemotherapy failed to produce promising results in several trials in patients with advanced BTCs ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdt416","ISSN":"09237534","PMID":"24146220","abstract":"BACKGROUND: Current data suggest that chemotherapy combinations may be superior to single agents in biliary tract cancer. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan.\\n\\nPATIENTS AND METHODS: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate organ function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m(2)) and irinotecan (100 mg/m(2)) on days 1 and 8 of a 21-day cycle. The primary objective was to evaluate the 5-month progression-free survival (PFS). Secondary objectives included overall response rate (ORR) and overall survival (OS). Mutational analyses of EGFR, KRAS and BRAF were carried out when feasible.\\n\\nRESULTS: Thirty-five patients received a median of 7 (0-30) cycles. The most common grade 3/4 toxic effects were neutropenia (10 patients, 29%), thrombocytopenia (10 patients, 29%), skin rash (13 patients, 37%) and dehydration (9 patients, 26%). Two patients had CR, 9 had partial response (PR), and 15 had SD for a disease-control rate of 74% (by RECIST) in 28 assessable patients. Two patients went on to have surgical resection. The 5-month PFS was 69%. The median PFS was 9.7 months and the median OS was 12.9 months. In 17 testable samples, no EGFR or BRAF mutations were identified; there were 7 KRAS mutations, with no difference in OS by KRAS status.\\n\\nCONCLUSIONS: This study showed encouraging efficacy of this regimen with good tolerability. Further study in this area is warranted. Clinical Trials Number: The trial was registered with the National Cancer Institute ( identifier NCT00948935).","author":[{"dropping-particle":"","family":"Sohal","given":"D. 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J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sepulveda","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"W.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2013"]]},"page":"3061-3065","title":"A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma","type":"article-journal","volume":"24"},"uris":[""]}],"mendeley":{"formattedCitation":"(55)","plainTextFormattedCitation":"(55)","previouslyFormattedCitation":"(55)"},"properties":{"noteIndex":0},"schema":""}(55) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdv035","ISBN":"1569-8041 (Electronic)\\r0923-7534 (Linking)","ISSN":"15698041","PMID":"25632066","abstract":"BACKGROUND Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. PATIENTS AND METHODS ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m(2) gemcitabine and 85 mg/m(2) oxaliplatin) or C-GEMOX (500 mg/m(2) cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). RESULTS The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. CONCLUSIONS Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status. CLINICAL TRIALS NUMBER This study is registered at (NCT01267344). All patients gave written informed consent.","author":[{"dropping-particle":"al","family":"Chen J, Hsu C","given":"Chiang N et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2015"]]},"page":"943-949","title":"A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"(56)","plainTextFormattedCitation":"(56)","previouslyFormattedCitation":"(56)"},"properties":{"noteIndex":0},"schema":""}(56) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(14)70212-8","ISBN":"14702045","ISSN":"14745488","PMID":"24852116","abstract":"Background: Gemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers. Methods: In this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) with or without cetuximab (500 mg/m2), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with , number NCT00552149. Findings: Between Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52-74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43-65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1-7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7-6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1-13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6-16·0) in the chemotherapy alone group. The most common grade 3-4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of a…","author":[{"dropping-particle":"","family":"Malka","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cervera","given":"Pascale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Foulon","given":"Stéphanie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trarbach","given":"Tanja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"la Fouchardière","given":"Christelle","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boucher","given":"Eveline","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fartoux","given":"Laetitia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faivre","given":"Sandrine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanc","given":"Jean Frédéric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viret","given":"Frédéric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Assenat","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seufferlein","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herrmann","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grenier","given":"Julien","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hammel","given":"Pascal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dollinger","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"André","given":"Thierry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hahn","given":"Philipp","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heinemann","given":"Volker","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rousseau","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ducreux","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pignon","given":"Jean Pierre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wendum","given":"Dominique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosmorduc","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Greten","given":"Tim F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Oncology","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2014"]]},"page":"819-828","title":"Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): A randomised, open-label, non-comparative phase 2 trial","type":"article-journal","volume":"15"},"uris":[""]}],"mendeley":{"formattedCitation":"(57)","plainTextFormattedCitation":"(57)","previouslyFormattedCitation":"(57)"},"properties":{"noteIndex":0},"schema":""}(57) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(11)70301-1","ISBN":"1474-5488 (Electronic)\\n1470-2045 (Linking)","ISSN":"14702045","PMID":"22192731","abstract":"Background: Combination chemotherapy with gemcitabine and a platinum-based agent is regarded as a standard treatment for patients with advanced biliary-tract cancer. Results of phase 2 trials of single-agent erlotinib in biliary-tract cancer and of gemcitabine plus erlotinib in pancreatic cancer have shown modest benefits. Therefore, we aimed to investigate the efficacy of gemcitabine and oxaliplatin plus erlotinib versus chemotherapy alone for advanced biliary-tract cancer. Methods: In this open label, randomised, phase 3 trial, we randomly assigned patients (in a 1:1 ratio) with metastatic biliary-tract cancer (cholangiocarcinoma, gallbladder cancer, or ampulla of Vater cancer) to receive either first-line treatment with chemotherapy alone (gemcitabine 1000 mg/m2on day 1 and oxaliplatin 100 mg/m2on day 2) or chemotherapy plus erlotinib (100 mg daily). Treatment was repeated every 2 weeks until disease progression or unacceptable toxic effects. Randomisation was done centrally (stratified by participating centre and presence of measurable lesion). The primary endpoint was progression-free survival. Analyses were by intention-to-treat. This study is registered with , number NCT01149122. Findings: 133 patients were randomly assigned to the chemotherapy alone group and 135 to the chemotherapy plus erlotinib group. The groups were balanced except for a higher proportion of patients with cholangiocarcinoma in the group given erlotinib than in the chemotherapy alone group (96 [71%] patients vs 84 [63%]). Median progression-free survival was 4·2 months (95% CI 2·7-5·7) in the chemotherapy alone group and 5·8 months (95% CI 4·6-7·0) in the chemotherapy plus erlotinib group (hazard ratio [HR] 0·80, 95% CI 0·61-1·03; p=0·087). Significantly more patients had an objective response in the chemotherapy plus erlotinib group than in the chemotherapy alone group (40 patients vs 21 patients; p=0·005), but median overall survival was the same in both groups (9·5 months [95% CI 7·5-11·5] in the chemotherapy alone group and 9·5 months [7·6-11·4] in the chemotherapy plus erlotinib group; HR 0·93, 0·69-1·25; p=0·611). All-cause deaths within 30 days of random assignment occurred in one (1%) of the patients in the chemotherapy alone group and in four (3%) of those in the chemotherapy plus erlotinib group. The most common grade 3-4 adverse event was febrile neutropenia (eight [6%] patients in the chemotherapy alone group and six [4%] in the chemotherapy plus…","author":[{"dropping-particle":"","family":"Lee","given":"Jeeyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Se Hoon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Heung Moon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Jun Suk","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Hye Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Myung Ah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Joung Soon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jeung","given":"Hei Cheul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kang","given":"Jung Hun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Hyun Woo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shin","given":"Dong Bok","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kang","given":"Hye Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"Jong Mu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Joon Oh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Young Suk","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kang","given":"Won Ki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Ho Yeong","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Oncology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"181-188","title":"Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: A multicentre, open-label, randomised, phase 3 study","type":"article-journal","volume":"13"},"uris":[""]}],"mendeley":{"formattedCitation":"(58)","plainTextFormattedCitation":"(58)","previouslyFormattedCitation":"(58)"},"properties":{"noteIndex":0},"schema":""}(58). Recently, the PICCA study confirmed these data, showing that Panitumumab in combination with chemotherapy does not improve neither ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejca.2017.12.028","ISSN":"18790852","PMID":"29413685","abstract":"Background: Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer. Patients and methods: Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v q3w). The primary end-point was the evaluation of progression-free survival (PFS) at 6 months. Secondary end-points included objective response rate (ORR), overall survival (OS), and toxicity. In addition, a post hoc assessment of genetic alterations was performed. Finally, we performed a meta-analysis of trials with chemotherapy with and without EGFR antibodies. Results: Sixty-two patients were randomised in arm A and 28 patients in arm B. Patients received 7 treatment cycles in median (1–35) with a median treatment duration of 4.7 months (141 days, 8–765). PFS rate at 6 months was 54% in patients treated with cisplatin/gemcitabine and panitumumab but was 73% in patients treated with cisplatin/gemcitabine without antibody, respectively. Secondary end-points were an ORR of 45% in treatment arm A compared with 39% receiving treatment B and a median OS of 12.8 months (arm A) and of 20.1 months (arm B), respectively. In contrast to the p53-status, genetic alterations in IDH1/2 were linked to a high response after chemotherapy and prolonged survival. In accordance with our results, the meta-analysis of 12 trials did not reveal a survival advantage for patients treated with EGFR antibodies compared with chemotherapy alone. Conclusions: Panitumumab in combination with chemotherapy does not improve ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer. Genetic profiling should be included in CCA trials to identify and validate predictive and prognostic biomarkers. Clinical Trials Number: The trial was registered with NCT01320254.","author":[{"dropping-particle":"","family":"Vogel","given":"Arndt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kasper","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bitzer","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Block","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sinn","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schulze-Bergkamen","given":"Henning","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moehler","given":"Markus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pfarr","given":"Nicole","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Endris","given":"Volker","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goeppert","given":"Benjamin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merx","given":"Kirsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schnoy","given":"Elisabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siveke","given":"Jens T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Michl","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waldschmidt","given":"Dirk","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuhlmann","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geissler","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahl","given":"Christoph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Evenkamp","given":"Ralf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmidt","given":"Torben","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuhlmann","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weichert","given":"Wilko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kubicka","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Cancer","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"11-19","title":"PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer—a randomised biomarker-driven clinical phase II AIO study","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"(59)","plainTextFormattedCitation":"(59)","previouslyFormattedCitation":"(59)"},"properties":{"noteIndex":0},"schema":""}(59). Despite this, recent data have demonstrated that CART-EGFR cell therapy, in the EGFR-positive advanced unresectable cholangiocarcinoma, is safe. Indeed, in a phase I study, 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) were treated with CART-EGFR within 6 months after conditioning treatment with nab-paclitaxel and cyclophosphamide. Out of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5-22 months) from the first cycle of treatment ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1186/s13045-015-0155-z","ISBN":"2123059781","ISSN":"17568722","PMID":"26022204","abstract":"BACKGROUND: Biliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown.\\n\\nPATIENTS AND METHODS: We retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu-directed therapy between 2007 and 2014. Clinical data were retrieved from medical records, and imaging studies were independently reviewed.\\n\\nRESULTS: Nine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab) during the study period. In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in eight cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu-directed therapy. One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy. The duration of response varied from 8+ to 168 weeks (median 40 weeks), and three patients are still on therapy. One patient developed HER2/neu amplification as a secondary event after FGFR-directed therapy for FGF3-TACC3 gene fusion. The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy.\\n\\nCONCLUSIONS: HER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study.","author":[{"dropping-particle":"","family":"Javle","given":"Milind","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Churi","given":"Chaitanya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kang","given":"Hyunseon C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shroff","given":"Rachna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janku","given":"Filip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Surapaneni","given":"Rakesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zuo","given":"Mingxin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barrera","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alshamsi","given":"Humaid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krishnan","given":"Sunil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mishra","given":"Lopa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolff","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaseb","given":"Ahmed O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomas","given":"Melanie B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegel","given":"Abby B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hematology and Oncology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015"]]},"title":"HER2/neu-directed therapy for biliary tract cancer","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"(60)","plainTextFormattedCitation":"(60)","previouslyFormattedCitation":"(60)"},"properties":{"noteIndex":0},"schema":""}(60).Regarding HER2, gene overexpression or amplification is observed in 5-25% of extrahepatic bile duct carcinomas; despite this, data summarized in a recently published retrospective review would not show any clinically meaningful response in patients with HER2+ cholangiocarcinoma treated with trastuzumab ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1186/s13045-015-0155-z","ISBN":"2123059781","ISSN":"17568722","PMID":"26022204","abstract":"BACKGROUND: Biliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown.\\n\\nPATIENTS AND METHODS: We retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu-directed therapy between 2007 and 2014. Clinical data were retrieved from medical records, and imaging studies were independently reviewed.\\n\\nRESULTS: Nine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab) during the study period. In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in eight cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu-directed therapy. One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy. The duration of response varied from 8+ to 168 weeks (median 40 weeks), and three patients are still on therapy. One patient developed HER2/neu amplification as a secondary event after FGFR-directed therapy for FGF3-TACC3 gene fusion. The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy.\\n\\nCONCLUSIONS: HER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study.","author":[{"dropping-particle":"","family":"Javle","given":"Milind","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Churi","given":"Chaitanya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kang","given":"Hyunseon C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shroff","given":"Rachna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janku","given":"Filip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Surapaneni","given":"Rakesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zuo","given":"Mingxin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barrera","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alshamsi","given":"Humaid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krishnan","given":"Sunil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mishra","given":"Lopa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolff","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaseb","given":"Ahmed O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomas","given":"Melanie B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siegel","given":"Abby B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hematology and Oncology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015"]]},"title":"HER2/neu-directed therapy for biliary tract cancer","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"(60)","plainTextFormattedCitation":"(60)","previouslyFormattedCitation":"(60)"},"properties":{"noteIndex":0},"schema":""}(60).There are currently ongoing trials aimed to evaluate the efficacy of the target therapy anti HER2 (NCT02999672, NCT02836847).d.???????IDH-pathwayIsocitrate dehydrogenase (IDH) belongs to the Krebs Cycle; this enzyme converts isocitrate to alpha-ketoglutarate (AKG). Various enzymes such as DNA and histone modifiers require AKG as a cofactor. Mutations in IDH1 and IDH2 genes occur in about 15-20% of iCCA with R132 and R172 as the most frequently mutated codons, respectively ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1586/era.12.32","ISSN":"14737140","PMID":"22594888","author":[{"dropping-particle":"","family":"Borger D","given":"Zhu A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Expert Review of Anticancer Therapy","id":"ITEM-1","issued":{"date-parts":[["2012"]]},"page":"543–546","title":"IDH mutations: New genetic signatures in cholangiocarcinoma and therapeutic implications","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(61)","plainTextFormattedCitation":"(61)","previouslyFormattedCitation":"(61)"},"properties":{"noteIndex":0},"schema":""}(61). Although the prognostic role of this mutation is not clear, it results in a gain of function ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1634/theoncologist.2015-0210","ISBN":"1549-490X (Electronic)\\r1083-7159 (Linking)","ISSN":"1083-7159","PMID":"26245674","abstract":"Background. Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. Methods. Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. Results. Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p 5.17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p 5.04) Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. Conclusion. The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation.","author":[{"dropping-particle":"","family":"Goyal","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Govindan","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheth","given":"R. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nardi","given":"V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blaszkowsky","given":"L. S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faris","given":"J. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clark","given":"J. 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X.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Oncologist","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2015"]]},"page":"1019-1027","title":"Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma","type":"article-journal","volume":"20"},"uris":[""]}],"mendeley":{"formattedCitation":"(62)","plainTextFormattedCitation":"(62)","previouslyFormattedCitation":"(62)"},"properties":{"noteIndex":0},"schema":""}(62). Mutated IDH (mIDH) induces the conversion of AKG to 2-OH-glutarate (2-HG) which has an oncogenic role by inhibiting the enzymes associated with AKG resulting in the dysregulation of gene expression. This is the rationale for clinical development of IDH inhibitors. AG120 (ivosidenib) is a first-in-class, potent, oral inhibitor of the mIDH1 enzyme. In a phase 1-2 trial, 73 IDH1-mutated cholangiocarcinoma patients were treated with ivosidenib achieving an interesting 12-month PFS of 20.7% ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2017.35.15_suppl.4015","ISSN":"0732-183X","abstract":"4015Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC. Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses. Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1?5), ECOG 0?1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year. Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy). Clinical trial information: NCT02073994.","author":[{"dropping-particle":"","family":"Lowery","given":"Maeve Aine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abou-Alfa","given":"Ghassan K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burris","given":"Howard A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janku","given":"Filip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shroff","given":"Rachna T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cleary","given":"James M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Azad","given":"Nilofer Saba","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goyal","given":"Lipika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maher","given":"Elizabeth A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gore","given":"Lia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hollebecque","given":"Antoine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beeram","given":"Muralidhar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trent","given":"Jonathan C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiang","given":"Liewen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ishii","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Auer","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gliser","given":"Camelia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Agresta","given":"Samuel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pandya","given":"Shuchi Sumant","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Andrew X","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"(15_suppl)","issued":{"date-parts":[["2017"]]},"page":"4015","title":"Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts.","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"(63)","plainTextFormattedCitation":"(63)","previouslyFormattedCitation":"(63)"},"properties":{"noteIndex":0},"schema":""}(63). This has led to the ClarIDHy trial, a phase III trial randomising pre-treated CC patients with IDH1 mutation to ivosidenib or placebo (NCT02989857). Recruitment has been recently completed and results are awaited. Other IDH1 inhibitors are being already tested in clinical trials as BAY143602 (NCT02746081). Other agents of potential interest in patients with mIDH would be OxFos inhibitors, as an association has been reported between mIDH and a signature with high mitochondrial but low chromatin remodelling expression in the CC-TCGA Project ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.celrep.2017.02.033","ISBN":"2211-1247 (Electronic)","ISSN":"22111247","PMID":"28297679","abstract":"Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.","author":[{"dropping-particle":"","family":"Farshidfar","given":"Farshad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zheng","given":"Siyuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gingras","given":"Marie Claude","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newton","given":"Yulia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shih","given":"Juliann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robertson","given":"A. 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Finally, it has been shown in vitro models that 2-HG sensitises CC to PARPi ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1126/scitranslmed.aal2463","ISSN":"19466242","PMID":"28148839","abstract":"2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This \"BRCAness\" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.","author":[{"dropping-particle":"","family":"Sulkowski","given":"Parker L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Corso","given":"Christopher D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robinson","given":"Nathaniel D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scanlon","given":"Susan E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Purshouse","given":"Karin R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bai","given":"Hanwen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Yanfeng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sundaram","given":"Ranjini K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hegan","given":"Denise C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fons","given":"Nathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Breuer","given":"Gregory A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Yuanbin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mishra-Gorur","given":"Ketu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feyter","given":"Henk M.","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graaf","given":"Robin A.","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Surovtseva","given":"Yulia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kachman","given":"Maureen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Halene","given":"Stephanie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Günel","given":"Murat","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Glazer","given":"Peter M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bindra","given":"Ranjit S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Science Translational Medicine","id":"ITEM-1","issue":"375","issued":{"date-parts":[["2017"]]},"title":"2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity","type":"article-journal","volume":"9"},"uris":[""]}],"mendeley":{"formattedCitation":"(65)","plainTextFormattedCitation":"(65)","previouslyFormattedCitation":"(65)"},"properties":{"noteIndex":0},"schema":""}(65); a clinical trial with olaparib in mIDH CC is ongoing (NCT03212274). e.??FGFR-2 pathwaySeveral studies have consistently identified fibroblast growth factor receptor (FGFR) fusions in patients with, predominantly, iCCA. The presence of such fusions also appears to carry a more favorable prognosis. A few therapies have rapidly emerged targeting FGFR-fusions, including BGJ398 (infigratinib; QED Therapeutics), INCB54828 (pemigatinib; Incyte), BAY1163877 (Bayer), TAS-120 (Taiho) and ARQ-087 (derazantinib; Arqule). The first of these studies to be published was a phase II study with BGJ398 in patients previously-treated with chemotherapy; although the study included patients with FGFR2 fusions (n = 48), mutations (n = 8), or amplifications (n = 3), all patients with a radiological response to treatment harbored FGFR2 fusions. In these patients, the ORR was 18.8%, DCR 83.3% and median PFS 5.8 months (95% CI 4.3 – 7.6 months). Hyperphosphatemia was the commonest adverse event (72.1% all grades; 16.4% grade 3-4); other grade 3-4 toxicities included stomatitis and plantar-palmar erythrodysesthesia in 6.6% and 4.9% of patients, respectively ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2017.75.5009","ISBN":"1527-7755 (Electronic) 0732-183X (Linking)","ISSN":"15277755","PMID":"29182496","abstract":"Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.","author":[{"dropping-particle":"","family":"Javle","given":"Milind","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lowery","given":"Maeve","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shroff","given":"Rachna T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiss","given":"Karl Heinz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Springfeld","given":"Christoph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borad","given":"Mitesh J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramanathan","given":"Ramesh K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goyal","given":"Lipika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sadeghi","given":"Saeed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Macarulla","given":"Teresa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"El-Khoueiry","given":"Anthony","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kelley","given":"Robin Kate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borbath","given":"Ivan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choo","given":"Su Pin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oh","given":"Do Youn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Philip","given":"Philip A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Li Tzong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reungwetwattana","given":"Thanyanan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cutsem","given":"Eric","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yeh","given":"Kun Huei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ciombor","given":"Kristen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Finn","given":"Richard S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Anuradha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sen","given":"Suman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Porter","given":"Dale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Isaacs","given":"Randi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Andrew X.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abou-Alfa","given":"Ghassan K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bekaii-Saab","given":"Tanios","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"276-282","title":"Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma","type":"article-journal","volume":"36"},"uris":[""]}],"mendeley":{"formattedCitation":"(66)","plainTextFormattedCitation":"(66)","previouslyFormattedCitation":"(66)"},"properties":{"noteIndex":0},"schema":""}(66). A number of patients treated with BGJ398 were identified (though sequencing of tumor tissue and circulating-free DNA) to develop secondary polyclonal mutations in the FGFR2 kinase domain (including the gatekeeper mutation FGFR2V564F), suggesting the emergence of a resistance mechanism ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1158/2159-8290.CD-16-1000","ISBN":"6176430798","ISSN":"21598290","PMID":"28034880","abstract":"Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ?2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.","author":[{"dropping-particle":"","family":"Goyal","given":"Lipika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saha","given":"Supriya K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Leah Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siravegna","given":"Giulia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leshchiner","given":"Ignaty","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahronian","given":"Leanne G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lennerz","given":"Jochen K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vu","given":"Phuong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deshpande","given":"Vikram","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kambadakone","given":"Avinash","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mussolin","given":"Benedetta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reyes","given":"Stephanie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henderson","given":"Laura","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"Jiaoyuan Elisabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seventer","given":"Emily E.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gurski","given":"Joseph M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baltschukat","given":"Sabrina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schacher-Engstler","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barys","given":"Louise","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stamm","given":"Christelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Furet","given":"Pascal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryan","given":"David P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stone","given":"James R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"John Iafrate","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Getz","given":"Gad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Porta","given":"Diana Graus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tiedt","given":"Ralph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bardelli","given":"Alberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Juric","given":"Dejan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Corcoran","given":"Ryan B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bardeesy","given":"Nabeel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Andrew X.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer Discovery","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2017"]]},"page":"252-263","title":"Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"(67)","plainTextFormattedCitation":"(67)","previouslyFormattedCitation":"(67)"},"properties":{"noteIndex":0},"schema":""}(67). A similar level of activity has been seen in another recently-published phase II study with derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, in 29 FGFR-fusion positive patients (2 of these were treatment-na?ve). The ORR was 20.7%, DCR 82.7%, median PFS 5.7 months (95%- CI: 4.04 - 9.2 months). Most common adverse events (all grades) were fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41416-018-0334-0","ISSN":"15321827","abstract":"Summary\\nRegulation of chromatin structure via histone modification has recently received intense attention. Here,?we demonstrate that the chromatin-modifying enzyme histone deacetylase 2 (Hdac2) functions with a small homeodomain factor, Hopx, to mediate deacetylation of Gata4, which is expressed by cardiac progenitor cells and plays critical roles in the regulation of cardiogenesis. In the absence of Hopx and Hdac2 in mouse embryos, Gata4 hyperacetylation is associated with a marked increase in?cardiac myocyte proliferation, upregulation of Gata4 target genes, and perinatal lethality. Hdac2 physically interacts with Gata4, and this interaction is stabilized by Hopx. The ability of Gata4 to transactivate cell cycle genes is impaired by Hopx/Hdac2-mediated deacetylation, and this effect is abrogated by loss of Hdac2-Gata4 interaction. These results suggest that Gata4 is a nonhistone target of Hdac2-mediated deacetylation and that Hdac2, Hopx, and Gata4 coordinately regulate cardiac myocyte proliferation during embryonic development.","author":[{"dropping-particle":"","family":"Mazzaferro","given":"Vincenzo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"El-Rayes","given":"Bassel F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Droz dit Busset","given":"Michele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cotsoglou","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harris","given":"William P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Damjanov","given":"Nevena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Masi","given":"Gianluca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rimassa","given":"Lorenza","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Personeni","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Braiteh","given":"Fadi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zagonel","given":"Vittorina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Papadopoulos","given":"Kyriakos P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hall","given":"Terence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Yunxia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kazakin","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhoori","given":"Sherrie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Braud","given":"Filippo","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shaib","given":"Walid L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"title":"Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma","type":"article-newspaper"},"uris":[""]}],"mendeley":{"formattedCitation":"(68)","plainTextFormattedCitation":"(68)","previouslyFormattedCitation":"(68)"},"properties":{"noteIndex":0},"schema":""}(68). A pivotal trial of derazantinib in iCCA is ongoing ( NCT03230318).Interim analyses results are available for two additional phase II studies. TAS-120 has been reported to have a confirmed ORR of 25% and a DCR of 78.6% among 28 patients with FGFR gene fusions, including some patients who had previously received an FGFR inhibitor ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdy149","ISSN":"0923-7534","abstract":"Poster presented at the ESMO World Congress on Gastrointestinal Cancer, 20-23 June 2018, Barcelona, Spain doi: 10.3252/pso.eu.20wcgic.2018","author":[{"dropping-particle":"","family":"Meric-Bernstam","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arkenau","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tran","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bahleda","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kelley","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hierro","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahn","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Javle","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Winkler","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"He","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goyal","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"(suppl_5)","issued":{"date-parts":[["2018"]]},"title":"O-001Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"(69)","plainTextFormattedCitation":"(69)","previouslyFormattedCitation":"(69)"},"properties":{"noteIndex":0},"schema":""}(69). A pivotal study is in set-up. In a separate study, patients treated with INCB054828 (pemigatinib); the ORR was 40.4%; although this is numerically higher, the evaluable population was limited to patients with ≥8 months follow-up ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Hollebecque A, Borad M, Sahai V","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"ESMO Congress","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"Annals of Oncology, Volume 29, Issue suppl_8, 1 Oc","title":"Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF recepto","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(70)","plainTextFormattedCitation":"(70)","previouslyFormattedCitation":"(70)"},"properties":{"noteIndex":0},"schema":""}(70). A pivotal study in iCCA is recruiting ( NCT03656536). FGFR-fusions appear to predict for response to an FGFR inhibitor, but not all patients respond; understanding the profile of responding (vs. non-responding) patients, the emergence of resistance and the role of other FGFR aberrations are under active evaluation. f.????????RAFi, MEKiBRAF mutations are more common in iCCA than extrahepatic cholangiocarcinoma or gallbladder cancer. The frequency of BRAF mutations in iCCA have ranged between 1% to 22% among various cases series or population studies. The frequency appears to be underestimated when assessed by immunohistochemistry studies in comparison to PCR. Irrespective of the true frequency, BRAF mutant cholangiocarcinoma appears to be a distinct molecular subtype of biliary cancers that can be associated with aggressive behaviour and chemotherapy resistance. The targeting of this subgroup of patients with single agent BRAF inhibitors has been associated with modest clinical responses and short duration of disease control. In a study by Hyman et al., single agent vemurafenib was associated with a 12% objective response rate in BRAF mutant cholangiocarcinoma (1 out of 8 patients had PR). In view of improved efficacy of dual BRAF and MEK inhibition in melanoma and colorectal cancer, some patients with BRAF mutant ICC have been treated with a combination of dabrafenib and trametinib. It is worthy to mention the ROAR study (NCT02034110), a basket trial involving different cohorts with BRAF V600E mutation treated with the dabra/trame combination. Preliminary results have been very recently presented. In the biliary cancer cohort (35 patients, 80% pre-treated with more than 2 lines of chemotherapy) a response rate of 42% has been described with a median overall of 11.7 months ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"187","author":[{"dropping-particle":"al","family":"Wainberg ZA, Lassen UN, Elez E","given":"et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"ASCO GI","id":"ITEM-1","issued":{"date-parts":[["2019"]]},"title":"Efficacy and safety of dabrafenib and trametinib in patients with BRAF V600E–mutated biliary tract cancer: A cohort of the ROAR basket trial","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(71)","plainTextFormattedCitation":"(71)","previouslyFormattedCitation":"(71)"},"properties":{"noteIndex":0},"schema":""}(71). Additional data from this and other on-going prospective clinical trials (NCT01713972, NCT01902173) will help to confirm the activity of dual MEK/BRAF inhibition as a standard approach in BRAF-mutant cholangiocarcinoma ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.21037/jgo.2016.09.13","ISBN":"2078-6891 (Print) 2078-6891","ISSN":"2219679X","PMID":"28078132","abstract":"Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control. Our first patient achieved CR (complete remission) at 6 months of treatment with ultimate disease progression at 9 months. The second patient achieved a PR (partial response) at 2 months from starting treatment and remains progression free at 5 months. Our results confirm the activity of dual BRAF and MEK targeting in BRAF mutated ICC, adding further support to 3 additional case-reports in the literature. Dual targeting appears superior to other case reports with BRAF inhibition alone and appear favorable to historic data with cytotoxic chemotherapy. Given the poor outlook and refractoriness of BRAF mutant ICC, future studies should focus on early integration of BRAF/MEK inhibition.","author":[{"dropping-particle":"","family":"Lavingia","given":"Viraj","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fakih","given":"Marwan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Gastrointestinal Oncology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2016"]]},"page":"E98-E102","title":"Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief review","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"(72)","plainTextFormattedCitation":"(72)","previouslyFormattedCitation":"(72)"},"properties":{"noteIndex":0},"schema":""}(72). g.?c-METi c-MET is a proto-oncogene that encodes a tyrosine kinase receptor binding the hepatocyte growth factor (HGF). The complex MET-HGF has a key role in cellular proliferation, resistance to apoptosis, increased cell motility, and angiogenesis. The over-expression of MET is present in about 34% biliary tract cancers, regardless of the tumor site ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.7150/jca.17898","ISSN":"18379664","abstract":"? Ivyspring International Publisher. Background: c-MET is a proto-oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Activation of HGF-c-MET signaling involves cell invasiveness and evokes metastasis through direct involvement of tumor angiogenesis. However, the value of c-MET overexpression is still unknown in metastatic biliary tract cancer (BTC). Methods: We analyzed the incidence and clinicopathologic characteristics of c-MET overexpression in advanced BTC. Moreover, we investigated the value of c-MET overexpression in predicting response to gemicitabine plus cisplatin (GC), a first line standard regimen, and as a prognostic marker in metastatic BTC. Results: The BTC subtype distribution (N=44) was as follows: intrahepatic cholangiocarcinoma (IHCC, n=7), extrahepatic cholangiocarcinoma (EHCC, n=25) and gallbladder cancer (GBC, n=12). Liver (52.3%) was the predominant metastatic site, followed by lymph nodes (36.4%) and bone (15.9%). Among the 44 patients analyzed for c-MET expression, 15 (34.1%) exhibited c-MET overexpression in tumor tissues. There was no significant difference in the prevalence of c-MET overexpression among primary sites in EHCC (7/25, 28.0%), IHCC (3/7, 42.9%), and GBC (5/12, 41.7%). There was also no significant correlation between specific clinicopathologic variables and c-MET expression. Comparing the tumor-response to GC according to c-MET expression (overexpression vs. non-overexpression), th ere was no significant difference in either RR or DCR (p=0.394 and p > 0.999, respectively). The median PFS for all 44 patients was 9.00 months (95%CI, 7.5-10.5 months) and there was no significant difference for PFS between patients with c-MET overexpression and those without (p=0.917). The median OS was 14.4 months (95%CI, 11.9-16.9 months). There was no significant difference in OS between patients with c-MET overexpression compared to those without (13.7 vs. 14.4 months, respectively; p=0.708). Conclusions: c-MET overexpression was detected in 34.1%of advanced BTC patients irrespective of tumorlocation. c-MET overexpression did not predict response to GC or survival. Further studies are needed to fully elucidate the value of c-MET overexpression as a novel biomarker in these patients.","author":[{"dropping-particle":"","family":"Heo","given":"Mi Hwa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Hee Kyung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Hansang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Kyoung Mee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Jeeyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Se Hoon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Joon Oh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Ho Yeong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kang","given":"Won Ki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Young Suk","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Cancer","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2017"]]},"page":"1395-1399","title":"The clinical impact of c-MET over-expression in advanced biliary tract cancer (BTC)","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"(73)","plainTextFormattedCitation":"(73)","previouslyFormattedCitation":"(73)"},"properties":{"noteIndex":0},"schema":""}(73) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2011.37.7929","ISBN":"1527-7755 (Electronic)\\n0732-183X (Linking)","ISSN":"0732183X","PMID":"22042966","abstract":"In Journal of Clinical Oncology (JCO), two groups of investigators provide important evidence for the critical role of MET in malignant transformation. Graziano et al1 report a dose-proportional risk of recurrence and decreased survival associated with increasing MET gene copy number in stages II to III gastric adenocarcinoma. Lennerz et al2 show that MET amplification in gastroesophogeal carcinomas is uncommon, observed in only 2% of their patient cohort. However, an increase in MET gene copy number was associated with higher presenting tumor stage and grade as well as shorter median survival. These two reports add to a growing body of evidence that MET is a key driver of oncogenic transformation in a defined subset of cancers. This Understanding the Pathway article will provide an overview of the MET signaling pathway, discuss the role of MET in malignancy, and consider the potential for targeting MET in cancer therapy.","author":[{"dropping-particle":"","family":"Appleman","given":"Leonard J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"36","issued":{"date-parts":[["2011"]]},"page":"4837-4838","title":"MET signaling pathway: A rational target for cancer therapy","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"(74)","plainTextFormattedCitation":"(74)","previouslyFormattedCitation":"(74)"},"properties":{"noteIndex":0},"schema":""}(74); high levels of MET seem to correlate with a shorter disease-free survival and are associated with older patient age, presence of hepatolithiasis, higher cancer stage, and larger primary tumor size ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Wang SC WY, Lui TT, Weng SW","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Int J Clin Exp Pathol","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2017"]]},"page":"6809-6817","title":"Amplification and overexpression of the MET gene in intrahepatic cholangiocarcinoma correlate with adverse pathological features and worse clinical outcome","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"(75)","plainTextFormattedCitation":"(75)","previouslyFormattedCitation":"(75)"},"properties":{"noteIndex":0},"schema":""}(75).Some trials have evaluated the efficacy of MET-inhibitors in solid tumors with limited results. In a phase I study, patients with solid tumors (including CCA) were treated with tivantinib (oral MET-inhibitor) in combination with gemcitabine; twenty-nine patients were treated and the 20% achieved a partial response and 46% had stable disease. ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdu157","ISSN":"15698041","PMID":"24737778","abstract":"BACKGROUND: Tivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination.\\n\\nPATIENTS AND METHODS: Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360 mg capsules) in combination with gemcitabine (1000 mg/m(2) weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration).\\n\\nRESULTS: Twenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120 mg b.i.d. (n = 4), 240 mg b.i.d. (n = 6) and 360 mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360 mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine.\\n\\nCONCLUSION: The combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma.\\n\\nCLINICALTRIALSGOV IDENTIFIER: NCT00874042.","author":[{"dropping-particle":"","family":"Pant","given":"Shubham","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saleh","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bendell","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Infante","given":"J. R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kurkjian","given":"C. D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moore","given":"K. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kazakin","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abbadessa","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Camacho","given":"L. H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2014"]]},"page":"1416-1421","title":"A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors","type":"article-journal","volume":"25"},"uris":[""]}],"mendeley":{"formattedCitation":"(76)","plainTextFormattedCitation":"(76)","previouslyFormattedCitation":"(76)"},"properties":{"noteIndex":0},"schema":""}(76) More recently cabozantinib was been evaluated in a Phase 2 study in patients with advanced CCA, after progression on first or second line chemotherapy and showed limited activity and significant toxicity ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/cncr.30571","ISBN":"1097-0142 (Electronic) 0008-543X (Linking)","ISSN":"10970142","PMID":"28192597","abstract":"BACKGROUND Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond first-line gemcitabine/platinum-based chemotherapy. A single-arm, phase 2 and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET, was performed for patients with advanced refractory cholangiocarcinoma. METHODS Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib (60 mg orally and daily on a continuous schedule). The primary endpoint was progression-free survival (PFS). Tumor MET expression and plasma biomarkers were evaluated. RESULTS The study enrolled 19 patients with cholangiocarcinoma (female, 68%; median age, 67 years; intrahepatic vs extrahepatic, 84% vs 16%). The median PFS was 1.8 months (95% confidence interval, 1.6-5.4 months), and the median overall survival (OS) was 5.2 months (95% confidence interval, 2.7-10.5 months). Grade 3/4 adverse events occurred in 89% of the patients and included neutropenia (5%), hyperbilirubinemia (5%), epistaxis (5%), bowel perforation (5%), enterocutaneous fistulas (5%), and hypertension (11%). One patient with 3 + MET expression in the tumor stayed on treatment for 278 days, but the MET expression did not correlate with the outcomes in the overall study population. Plasma vascular endothelial growth factor, placental growth factor, and stromal cell-derived factor 1α increased and soluble VEGFR2 and angiopoietin 2 decreased after treatment (all P values < .01). Plasma tissue inhibitor of matrix metalloproteinase 1 was inversely correlated with PFS, and soluble MET (sMET) and interleukin 6 were inversely correlated with OS. CONCLUSIONS In unselected patients with cholangiocarcinoma, cabozantinib demonstrated limited activity and significant toxicity. In the first clinical trial to assess the role of MET inhibition in cholangiocarcinoma, 1 patient with a MET-high tumor had a prolonged benefit from treatment. Baseline plasma soluble MET was associated with OS. Any further development of this drug in cholangiocarcinoma should include a dose reduction and a biomarker-driven approach. Cancer 2017;123:1979-1988. ? 2017 American Cancer Society.","author":[{"dropping-particle":"","family":"Goyal","given":"Lipika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zheng","given":"Hui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yurgelun","given":"Matthew B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abrams","given":"Thomas A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allen","given":"Jill N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cleary","given":"James M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Knowles","given":"Michelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Regan","given":"Eileen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reardon","given":"Amanda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khachatryan","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jain","given":"Rakesh K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nardi","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borger","given":"Darrell R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Duda","given":"Dan G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Andrew X.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2017"]]},"page":"1979-1988","title":"A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma","type":"article-journal","volume":"123"},"uris":[""]}],"mendeley":{"formattedCitation":"(77)","plainTextFormattedCitation":"(77)","previouslyFormattedCitation":"(77)"},"properties":{"noteIndex":0},"schema":""}(77).Some positive data were obtained in vitro with MET?RON dual inhibition ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Cheng CT, Chen YY, Wu RC","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Oncol Rep.","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"1411-1421","title":"MET?RON dual inhibitor, BMS?777607, suppresses cholangiocarcinoma cell growth, and MET?RON upregulation indicates worse prognosis for intra?hepatic cholangiocarcinoma patients","type":"article-journal","volume":"40"},"uris":[""]}],"mendeley":{"formattedCitation":"(78)","plainTextFormattedCitation":"(78)","previouslyFormattedCitation":"(78)"},"properties":{"noteIndex":0},"schema":""}(78).h. Pi3Ki / AKTi / mTORiSome studies show that somatic PIK3CA mutations contribute to the frequent activation of the PI3K/AKT pathway in BTC. But phase II trials with AKT selective inhibitors as MK-2206 have been disappointing. A first-line phase II study with everolimus showed evidence of antitumor activity with 14 out of 27 patients (56%, 95%-CI 35–76), achieving tumour control at 12 weeks. Median PFS was 6.0 months (95%-CI 2.1–11.2) and median OS 9.5 months (95%-CI 5.5–16.6). KRAS mutational status and basal p-AKT might be associated with resistance to treatment. A phase II trial using a PI3K inhibitor, copanlisib (BAY 80-6946) in first-line in combination with chemotherapy is ongoing (NCT02631590). ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1158/2159-8290.CD-17-0245","ISBN":"1614463468","ISSN":"21598290","PMID":"28818953","abstract":"Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review. SIGNIFICANCE: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. (C) 2017 AACR.","author":[{"dropping-particle":"","family":"Valle","given":"Juan W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamarca","given":"Angela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goyal","given":"Lipika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barriuso","given":"Jorge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Andrew X.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer Discovery","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"943-962","title":"New horizons for precision medicine in biliary tract cancers","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(79)","plainTextFormattedCitation":"(79)","previouslyFormattedCitation":"(79)"},"properties":{"noteIndex":0},"schema":""}(79)i. NTRKiRecently,?larotrectinib has received FDA agnostic tumour?approval for?TRK fusion cancer. This drug?is a selective TRK inhibitor, and has demonstrated an overall response rate (ORR) of 75% with a favourable safety profile ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa1714448","ISBN":"0960-7692 (Print)\\r0960-7692 (Linking)","ISSN":"0028-4793","PMID":"12100414","abstract":"OBJECTIVE: To assess the feasibility of ultrasound identification of aortic valve anatomy in the fetus, with particular emphasis on the detection of bicuspid aortic valve.\\n\\nMETHODS: This study was a prospective analysis of 21 fetuses with prenatally diagnosed congenital left heart obstructive lesions and 45 normal fetuses undergoing routine ultrasound evaluated at a tertiary referral center. These fetuses underwent detailed echocardiography, including the study of the aortic valve on a targeted short-axis view of the right ventricle. Necropsies or postnatal echocardiograms were available for confirmation of the diagnosis in all cases.\\n\\nRESULTS: Aortic cusps and commissures were satisfactorily visualized in 38/45 (84%) normal fetuses and in 18/21 (86%) fetuses with congenital heart disease. The aortic valve was correctly defined as bicuspid in one normal fetus and in six fetuses with congenital heart disease. In two fetuses with a positive family history, the bicuspid aortic valve was isolated. There was one incorrect diagnosis (a unicuspid unicommissural valve diagnosed prenatally as a bicuspid aortic valve in a fetus with severe aortic stenosis) and one false-positive diagnosis in a fetus diagnosed with a coarctation and a bicuspid aortic valve late in the third trimester of pregnancy and in which both anomalies were not confirmed at neonatal echocardiography.\\n\\nCONCLUSIONS: This study demonstrated that aortic valve anatomy can be satisfactorily assessed in fetuses with and without left heart obstructive lesions. We believe that a detailed search for a bicuspid aortic valve should be attempted in all patients referred for a positive family history of congenital heart disease, in general, and of left ventricle outflow tract obstruction or bicuspid aortic valve, in particular. In fact, the presence of an asymptomatic bicuspid aortic valve has been demonstrated to represent an important factor predisposing to the development of bacterial endocarditis and dissecting aortic aneurysm late in adult life. Therefore, an early detection of such an anomaly may contribute to ensure a longer symptom-free lifespan of individuals with the most common cardiac anomaly at birth.","author":[{"dropping-particle":"","family":"Drilon","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laetsch","given":"Theodore W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kummar","given":"Shivaani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"DuBois","given":"Steven G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lassen","given":"Ulrik N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Demetri","given":"George 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P.S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Patrick C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raez","given":"Luis E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hechtman","given":"Jaclyn F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benayed","given":"Ryma","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladanyi","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuch","given":"Brian 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Medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2018"]]},"page":"731-739","title":"Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children","type":"article-journal","volume":"378"},"uris":[""]}],"mendeley":{"formattedCitation":"(80)","plainTextFormattedCitation":"(80)","previouslyFormattedCitation":"(80)"},"properties":{"noteIndex":0},"schema":""}(80).?Although?just 2 CCA cases were included in?this trial, and NTRK fusion rate?reported?in CCA is less than 5%, testing patients for this aberration when drug is available seems reasonable.??j.?BETi / HDACiThe bromodomain and extra terminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed as?potent anticancer drugs by the inhibition?of MYC transcription ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cell.2011.08.017","ISBN":"0092-8674","ISSN":"00928674","PMID":"21889194","abstract":"MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc. PaperFlick: ? 2011 Elsevier Inc.","author":[{"dropping-particle":"","family":"Delmore","given":"Jake E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Issa","given":"Ghayas C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lemieux","given":"Madeleine E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rahl","given":"Peter B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shi","given":"Junwei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobs","given":"Hannah M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kastritis","given":"Efstathios","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilpatrick","given":"Timothy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paranal","given":"Ronald M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Qi","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chesi","given":"Marta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schinzel","given":"Anna C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McKeown","given":"Michael R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heffernan","given":"Timothy P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vakoc","given":"Christopher R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsagel","given":"P. 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This could represent an active therapy in CCA patients since?upregulation of MYC?seems to be as a?result of the?recurrent mutations in the SWI/SNF?chromatin-modifying complex components (as ARID1A/B/2, PBRM1)?enzymes and in the TGFbeta genes which are commonly found?in CCA ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ng.3375","ISBN":"1546-1718 (Electronic)\\r1061-4036 (Linking)","ISSN":"15461718","PMID":"26258846","abstract":"The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.","author":[{"dropping-particle":"","family":"Nakamura","given":"Hiromi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arai","given":"Yasuhito","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Totoki","given":"Yasushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shirota","given":"Tomoki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Elzawahry","given":"Asmaa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kato","given":"Mamoru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hama","given":"Natsuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hosoda","given":"Fumie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Urushidate","given":"Tomoko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohashi","given":"Shoko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hiraoka","given":"Nobuyoshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ojima","given":"Hidenori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shimada","given":"Kazuaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okusaka","given":"Takuji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kosuge","given":"Tomoo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Shinichi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shibata","given":"Tatsuhiro","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Genetics","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2015"]]},"page":"1003-1010","title":"Genomic spectra of biliary tract cancer","type":"article-journal","volume":"47"},"uris":[""]}],"mendeley":{"formattedCitation":"(7)","plainTextFormattedCitation":"(7)","previouslyFormattedCitation":"(7)"},"properties":{"noteIndex":0},"schema":""}(7).?On the other hand, recurrent aberrations both?in the chromatin-modifiers and in?the deubiquiting enzyme BAP1, as well as epigenetic alterations in DNA/Histone me/demethylation enzymes like?EZH2 and TET1,?are associated in CCA?with a DNA hypermethylation phenotype.?At least one DNA hypermethylation promoter of a tumour suppressor gene is present in 85% cases ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/modpathol.3800287","ISBN":"0893-3952 (Print)\\n0893-3952 (Linking)","ISSN":"08933952","PMID":"15467712","abstract":"Recent studies indicate that tumor suppressor genes can be epigenetically silenced through promoter hypermethylation. To further understand epigenetic alterations in cholangiocarcinoma, we have studied the methylation profiles of 12 candidate tumor suppressor genes (APC, E-cadherin/CDH1, MGMT, RASSF1A, GSTP, RAR-beta, p14ARF, p15INK4b, p16INK4a, p73, hMLH1 and DAPK) in 72 cases of cholangiocarcinoma, including equal number cases of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. A total of 10 cases of benign biliary epithelia were included as controls. The methylation status of tumor suppressor genes was analyzed using methylation-specific PCR. We found that 85% of all cholangiocarcinomas had methylation of at least one tumor suppressor gene. The frequency of tumor suppressor gene methylation in cholangiocarcinoma was: RASSF1A (65%), p15INK4b (50%), p16INK4a (50%), APC (46%), E-cadherin/CDH1 (43%), p14(ARF) (38%), p73 (36%), MGMT (33%), hMHL1 (25%), GSTP (14%), RAR-beta (14%) and DAPK (3%). Although single tumor suppressor gene methylation can be seen in benign biliary epithelium, methylation of multiple tumor suppressor genes is only seen in cholangiocarcinoma. About 70% (50/72) of the cholangiocarcinomas had three or more tumor suppressor genes methylated and 52% (38/72) of cases had four or more tumor suppressor genes methylated. Concerted methylation of multiple tumor suppressor genes was closely associated with methylation of RASSF1A, p16 and/or hMHL1. Methylation of RASSF1A was more common in extrahepatic cholangiocarcinoma than intrahepatic cholangiocarcinoma (83 vs 47%, P=0.003) while GSTP was more frequently seen in intrahepatic compared to extrahepatic cholangiocarcinoma (31 vs 6%, P=0.012). Our study indicates that methylation of promoter CpG islands of tumor suppressor genes is a common epigenetic event in cholangiocarcinoma. Based on distinct methylation profiles, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma are two closely related but biologically unique neoplastic processes. Taking advantage of the unique concurrent methylation profile of multiple genes in cholangiocarcinoma may facilitate the distinction of cholangiocarcinoma from benign biliary epithelium in clinical settings.","author":[{"dropping-particle":"","family":"Yang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"House","given":"Michael G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guo","given":"Mingzhou","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herman","given":"James G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clark","given":"Douglas P.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Modern Pathology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2005"]]},"page":"412-420","title":"Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma","type":"article-journal","volume":"18"},"uris":[""]}],"mendeley":{"formattedCitation":"(82)","plainTextFormattedCitation":"(82)","previouslyFormattedCitation":"(82)"},"properties":{"noteIndex":0},"schema":""}(82). Therefore, Hypomethylating?Agents as azacytidine or EZH2 inhibitors?(e.g., tazemetostat) could represent an attractive strategy in this subgroup.?k.???????BRCAi BRCA1/2 mutations occur at 1–7% across BTCs (most frequently BRCA2 in GBC).?BRCA1 and BRCA2 cholangiocarcinoma mutated cases?with prolonged PFS to PARP?inhibitors?have been reported ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1634/theoncologist.2016-0415","ISSN":"1083-7159","PMID":"28487467","abstract":"BACKGROUND Biliary tract malignancies, in particular cholangiocarcinomas (CCA), are rare tumors that carry a poor prognosis. BRCA2 mutation carriers have an increased risk of developing CCA with a reported relative risk of ～5 according to the Breast Cancer Linkage Consortium. In addition to this risk, there are potential therapeutic implications in those harboring somatic and/or germline (GL) BRCA mutations. Therefore, it is important to define the clinical characteristics of GL/somatic BRCA1/2 variants in CCA patients. MATERIALS AND METHODS We performed a multicenter retrospective analysis of CCA patients diagnosed between January 2000 and December 2013 with GL or somatic variants in BRCA1/2 genes detected by GL mutations testing and/or by tumor next generation sequencing. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures, and systemic chemotherapy or radiation were extracted from patients' records. RESULTS Overall, 18 cases were identified: 5 carriers of GL BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic variations (7 BRCA1; 6 BRCA2). Mean age at diagnosis was 60, SD ± 10 years (range 36-75 years), with male and female prevalence rates of 61.2% and 38.8%, respectively. Stage at diagnosis was I (n = 4), II (n = 3), III (n = 3), and IV (n = 8). Six patients had extrahepatic CCA and the rest intrahepatic CCA. Thirteen patients received platinum-based therapy and four were treated with poly ADP ribose polymerase inhibitors, of whom one experienced sustained disease response with a progression-free survival of 42.6 months. Median overall survival from diagnosis for patients with stage I/II in this study was 40.3 months (95% confidence interval [CI], 6.73-108.15) and with stages III/IV was 25 months (95% CI, 15.23-40.57). CONCLUSION BRCA-associated CCA is uncommon. This multicenter retrospective study provides a thorough clinical analysis of a BRCA-associated CCA cohort, which can serve as a benchmark for future development and design of expanded analyses and clinical trials. IMPLICATIONS FOR PRACTICE BRCA-associated CCA is uncommon but a very important subtype of hepatic malignancies, due to its rising prevalence. Better clinical characterization of this subtype might allow application of targeted therapy for CCA patients with germline or somatic mutations in BRCA1/2 genes, especially due to previously reported success of such therapies in other BRCA…","author":[{"dropping-particle":"","family":"Golan","given":"Talia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raitses‐Gurevich","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kelley","given":"Robin K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bocobo","given":"Andrea G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borgida","given":"Ayelet","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shroff","given":"Rachna T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holter","given":"Spring","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallinger","given":"Steven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahn","given":"Daniel H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aderka","given":"Dan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Apurva","given":"Jain","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bekaii‐Saab","given":"Tanois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friedman","given":"Eitan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Javle","given":"Milind","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Oncologist","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2017"]]},"page":"804-810","title":"Overall Survival and Clinical Characteristics of BRCA‐Associated Cholangiocarcinoma: A Multicenter Retrospective Study","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(83)","plainTextFormattedCitation":"(83)","previouslyFormattedCitation":"(83)"},"properties":{"noteIndex":0},"schema":""}(83) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3748/wjg.v22.i46.10254","ISSN":"22192840","PMID":"28028375","abstract":"Gallbladder cancer (GBC), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. The late diagnosis and abysmal prognosis present challenges to treatment. The overall 5-year survival rate for metastatic GBC patients is extremely low. BRCA1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European Commission for the treatment of ovarian cancer with any BRCA1/2 mutations. The first case of a BRCA1-mutated GBC patient who responded to olaparib treatment is reported here.","author":[{"dropping-particle":"","family":"Xie","given":"Yuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiang","given":"Yan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Xiao Bo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"An Qiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zheng","given":"Yong Chang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wan","given":"Xue Shuai","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sang","given":"Xin Ting","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Kai","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Da Dong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Jia Jia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Fu Gen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhao","given":"Hai Tao","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"World Journal of Gastroenterology","id":"ITEM-1","issue":"46","issued":{"date-parts":[["2016"]]},"page":"10254-10259","title":"Response of BRCA1-mutated gallbladder cancer to olaparib: A case report","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(84)","plainTextFormattedCitation":"(84)","previouslyFormattedCitation":"(84)"},"properties":{"noteIndex":0},"schema":""}(84). Finding of this mutation because of a suspicious family history but also because of the use of molecular panels?might be beneficial to?these?patients and their family members, enabling assessment of their cancer development risk and the effectiveness of new anti-cancer drugs as PARPi but also of the traditional?platine agents as happens in other solid tumours. Other?predictive responsive factors to PPARi such?ARID1A mutation, common in CCA, have also?been suggested ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1158/2159-8290.CD-14-0849","ISBN":"2159-8290 (Electronic)\\r2159-8274 (Linking)","ISSN":"21598290","PMID":"26069190","abstract":"UNLABELLED: ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.\\n\\nSIGNIFICANCE: ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors.","author":[{"dropping-particle":"","family":"Shen","given":"Jianfeng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peng","given":"Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wei","given":"Leizhen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Wei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Lin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lan","given":"Li","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kapoor","given":"Prabodh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ju","given":"Zhenlin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mo","given":"Qianxing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shih","given":"Ie Ming","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Uray","given":"Ivan P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wu","given":"Xiangwei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brown","given":"Powel H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shen","given":"Xuetong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mills","given":"Gordon B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peng","given":"Guang","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer discovery","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2015"]]},"page":"752-767","title":"ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors","type":"article-journal","volume":"5"},"uris":[""]}],"mendeley":{"formattedCitation":"(85)","plainTextFormattedCitation":"(85)","previouslyFormattedCitation":"(85)"},"properties":{"noteIndex":0},"schema":""}(85).l.?????????Immunotherapy: checkpoint modulators (CTLA4, PD1/PDL1, CD40) and adoptive cell therapyAntibodies blocking the interaction of PD-1 and CTLA-4 with their specific ligands have been successful in the treatment of several hematological and solid malignancies and their evaluation is also emerging in CCA ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.21037/tgh.2018.07.02","ISSN":"24151289","PMID":"30148225","abstract":"Cholangiocarcinoma is one of the epithelial cancers with the poorest prognosis and the narrowest therapeutic choice in humans. Compared with other cancer types, cholangiocarcinoma has been often neglected by oncology and liver research studies, thereby leaving many issues unsolved. Apart from the early and marked aggressiveness, one of the main reasons of the still unsatisfying clinical management of cholangiocarcinoma is its wide tumor heterogeneity needing more than other diseases a 'precision medicine' approach. In this regard, in the last few years there has been an awakening of interest aimed at dissecting the complex molecular and genomic profile of cholangiocarcinoma. Thus, a range of molecular players have been recently identified as putative mechanistic determinants of cholangiocarcinoma invasiveness, encompassing tyrosine kinase receptors, metabolic enzymes, transcription factors, small GTPases, ubiquitin ligases, and chromatin-remodelling proteins, whose aberrant expression may derive from stochastic mutations as well as from pro-oncogenic paracrine signals released by the stromal microenvironment, which is particularly exuberant in cholangiocarcinoma. Herein, we sought to overview the most relevant observations unravelling the genomic landscape of cholangiocarcinoma, and the prognostic and predictive biomarkers that consequently have been emerging. Then, we will discuss innovative treatment approaches derived from conventional chemotherapy, targeted therapies, antiangiogenic therapies and immunotherapy, and how they are opening new avenues towards a precision medicine in cholangiocarcinoma.","author":[{"dropping-particle":"","family":"Pellino","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Loupakis","given":"Fotios","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cadamuro","given":"Massimiliano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dadduzio","given":"Vincenzo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fassan","given":"Matteo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guido","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cillo","given":"Umberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Indraccolo","given":"Stefano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fabris","given":"Luca","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Translational Gastroenterology and Hepatology","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"40-40","title":"Precision medicine in cholangiocarcinoma","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"(86)","plainTextFormattedCitation":"(86)","previouslyFormattedCitation":"(86)"},"properties":{"noteIndex":0},"schema":""}(86). PD-1/PD-L1 and CTLA-4 checkpoints are negative regulators of local inflammatory response against tumor cells ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1021/es201524q","ISBN":"1260800040937","ISSN":"0013936X","PMID":"21710986","abstract":"In the current study, the toxicity mechanism of nanosized CuO (nCuO) to the freshwater ciliated protozoa Tetrahymena thermophila was studied. Changes in fatty acid profile, lipid peroxidation metabolites and reactive oxygen species (ROS) were measured. Bulk CuO and CuSO(4) served as controls for size and solubility and 3,5-dichorophenol (3,5-DCP) as a control for a chemical known to directly affect the membrane composition. Exposure to all copper compounds induced the generation of ROS, whereas nCuO was most potent. The latter effect was not solely explained by solubilized Cu-ions and was apparently particle-related. 24 h exposure of protozoa to 80 mg/L of nCuO (EC50) significantly decreased the proportion of two major unsaturated fatty acids (UFA) (C18:3 cis-6,9,12, C18:2 cis-9,12), while it increased the relative amount of two saturated fatty acids (SFA) (C18:0, C16:0). Analogous effect was not observed when protozoa were exposed to equitoxic suspensions of bulk CuO, Cu-ions or 3,5-DCP. As changes in the UFA:SFA upon exposure of protozoa to nCuO were not detected at 2 h exposure and no simultaneous dose- or time-dependent lipid peroxidation occurred, it is likely that one of the adaptation mechanisms of protozoa to nCuO was lowering membrane fluidity by the inhibition of de novo synthesis of fatty acid desaturases. This is the first study of the effects of nanoparticles on the membrane fatty acid composition.","author":[{"dropping-particle":"","family":"Topalian","given":"SL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hodi","given":"FS","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England journal of Medicine","id":"ITEM-1","issued":{"date-parts":[["2012"]]},"title":"Safety, activity, and immune correlates of anti–PD-1 antibody in cancer","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(87)","plainTextFormattedCitation":"(87)","previouslyFormattedCitation":"(87)"},"properties":{"noteIndex":0},"schema":""}(87). Discovering specific histological and molecular biomarkers predictive of response to immune checkpoint inhibitors (ICI) is the current challenge ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.21037/tgh.2018.07.02","ISSN":"24151289","PMID":"30148225","abstract":"Cholangiocarcinoma is one of the epithelial cancers with the poorest prognosis and the narrowest therapeutic choice in humans. Compared with other cancer types, cholangiocarcinoma has been often neglected by oncology and liver research studies, thereby leaving many issues unsolved. Apart from the early and marked aggressiveness, one of the main reasons of the still unsatisfying clinical management of cholangiocarcinoma is its wide tumor heterogeneity needing more than other diseases a 'precision medicine' approach. In this regard, in the last few years there has been an awakening of interest aimed at dissecting the complex molecular and genomic profile of cholangiocarcinoma. Thus, a range of molecular players have been recently identified as putative mechanistic determinants of cholangiocarcinoma invasiveness, encompassing tyrosine kinase receptors, metabolic enzymes, transcription factors, small GTPases, ubiquitin ligases, and chromatin-remodelling proteins, whose aberrant expression may derive from stochastic mutations as well as from pro-oncogenic paracrine signals released by the stromal microenvironment, which is particularly exuberant in cholangiocarcinoma. Herein, we sought to overview the most relevant observations unravelling the genomic landscape of cholangiocarcinoma, and the prognostic and predictive biomarkers that consequently have been emerging. Then, we will discuss innovative treatment approaches derived from conventional chemotherapy, targeted therapies, antiangiogenic therapies and immunotherapy, and how they are opening new avenues towards a precision medicine in cholangiocarcinoma.","author":[{"dropping-particle":"","family":"Pellino","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Loupakis","given":"Fotios","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cadamuro","given":"Massimiliano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dadduzio","given":"Vincenzo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fassan","given":"Matteo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guido","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cillo","given":"Umberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Indraccolo","given":"Stefano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fabris","given":"Luca","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Translational Gastroenterology and Hepatology","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"40-40","title":"Precision medicine in cholangiocarcinoma","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"(86)","plainTextFormattedCitation":"(86)","previouslyFormattedCitation":"(86)"},"properties":{"noteIndex":0},"schema":""}(86). The immunohistochemical expression of PD-L1 is considered a biomarker associated with response to anti PD-L1 antibodies and a better OS in a number of tumour types ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1158/1078-R-13-3271","ISBN":"4105021958","ISSN":"15573265","PMID":"24714771","abstract":"PURPOSE Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. RESULTS Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. CONCLUSIONS Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. Clin Cancer Res; 20(19); 5064-74. ?2014 AACR.","author":[{"dropping-particle":"","family":"Taube","given":"Janis M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klein","given":"Alison","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brahmer","given":"Julie R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Haiying","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pan","given":"Xiaoyu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Jung H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Lieping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pardoll","given":"Drew M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Topalian","given":"Suzanne L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anders","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Cancer Research","id":"ITEM-1","issue":"19","issued":{"date-parts":[["2014"]]},"page":"5064-5074","title":"Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy","type":"article-journal","volume":"20"},"uris":[""]}],"mendeley":{"formattedCitation":"(88)","plainTextFormattedCitation":"(88)","previouslyFormattedCitation":"(88)"},"properties":{"noteIndex":0},"schema":""}(88) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/cncr.29824","ISBN":"0002-9297","ISSN":"10970142","PMID":"26695839","abstract":"BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is associated with poor survival. This study compared the outcomes of patients with unresectable ICC treated with hepatic arterial infusion (HAI) plus systemic chemotherapy (SYS) with the outcomes of patients treated with SYS alone. METHODS Consecutive patients with ICC were retrospectively reviewed. Clinicopathologic data were reviewed. Survival rates were compared by Kaplan-Meier analysis and log-rank testing. RESULTS Between January 2000 and August 2012, 525 patients with ICC were evaluated at Memorial Sloan Kettering Cancer Center, and 236 patients with unresectable tumors (locally advanced or metastatic) were analyzed. Disease was confined to the liver in 104 patients, who underwent treatment with combined HAI and SYS (n = 78 or 75%) or SYS alone (n = 26 or 25%). The response rate in the combined group was better than the rate in the group receiving SYS alone, although this did not reach statistical significance (59% vs 39%, P = .11). Overall survival for the combined group was longer than overall survival for the patients who received SYS alone (30.8 vs 18.4 months, P < .001), and this difference was maintained when patients with portal lymph node disease were included in the survival analysis (29.6 months with HAI and SYS [n = 93] vs 15.9 months with SYS [n = 74], P < .001). Eight patients who initially presented with unresectable tumors responded enough to undergo complete resection and had a median overall survival of 37 months (range, 10.4-92.3 months). CONCLUSIONS In patients with unresectable ICC confined to the liver or with limited regional nodal disease, a combination of SYS and HAI chemotherapy is associated with greater survival than SYS alone. Cancer 2016;122:758-765. ? 2015 American Cancer Society.","author":[{"dropping-particle":"","family":"Konstantinidis","given":"Ioannis T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koerkamp","given":"Bas Groot","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Do","given":"Richard K.G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"G?nen","given":"Mithat","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fong","given":"Yuman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allen","given":"Peter J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Angelica","given":"Michael I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kingham","given":"T. Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dematteo","given":"Ronald P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klimstra","given":"David S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kemeny","given":"Nancy E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jarnagin","given":"William R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2016"]]},"page":"758-765","title":"Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone","type":"article-journal","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"(89)","plainTextFormattedCitation":"(89)","previouslyFormattedCitation":"(89)"},"properties":{"noteIndex":0},"schema":""}(89) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.18632/oncotarget.15602","ISSN":"1949-2553","PMID":"28445951","abstract":"// Jacqueline Fontugne 1, 2, 3 , Jérémy Augustin 1 , Ana?s Pujals 1, 3 , Philippe Compagnon 3, 4 , Benoit Rousseau 2, 3, 5 , Alain Luciani 2, 3, 6 , Christophe Tournigand 3, 5 , Daniel Cherqui 7 , Daniel Azoulay 3, 4 , Jean-Michel Pawlotsky 2, 3, 8 , Julien Calderaro 1, 2, 3 1 AP-HP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France 2 INSERM, U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France 3 Université Paris Est Créteil, Créteil, France 4 AP-HP, Groupe Hospitalier Henri Mondor, Département de Chirurgie Hépato-Biliaire et Transplantation Hépatique, Créteil, France 5 AP-HP, Groupe Hospitalier Henri Mondor, Département d’Oncologie Médicale, Créteil, France 6 AP-HP, Groupe Hospitalier Henri Mondor, Département d’Imagerie Médicale, Créteil, France 7 AP-HP, Centre Hépatobiliaire, Service de Chirurgie Hépatobiliaire, Hopital Paul Brousse, Créteil, France 8 AP-HP, Groupe Hospitalier Henri Mondor, Service de Virologie, Bactériologie-Hygiène, Mycologie-Parasitologie et Unité Transversale de Traitement des Infections, Créteil, France Correspondence to: Jacqueline Fontugne, email: fontugnej@ Keywords: cholangiocarcinoma, PD-1, PD-L1, immunotherapy Received: August 02, 2016 Accepted: February 12, 2017 Published: February 21, 2017 ABSTRACT Cholangiocarcinoma is an aggressive biliary neoplasm lacking effective therapeutic agents. Immunotherapies targeting the PD-L1/PD-1 immune checkpoint have shown encouraging results in solid and hematologic cancers in clinical trials. Response to these immunomodulators is correlated with PD-L1 expression. Our goal was to characterize PD-L1 expression in intra-hepatic (iCCA) and perihilar (pCCA) cholangiocarcinomas, and to correlate our results with clinicopathological features, density of tumor-infiltrating lymphocytes (TILs) and PD-1 expression. A series of 58 iCCAs and 41 pCCAs was included in the study. PD-L1, PD-1 and CD3 expression was investigated using immunohistochemistry. Density of TILs was evaluated by immunohistochemistry using a quantitative score of CD3-stained intratumoral lymphocytes. PD-L1 expression by neoplastic cells was observed in 9 cases (9%, 5 iCCAs and 4 pCCAs). PD-L1 positive inflammatory cell aggregates were identified in 46% ( n = 46) of the cases (31 iCCAs and 15 pCCAs). PD-L1 expression by either neoplastic or inflammatory cells was associated to high density of CD3-positive TILs ( p = 0.01 and p = 0.005, respectively). The number of PD-L1 posi…","author":[{"dropping-particle":"","family":"Fontugne","given":"Jacqueline","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Augustin","given":"Jérémy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pujals","given":"Ana?s","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Compagnon","given":"Philippe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rousseau","given":"Benoit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luciani","given":"Alain","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tournigand","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cherqui","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Azoulay","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pawlotsky","given":"Jean-Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calderaro","given":"Julien","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Oncotarget","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2017"]]},"title":"PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"(90)","plainTextFormattedCitation":"(90)","previouslyFormattedCitation":"(90)"},"properties":{"noteIndex":0},"schema":""}(90). PD-L1 may be expressed not only on tumor cells, but also on immune infiltrating cells ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1158/1078-R-13-3271","ISBN":"4105021958","ISSN":"15573265","PMID":"24714771","abstract":"PURPOSE Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. RESULTS Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. CONCLUSIONS Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. Clin Cancer Res; 20(19); 5064-74. ?2014 AACR.","author":[{"dropping-particle":"","family":"Taube","given":"Janis M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klein","given":"Alison","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brahmer","given":"Julie R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Haiying","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pan","given":"Xiaoyu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Jung H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Lieping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pardoll","given":"Drew M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Topalian","given":"Suzanne L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anders","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Cancer Research","id":"ITEM-1","issue":"19","issued":{"date-parts":[["2014"]]},"page":"5064-5074","title":"Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy","type":"article-journal","volume":"20"},"uris":[""]}],"mendeley":{"formattedCitation":"(88)","plainTextFormattedCitation":"(88)","previouslyFormattedCitation":"(88)"},"properties":{"noteIndex":0},"schema":""}(88). In the KEYNOTE-028 study, a multicohort phase 1b trial of pembrolizumab monotherapy, 89 patients with biliary tract cancer were evaluated for PD-L1 expression, 37 (42%) had PD-L1-positive tumors; 24 (65%) were enrolled and treated with pembrolizumab with promising results: 4 patients (17%) had a partial response and 4 (17%) had stable disease ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"(16)30304-5","ISBN":"095-9804","ISSN":"0959-8049","abstract":"Background: Expression of PD-L1, ligand to programmed cell death 1 (PD-1) receptor, is associated with poor prognosis in CRC and has been shown to promote invasion of colorectal cancer cells in vitro. Pembrolizumab is a highly selective, humanized monoclonal anti-PD-1 antibody designed to block the interaction between PD-1 and its ligands, thereby enhancing antitumor immune activity. We evaluated the safety and antitumor activity of pembrolizumab in pts with advanced PD-L1-positive CRC enrolled in KEYNOTE-028. Methods: KEYNOTE-028 ( identifier, NCT02054806) is an ongoing, multicohort, phase 1b trial of pembrolizumab for PD-L1- positive advanced solid tumors. Key eligibility criteria for this cohort included advanced adenocarcinoma of the colon or rectum, failure of standard therapy or inability to receive it, PD-L1 expression in {\\textgreater}1{%} of cells in tumor nests or PD-L1-positive stromal bands determined centrally by a prototype IHC assay, ECOG PS 0-1, and absence of autoimmune disease. Pembrolizumab 10 mg/kg is administered every 2 weeks and continued for up to 2 years or until confirmed progression or unacceptable toxicity. Response is assessed every 8 weeks for the first 6 months and then every 12 weeks thereafter. Primary end points are safety, tolerability, and objective response rate (ORR) per RECIST v1.1 by investigator review. Results: Of the 156 screened pts with advanced CRC, 33 (21{%}) had PD-L1-positive tumors. Of these, 23 (70{%}) enrolled between Mar and Jun 2014; 57{%} were men, and median age was 57 years. All but 1 pt received {\\textgreater}1 prior treatment for advanced disease, including 15 (65{%}) who received {\\textgreater}3 prior therapies for recurrent or metastatic disease. In total, 9 (39{%}) pts experienced {\\textgreater}1 treatment-related AE. Only 1 pt experienced a grade {\\textgreater}3 treatment-related AE (grade 3 blood bilirubin increased). No pts died or discontinued because of a treatment-related AE. One pt, who was known to have microsatellite instability high disease, experienced a partial response (ORR, 4{%}; 95{%} CI, 0-22{%}). This patient remains on treatment, and at the time of data cutoff, treatment duration was 46 weeks. Best overall response in the remaining pts was stable disease in 4 (17{%}) pts and progressive disease in 16 (70{%}); 2 pts did not have a postbaseline assessment at the time of analysis. Median treatment duration for the 4 pts with SD, 1 of whom remains on treatment,…","author":[{"dropping-particle":"al","family":"O’Neil B, Wallmark J","given":"Lorente D et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Cancer","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"abstr 502","title":"Pembrolizumab (MK-3475) for patients (pts) with advanced colorectal carcinoma (CRC): Preliminary results from KEYNOTE-028","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(91)","plainTextFormattedCitation":"(91)","previouslyFormattedCitation":"(91)"},"properties":{"noteIndex":0},"schema":""}(91) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.21037/tgh.2018.07.02","ISSN":"24151289","PMID":"30148225","abstract":"Cholangiocarcinoma is one of the epithelial cancers with the poorest prognosis and the narrowest therapeutic choice in humans. Compared with other cancer types, cholangiocarcinoma has been often neglected by oncology and liver research studies, thereby leaving many issues unsolved. Apart from the early and marked aggressiveness, one of the main reasons of the still unsatisfying clinical management of cholangiocarcinoma is its wide tumor heterogeneity needing more than other diseases a 'precision medicine' approach. In this regard, in the last few years there has been an awakening of interest aimed at dissecting the complex molecular and genomic profile of cholangiocarcinoma. Thus, a range of molecular players have been recently identified as putative mechanistic determinants of cholangiocarcinoma invasiveness, encompassing tyrosine kinase receptors, metabolic enzymes, transcription factors, small GTPases, ubiquitin ligases, and chromatin-remodelling proteins, whose aberrant expression may derive from stochastic mutations as well as from pro-oncogenic paracrine signals released by the stromal microenvironment, which is particularly exuberant in cholangiocarcinoma. Herein, we sought to overview the most relevant observations unravelling the genomic landscape of cholangiocarcinoma, and the prognostic and predictive biomarkers that consequently have been emerging. Then, we will discuss innovative treatment approaches derived from conventional chemotherapy, targeted therapies, antiangiogenic therapies and immunotherapy, and how they are opening new avenues towards a precision medicine in cholangiocarcinoma.","author":[{"dropping-particle":"","family":"Pellino","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Loupakis","given":"Fotios","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cadamuro","given":"Massimiliano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dadduzio","given":"Vincenzo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fassan","given":"Matteo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guido","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cillo","given":"Umberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Indraccolo","given":"Stefano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fabris","given":"Luca","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Translational Gastroenterology and Hepatology","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"40-40","title":"Precision medicine in cholangiocarcinoma","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"(86)","plainTextFormattedCitation":"(86)","previouslyFormattedCitation":"(86)"},"properties":{"noteIndex":0},"schema":""}(86). Durable responses were obtained with pembrolizumab in patients with advanced biliary tract cancer expressing PD-L1 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1158/1078-R-13-3271","ISBN":"4105021958","ISSN":"15573265","PMID":"24714771","abstract":"PURPOSE Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. RESULTS Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. CONCLUSIONS Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. Clin Cancer Res; 20(19); 5064-74. ?2014 AACR.","author":[{"dropping-particle":"","family":"Taube","given":"Janis M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klein","given":"Alison","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brahmer","given":"Julie R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Haiying","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pan","given":"Xiaoyu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Jung H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Lieping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pardoll","given":"Drew M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Topalian","given":"Suzanne L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anders","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Cancer Research","id":"ITEM-1","issue":"19","issued":{"date-parts":[["2014"]]},"page":"5064-5074","title":"Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy","type":"article-journal","volume":"20"},"uris":[""]}],"mendeley":{"formattedCitation":"(88)","plainTextFormattedCitation":"(88)","previouslyFormattedCitation":"(88)"},"properties":{"noteIndex":0},"schema":""}(88) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ctrv.2015.11.001","ISBN":"1532-1967 (Electronic)\\r0305-7372 (Linking)","ISSN":"15321967","PMID":"26589760","abstract":"Checkpoint blockades turn on a new paradigm shift in immunotherapy for cancer. Remarkable clinical efficacy, durable response and low toxicity of programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockades have been observed in various malignancies. However, a lot of cancer patients failed to respond to the PD-1/PD-L1 checkpoint blockades. It is crucial to identify a biomarker to predict the response to checkpoint blockades. The overexpression of PD-L1 is an important and widely-explored predictive biomarker for the response to PD-1/PD-L1 antibodies. However PD-L1 staining cannot be used to accurately select patients for PD-1/PD-L1 pathway blockade due to the low prediction accuracy and dynamic changes. Tumor-infiltrating immune cells and molecules in the tumor microenvironment, or along with PD-L1 expression, may be important in predicting clinical benefits of PD-1/PD-L1 checkpoint blockades. Gene analysis has proven to be new approach for judging the potential clinical benefit of immune checkpoint inhibitors, such as mutational landscape and mismatch-repair deficiency. Further preclinical and clinical studies are necessary to carry out before its application in clinical practice. Challenges should be overcome to identify patients accurately who will benefit from PD-1/PD-L1 checkpoint blockades. In this review, we focus on the predictive biomarkers for checkpoint blockades of PD-1/PD-L1 pathway.","author":[{"dropping-particle":"","family":"Meng","given":"Xiangjiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"Zhaoqin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teng","given":"Feifei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xing","given":"Ligang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Jinming","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer Treatment Reviews","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"868-876","title":"Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy","type":"article-journal","volume":"41"},"uris":[""]}],"mendeley":{"formattedCitation":"(92)","plainTextFormattedCitation":"(92)","previouslyFormattedCitation":"(92)"},"properties":{"noteIndex":0},"schema":""}(92)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1245/s10434-016-5101-y","ISBN":"1534-4681 (Electronic)\\r1068-9265 (Linking)","ISSN":"15344681","PMID":"27012989","abstract":"BACKGROUND: Program death 1 (PD-1) and its ligand (PD-L1) have been identified as potential therapeutic targets for solid and hematologic malignancies. The current study aimed to assess PD-L1 expression in intrahepatic cholangiocarcinoma (ICC) and relate clinical outcomes to its expression.\\n\\nMETHODS: Formalin-fixed, paraffin-embedded tumor specimens were obtained for patients undergoing surgery at Johns Hopkins Hospital between 1991 and 2011. Immunohistochemistry was used to assess PD-L1 expression in tumor-associated macrophages (TAMs) and within the tumor front (TF).\\n\\nRESULTS: Of 54 tumor samples analyzed, 34 stained positive for PD-L1 expression on TAMs (TAMs+), and 39 stained positive for PD-L1 expression on cells within the tumor front (TF+). The TF+ patients were less likely to present with metastatic lymph nodes (N1 patients: 26.7 vs 7.7 %; p = 0.011), whereas all tumors with intrahepatic metastasis failed to demonstrate staining for PD-L1 around the tumor front (p = 0.020). Patients with tumors shown to be TAMs+ were less likely to present with multiple lesions (35.0 vs 8.8 %; p = 0.017). Patients with tumors exhibiting PD-L1 expression around the tumor front demonstrated a worse overall survival than TF patients (p = 0.008). Multivariable analysis showed that patients with tumors staining for PD-L1 in the tumor front had a 59.5 % reduced survival (TF- vs TF+: time ratio, 0.405; 95 % confidence interval, 0.215-0.761; p = 0.005).\\n\\nCONCLUSION: Expression of PD-L1 was noted among a majority of patients, and PD-L1 expression within the tumor front was associated with a 60 % decreased survival. Future clinical trials are necessary to assess the safety and efficacy of anti-PD-L1 therapies among patients with ICC.","author":[{"dropping-particle":"","family":"Gani","given":"Faiz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagarajan","given":"Neeraja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Yuhree","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Qingfeng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luan","given":"Lan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhaijjee","given":"Feriyl","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anders","given":"Robert A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pawlik","given":"Timothy M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Surgical Oncology","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"2610-2617","title":"Program Death 1 Immune Checkpoint and Tumor Microenvironment: Implications for Patients With Intrahepatic Cholangiocarcinoma","type":"article-journal","volume":"23"},"uris":[""]}],"mendeley":{"formattedCitation":"(93)","plainTextFormattedCitation":"(93)","previouslyFormattedCitation":"(93)"},"properties":{"noteIndex":0},"schema":""}(93). KEYNOTE-158, a phase II basket trial of pembrolizumab in cancer patients including CCA with disease progression on standard therapy, is ongoing. Another phase II trial in progress is investigating durvalumab (anti PD-L1) plus tremelimumab (anti-CTLA-4) with or without paclitaxel in patients with advanced CCA after failure of platinum-based chemotherapy (Immuno-Bil). A promising predictive biomarker of response to ICI is tumor mutational burden (TMB). Tumors with higher TMB have more neoantigens that can be recognized by the immune system ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Steuer CE, Ramalingam SS","given":"Et.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Clin Oncol","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2018"]]},"page":"631-632.","title":"Tumor Mutation Burden: Leading Immunotherapy to the Era of PrecisionNo Title","type":"article-journal","volume":"1"},"uris":[""]}],"mendeley":{"formattedCitation":"(94)","plainTextFormattedCitation":"(94)","previouslyFormattedCitation":"(94)"},"properties":{"noteIndex":0},"schema":""}(94) and, as the TMB increases, PFS rates and ORRs may improve in cancer patients treated with ICI ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Rizvi H, Sanchez-Vega F, La K","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Clin Oncol","id":"ITEM-1","issue":"(7)","issued":{"date-parts":[["2018"]]},"page":"633-641","title":"Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung CancerProfiled With Targeted Next-Generation Sequencing.","type":"article-journal","volume":"1;36"},"uris":[""]}],"mendeley":{"formattedCitation":"(95)","plainTextFormattedCitation":"(95)","previouslyFormattedCitation":"(95)"},"properties":{"noteIndex":0},"schema":""}(95) A randomized, single-centre, phase II study has looked at the association of lenvatinib with pembrolizumab or nivolumab. Fourteen patients with CCA were enrolled; 450 cancer genes, TMB and microsatellite instability (MSI) status were analyzed. This study indicates that combining lenvatinib with PD-1 inhibitors is a promising strategy in advanced CCA with high TMB ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Lin J, Shi W, Zhao S","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"(4_suppl)","issued":{"date-parts":[["2018"]]},"page":"Abstract 500","title":"Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing.","type":"article-journal","volume":"36"},"uris":[""]}],"mendeley":{"formattedCitation":"(96)","plainTextFormattedCitation":"(96)","previouslyFormattedCitation":"(96)"},"properties":{"noteIndex":0},"schema":""}(96). Tumours associated with DNA mismatch repair deficiency (dMMR) or high MSI (MSI-H) accumulate many DNA mutations and have a high level of mutation-associated neoantigens, recognized by immune cells, and potentially candidate for treatment with ICI [18]. MSI has been found in approximately 3% of biliary tract cancers. Pembrolizumab has been approved for patients with advanced disease showing MSI/dMMR regardless of tumor origin. In a phase II trial investigating early efficacy in such patients, 4 patients with CCA were enrolled, with one documented CR and three patients with SD ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1126/science.aan6733","ISBN":"1095-9203 (Electronic) 0036-8075 (Linking)","ISSN":"10959203","PMID":"28596308","abstract":"The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.","author":[{"dropping-particle":"","family":"Le","given":"Dung T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Durham","given":"Jennifer N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Kellie N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Hao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartlett","given":"Bjarne R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aulakh","given":"Laveet K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lu","given":"Steve","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kemberling","given":"Holly","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilt","given":"Cara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luber","given":"Brandon S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wong","given":"Fay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Azad","given":"Nilofer S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rucki","given":"Agnieszka A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laheru","given":"Dan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Donehower","given":"Ross","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zaheer","given":"Atif","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fisher","given":"George A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crocenzi","given":"Todd S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"James J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Greten","given":"Tim F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Duffy","given":"Austin G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ciombor","given":"Kristen K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eyring","given":"Aleksandra D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lam","given":"Bao H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Joe","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kang","given":"S. 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Tumor microenvironment seems implicated in the response to ICI and tumor-infiltrating lymphocytes (TILs) have a major role in this. A recent study analyzed the correlation in 39 cancer patients between the concentration of TILs in the tumor environment and the response to ICI and demonstrated that quantifying TILs is a prescreening strategy that may help to select patients for ICI therapy in early clinical trials ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Martin-Liberal J., Pagliuca F, Hierro C","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"title":"Tumor infiltrating lymphocytes (TILs) and PDL1 expression as prescreening enrichment biomarkers of clinical benefit to immune checkpoint inhibitors (CI) in early clinical trials (ECT)","type":"article-journal","volume":"29 (suppl_"},"uris":[""]}],"mendeley":{"formattedCitation":"(98)","plainTextFormattedCitation":"(98)","previouslyFormattedCitation":"(98)"},"properties":{"noteIndex":0},"schema":""}(98). An emerging immunological treatment strategy includes Adoptive Cell therapy (ACT). Patient’s T-cells are extracted from a tumour biopsy or peripheral blood, modified, expanded in vitro, and then reinfused into the patient after host lymphodepletion. In BTC, the evidence for use of ACT is limited to case reports or small case series of patients treated in single-arm phase II studies ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000488997","ISSN":"22965262","author":[{"dropping-particle":"","family":"Tariq","given":"Noor Ul Ain","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vogel","given":"Arndt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McNamara","given":"Mairead G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valle","given":"Juan W.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Oncology Research and Treatment","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"298-304","title":"Biliary Tract Cancer: Implicated Immune-Mediated Pathways and Their Associated Potential Targets","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(99)","plainTextFormattedCitation":"(99)","previouslyFormattedCitation":"(99)"},"properties":{"noteIndex":0},"schema":""}(99). Another potential target for cancer immunotherapy is CD40, a costimulatory protein found on antigen presenting cells, required for their activation and for presenting the antigens to T-cells. Agonistic anti-CD40 has been shown to induce T-cell antitumor responses in mice ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1053/j.seminoncol.2010.09.002","ISBN":"1532-8708 (Electronic)\\r0093-7754 (Linking)","ISSN":"00937754","PMID":"21074067","abstract":"CD40 is a costimulatory molecule widely expressed by immune cells and by neoplastic cells of different histotypes. Engagement of surface CD40 mediates different effects depending on cell type and microenvironment. In particular, CD40 expression on immune cells regulates humoral and cellular immunity, while it has apoptotic and antiproliferative activity on selected neoplastic cells. Thus, CD40 targeting may indirectly affect tumor growth through the activation of immune cells and/or directly by mediating cytotoxic effects on neoplastic cells. Preliminary findings emerging from clinical trials indicate that antibodies to CD40 can induce immune modulation and clinical responses in cancer patients. ? 2010 Elsevier Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Fonsatti","given":"Ester","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maio","given":"Michele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Altomonte","given":"Maresa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hersey","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Seminars in Oncology 37","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"page":"517-523","title":"Biology and clinical applications of CD40 in cancer treatment","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(100)","plainTextFormattedCitation":"(100)","previouslyFormattedCitation":"(100)"},"properties":{"noteIndex":0},"schema":""}(100) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3109/08830185.2012.698338","ISBN":"1563-5244 (Electronic) 0883-0185 (Linking)","ISSN":"08830185","PMID":"22804570","abstract":"Agonistic anti-CD40 antibody is a potent stimulator of anti-tumor immune responses due to its action on both immune and tumor cells. It has the ability to \" precondition \" dendritic cells, allowing them to prime effective cytotoxic T-cell responses. Thus, anti-CD40 antibody provides an ideal therapy for combination with traditional cancer treatments (i.e., chemotherapy, surgery) in order to elicit immune-mediated anti-tumor effects. This review summarizes the mechanisms of action of agonistic anti-CD40, the use of mouse models to investigate its effects and combinations with other therapies in vivo, and current clinical trials combining humanized anti-CD40 antibody with chemotherapy and/or other immunotherapies.","author":[{"dropping-particle":"","family":"Khong","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Delia J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nowak","given":"Anna K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lake","given":"Richard A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robinson","given":"Bruce W.S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Reviews of Immunology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2012"]]},"page":"246-266","title":"The use of agonistic anti-CD40 therapy in treatments for cancer","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"(101)","plainTextFormattedCitation":"(101)","previouslyFormattedCitation":"(101)"},"properties":{"noteIndex":0},"schema":""}(101), which encourages its clinical testing as a cancer treatment ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2006.08.3311","ISBN":"1527-7755 (Electronic)","ISSN":"0732183X","PMID":"17327609","abstract":"PURPOSE: The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study. PATIENTS AND METHODS: Patients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response. RESULTS: Twenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. Dose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MTD was estimated as 0.2 mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocytes, monocytes, platelets, D-dimer and liver function tests were observed 24 to 48 hours after infusion. Four patients with melanoma (14% of all patients and 27% of melanoma patients) had objective partial responses at restaging (day 43). CP-870,893 infusion resulted in transient depletion of CD19+ B cells in blood (93% depletion at the MTD for < 1 week). Among B cells remaining in blood, we found a dose-related upregulation of costimulatory molecules after treatment. CONCLUSION: The CD40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity. Further studies of repeated doses of CP-870,893 alone and in combination with other antineoplastic agents are warranted.","author":[{"dropping-particle":"","family":"Vonderheide","given":"Robert H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Flaherty","given":"Keith T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khalil","given":"Magi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stumacher","given":"Molly S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bajor","given":"David L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hutnick","given":"Natalie A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sullivan","given":"Patricia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mahany","given":"J. 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Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.","author":[{"dropping-particle":"","family":"Beatty","given":"Gregory L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chiorean","given":"Elena G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fishman","given":"Matthew P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saboury","given":"Babak","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teitelbaum","given":"Ursina R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"Weijing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huhn","given":"Richard D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"Wenru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Dongguang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharp","given":"Leslie L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Torigian","given":"Drew A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Dwyer","given":"Peter J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vonderheide","given":"Robert H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Science","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"title":"CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(49)","plainTextFormattedCitation":"(49)","previouslyFormattedCitation":"(49)"},"properties":{"noteIndex":0},"schema":""}(49).Locoregional treatmentsA high proportion of patients with cholangiocarcinoma have disease confined to the liver. This may be the case for tumor at a locally-advanced stage, non-resectable due to surgical difficulties (mainly vascular or biliary extension of the tumor, as frequently seen in both intrahepatic and perihilar CCA), or with a metastatic extension or recurrence involving only the liver. Liver locoregional treatments have thus been studied mostly for iCCA.a. Intra-arterial hepatic therapyIntra-arterial hepatic therapy refers to treatments delivered through the hepatic arteries to improve the access to the tumor due to the preferential arterial blood supply of liver tumors. Three main approaches have been tested in CCA: Hepatic Artery Infusion (HAI): consists of the injection of chemotherapeutic agents directly into the hepatic artery, usually in repeated cycles similar to systemic chemotherapy.Trans-arterial Chemo-embolization (TACE): consists of the injection of chemotherapeutic agents mixed the oily contrast-agent lipiodol or loaded into drug-eluting beads, followed by embolic agents (gelatin-sponge or calibrated beads).Selective Internal Radiation Therapy (SIRT): also known as radioembolization, this consists of the injection of a radio-isotope (usually Yttrium-90) loaded on to glass or resin microspheres.Selected studies of the 3 strategies are summarized in Table 3, focusing on prospective or comparative studies when available ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdp029","ISBN":"1569-8041 (Electronic)\\r0923-7534 (Linking)","ISSN":"09237534","PMID":"19491285","abstract":"BACKGROUND: This study reports the results of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (dex) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) and investigates dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor vascularity as a biomarker of outcome.\\n\\nPATIENTS AND METHODS: Thirty-four unresectable patients (26 ICC and eight HCC) were treated with HAI FUDR/dex. Radiologic dynamic and pharmacokinetic parameters related to tumor perfusion were analyzed and correlated with response and survival.\\n\\nRESULTS: Partial responses were seen in 16 patients (47.1%); time to progression and response duration were 7.4 and 11.9 months, respectively. Median follow-up and median survival were 35 and 29.5 months, respectively; 2-year survival was 67%. DCE-MRI data showed that patients with pretreatment integrated area under the concentration curve of gadolinium contrast over 180 s (AUC 180) >34.2 mM.s had a longer median survival than those with AUC 180 <34 mM.s (35.1 versus 19.1 months, P = 0.002). Decreased volume transfer exchange between the vascular space and extracellular extravascular space (-DeltaK(trans)) and the corresponding rate constant (-Deltak(ep)) on the first post-treatment scan both predicted survival.\\n\\nCONCLUSIONS: In patients with unresectable primary liver cancer, HAI therapy can be effective and safe. Pretreatment and early post-treatment changes in tumor perfusion characteristics may predict treatment outcome.","author":[{"dropping-particle":"","family":"Jarnagin","given":"W. R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"L. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gultekin","given":"D. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"G?nen","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haviland","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shia","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Angelica","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fong","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"DeMatteo","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tse","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blumgart","given":"L. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kemeny","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2009"]]},"page":"1589-1595","title":"Regional chemotherapy for unresectable primary liver cancer: Results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival","type":"article-journal","volume":"20"},"uris":[""]}],"mendeley":{"formattedCitation":"(103)","plainTextFormattedCitation":"(103)","previouslyFormattedCitation":"(103)"},"properties":{"noteIndex":0},"schema":""}(103) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/COC.0b013e3181d2709a","ISBN":"1537-453X (Electronic)\\r0277-3732 (Linking)","ISSN":"02773732","PMID":"20177362","abstract":"OBJECTIVES: No established therapy exists for unresectable intrahepatic cholangiocarcinoma (ICC). We conducted a phase I/II study to ascertain the recommended dose (RD) of hepatic arterial infusion using gemcitabine (GEM) for ICC and to assess the efficacy and safety. METHODS: For patients with unresectable ICC, GEM was administered through the hepatic artery via the port system as a 30-minute infusion on days 1, 8, and 15 every 4 weeks for 5 cycles. In phase I, dosage for levels 1, 2, and 3 was set at 600, 800, and 1000 mg/m, respectively, and was increased in 3 to 6 patients at a time. Maximum tolerated dose was defined as a dosage resulting in dose-limiting toxicity in 2 of 3 patients or 3 of 6 patients, and RD was estimated during the first cycle. In the phase II, more RD patients were added to assess tumor response and toxicity. RESULTS: During the phase I, 16 patients were enrolled. Maximum tolerated dose was not reached. Assuming RD at 1000 mg/m, the phase II enrolled a total of 13 patients. The following Grade 3 toxicities were observed: neutropenia 20%, increased gamma-glutamyl transpeptidase 8%, increased aspartate aminotransferase 4%, increased alanine aminotransferase 4%, increased bilirubin 4%, nausea 4%, and fatigue 4%. The tumor response rate was 7.7% (complete response 0, partial response 1, stable disease 8, and progressive disease 4). CONCLUSION: Whereas the toxicity of hepatic arterial infusion with 1000 mg/m GEM for ICC was tolerable, expected efficacy could not be obtained, thus suggesting only minimal activity.","author":[{"dropping-particle":"","family":"Inaba","given":"Yoshitaka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arai","given":"Yasuaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamaura","given":"Hidekazu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sato","given":"Yozo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Najima","given":"Mina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aramaki","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sone","given":"Miyuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumada","given":"Takashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanigawa","given":"Noboru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anai","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoshioka","given":"Tetsuya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ikeda","given":"Masafumi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Clinical Oncology: Cancer Clinical Trials","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2011"]]},"page":"58-62","title":"Phase I/II study of hepatic arterial infusion chemotherapy with gemcitabine in patients with unresectable intrahepatic cholangiocarcinoma (JIVROSG-0301)","type":"article-journal","volume":"34"},"uris":[""]}],"mendeley":{"formattedCitation":"(104)","plainTextFormattedCitation":"(104)","previouslyFormattedCitation":"(104)"},"properties":{"noteIndex":0},"schema":""}(104) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1148/radiol.2016160572","ISBN":"1527-1315 (Electronic)\\r0033-8419 (Linking)","ISSN":"0033-8419","PMID":"27820684","abstract":"Purpose To evaluate the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin and 5-fluorouracil for advanced perihilar cholangiocarcinoma (PCC) in this prospective phase II study. Materials and Methods The protocol was approved by the local ethics committee, and all patients gave informed consent. Patients with nonresectable PCC were included in a prospective, open phase II study investigating HAI through interventionally implanted port catheters. HAI consisted of infusions of oxaliplatin 40 mg/m2 for 2 hours, followed by 5-fluorouracil 800 mg/m2 for 22 hours on days 1-3 every 3-4 weeks. A maximum of six cycles of HAI were applied for tumor control patients followed by maintenance with oral capecitabine until tumor progression. The primary end points were tumor response and progression-free survival (PFS). The secondary end points were local PFS, overall survival, and adverse events. Kaplan-Meier methodology and Cox regression analysis were used to evaluate the risk factors for survival. Results Between 2012 and 2015, 37 patients were enrolled. The overall response rate was 67.6% (25 of 37), and the disease control rate was 89.2% (33 of 37). Median PFS, local PFS, and overall survival were 12.2, 25.0, and 20.5 months, respectively. All three survival lengths in patients with periductal infiltrating pattern were found to be significantly longer than those in patients with mass-forming pattern (P < .001, hazard ratio < 0.2). Macroscopic growth patterns (P = .018) and number of HAI cycles (P < .001) were independent risk factors of survival. The most frequent adverse events were grades 1 and 2 gastrointestinal side effects and sensory neuropathy in 31 (83.8%) and 28 (75.7%) patients, respectively. Conclusion HAI with oxaliplatin and 5-fluorouracil may be an encouraging treatment choice for advanced PCC due to its high tumor control, survival benefit, and low toxicity, especially in patients with periductal infiltrating pattern. (c) RSNA, 2016.","author":[{"dropping-particle":"","family":"Wang","given":"Xiaodong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Jungang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cao","given":"Guang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Xu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cui","given":"Yong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ji","given":"Xinqiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Xuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Renjie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Hui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Haifeng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Peng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Jian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hao","given":"Chunyi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xing","given":"Baocai","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shen","given":"Lin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Radiology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2017"]]},"page":"580-589","title":"Phase II Study of Hepatic Arterial Infusion Chemotherapy with Oxaliplatin and 5-Fluorouracil for Advanced Perihilar Cholangiocarcinoma","type":"article-journal","volume":"283"},"uris":[""]}],"mendeley":{"formattedCitation":"(105)","plainTextFormattedCitation":"(105)","previouslyFormattedCitation":"(105)"},"properties":{"noteIndex":0},"schema":""}(105) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/cncr.29824","ISBN":"0002-9297","ISSN":"10970142","PMID":"26695839","abstract":"BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is associated with poor survival. This study compared the outcomes of patients with unresectable ICC treated with hepatic arterial infusion (HAI) plus systemic chemotherapy (SYS) with the outcomes of patients treated with SYS alone. METHODS Consecutive patients with ICC were retrospectively reviewed. Clinicopathologic data were reviewed. Survival rates were compared by Kaplan-Meier analysis and log-rank testing. RESULTS Between January 2000 and August 2012, 525 patients with ICC were evaluated at Memorial Sloan Kettering Cancer Center, and 236 patients with unresectable tumors (locally advanced or metastatic) were analyzed. Disease was confined to the liver in 104 patients, who underwent treatment with combined HAI and SYS (n = 78 or 75%) or SYS alone (n = 26 or 25%). The response rate in the combined group was better than the rate in the group receiving SYS alone, although this did not reach statistical significance (59% vs 39%, P = .11). Overall survival for the combined group was longer than overall survival for the patients who received SYS alone (30.8 vs 18.4 months, P < .001), and this difference was maintained when patients with portal lymph node disease were included in the survival analysis (29.6 months with HAI and SYS [n = 93] vs 15.9 months with SYS [n = 74], P < .001). Eight patients who initially presented with unresectable tumors responded enough to undergo complete resection and had a median overall survival of 37 months (range, 10.4-92.3 months). CONCLUSIONS In patients with unresectable ICC confined to the liver or with limited regional nodal disease, a combination of SYS and HAI chemotherapy is associated with greater survival than SYS alone. Cancer 2016;122:758-765. ? 2015 American Cancer Society.","author":[{"dropping-particle":"","family":"Konstantinidis","given":"Ioannis T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koerkamp","given":"Bas Groot","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Do","given":"Richard K.G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"G?nen","given":"Mithat","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fong","given":"Yuman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allen","given":"Peter J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Angelica","given":"Michael I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kingham","given":"T. Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dematteo","given":"Ronald P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klimstra","given":"David S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kemeny","given":"Nancy E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jarnagin","given":"William R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2016"]]},"page":"758-765","title":"Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone","type":"article-journal","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"(89)","plainTextFormattedCitation":"(89)","previouslyFormattedCitation":"(89)"},"properties":{"noteIndex":0},"schema":""}(89) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.crad.2010.11.002","ISBN":"1365-229X (Electronic)\\r0009-9260 (Linking)","ISSN":"00099260","PMID":"21356394","abstract":"322-328Aim: To evaluate the clinical outcome and the survival benefits of transarterial chemoembolization (TACE) for unresectable intrahepatic cholangiocarcinoma (ICC) compared with supportive therapy. Materials and methods: From January 1996 to April 2009, a total of 155 patients with unresectable ICC met the entry criteria and underwent TACE (72 patients) or supportive treatment (83 patients). Their survival was the primary end point. Results: The baseline patients and tumour characteristics were well-balanced in the two groups. The median number of sessions per patient was 2.5 (range 1-17 sessions) in the TACE group. After TACE, the incidence of significant (≥grade 3) haematological and non-haematological toxicities was 13 and 24%, respectively, and no patients died within 30 days following TACE. The objective tumour regression (≥partial response) was achieved in 23% of the patients in the TACE group. The Kaplan-Meier survival analysis showed that the survival period was significantly longer in the TACE group (median 12.2 months) than in the symptomatic treatment (median 3.3 months) group (p < 0.001). Conclusions: TACE is safe and offers greater survival benefits than supportive treatment for the palliative treatment of unresectable ICC. ? 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.","author":[{"dropping-particle":"","family":"Park","given":"S. Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"J. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoon","given":"H. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"I. S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoon","given":"H. K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"K. P.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Radiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2011"]]},"page":"322-328","title":"Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma","type":"article-journal","volume":"66"},"uris":[""]}],"mendeley":{"formattedCitation":"(106)","plainTextFormattedCitation":"(106)","previouslyFormattedCitation":"(106)"},"properties":{"noteIndex":0},"schema":""}(106) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/cncr.25625","ISBN":"0008-543X (Print)\\r0008-543X (Linking)","ISSN":"0008543X","PMID":"21425151","abstract":"BACKGROUND: Unresectable intrahepatic cholangiocarcinoma has a poor prognosis, with a median survival of 5 to 8 months without treatment. Response and survival after chemoembolization were evaluated.\\n\\nMETHODS: Lobar or segmental chemoembolization with cisplatinum, doxorubicin, mitomycin-C, ethiodol, and polyvinyl alcohol particles was performed at monthly intervals for 1-4 sessions until the entire intrahepatic tumor burden was treated. Cross-sectional imaging and clinical and laboratory evaluation were performed before treatment, 1 month after treatment, and then every 3 months. A second cycle of treatment was performed for intrahepatic recurrence. Toxicity was assessed using NCI CTC v.3.0. Response was evaluated using RECIST criteria, and survival was estimated with Kaplan-Meier analysis.\\n\\nRESULTS: Sixty-two patients were treated. Thirty-seven had pathologically proven cholangiocarcinoma, and 25 had poorly differentiated adenocarcinoma of unknown primary, likely cholangiocarcinoma. One hundred and twenty-two total procedures were performed during the initial cycle of treatment (mean, 2.0 per patient). Twenty patients received a second cycle, for a total of 165 procedures. There were 5 major complications. Thirty-day disease-specific mortality was 0%. Forty-five of 62 patients were evaluable for morphologic response after completion of their initial cycle: 11% (n = 5) partial responses, 64% (n = 29) stable, and 24% (n = 11) progressed. Median time to progression from first chemoembolization was 8 months, with 28% free of progression at 12 months. Median survival from time of diagnosis was 20 months, with 1-, 2-, and 3-year survival of 75%, 39%, and 17%, respectively. Median survival from time of first chemoembolization was 15 months, with 1-, 2-, and 3-year survival of 61%, 27%, and 8%, respectively. There was no statistically significant difference in survival between patients with cholangiocarcinoma and those with poorly differentiated adenocarcinoma. Patients who also received systemic chemotherapy had improved overall survival (median 28 vs 16 months, P = .02; HR, 1.94; 95% CI, 1.13-3.33).\\n\\nCONCLUSIONS: Chemoembolization provided local disease control (PR + SD) of intrahepatic cholangiocarcinoma and adenocarcinoma of unknown primary in 76%. Overall survival after chemoembolization showed the best outcomes for those receiving multidisciplinary integrated liver-directed and systemic therapies.","author":[{"dropping-particle":"V.","family":"Kiefer","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Albert","given":"Marissa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McNally","given":"Madeline","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robertson","given":"Mary","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"Weijing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fraker","given":"Douglas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Olthoff","given":"Kim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christians","given":"Kathleen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pappas","given":"Sam","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rilling","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soulen","given":"Michael C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2011"]]},"page":"1498-1505","title":"Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol","type":"article-journal","volume":"117"},"uris":[""]}],"mendeley":{"formattedCitation":"(107)","plainTextFormattedCitation":"(107)","previouslyFormattedCitation":"(107)"},"properties":{"noteIndex":0},"schema":""}(107) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISBN":"0954-691X","abstract":"Background Unresectable cholangiocarcinoma (CCC) has a poor prognosis. Patients with intrahepatic CCC have a very limited benefit from systemic chemotherapy (ChT). The aim of this prospective study was to evaluate the feasibility, safety, and efficacy of conventional transarterial chemoembolization (cTACE) with mitomycin-C and of irinotecan-eluting beads (iDEB-TACE), and to retrospectively compare them with ChT with oxaliplatin and gemcitabine. Materials and methods Between June 2002 and June 2010, three independent prospective trials were carried out and compared retrospectively. Following predefined study protocols, 26 patients with histologically proven intrahepatic CCC were treated with iDEB-TACE (200mg irinotecan), 10 patients were treated with cTACE using 15mg mitomycin-C mixed with 5-10ml of ionized oil (lipiodol), followed by embolization with gelfoam, and 31 patients received systemic ChT with gemcitabine and oxaliplatin. Treatment response and progression-free survival (PFS) were assessed by computer tomography or MRI every 2 months according to Response Evaluation Criteria in Solid Tumors. Clinical and laboratory data were assessed for side-effects according to National Cancer Institute-Common Toxicity Criteria. Results iDEB-TACE resulted in PFS of 3.9 months and overall survival (OS) of 11.7 months, compared with a PFS of 1.8 months and OS of 5.7 months, respectively, in patients treated with cTACE, and a PFS of 6.2 months and OS of 11.0 months, respectively, in patients treated with oxaliplatin and gemcitabine. The medium follow-up of patients treated with iDEB-TACE was 12 months; 2 months after treatment, 13 patients (50%) had progressive disease, 11 patients (42%) had stable disease, and one patient had a partial response and became eligible for secondary liver resection. Local tumor control was achieved in 66% of patients; 4% had a partial response, 62% had stable disease, and 27% progressive disease. Common Toxicity Criteria grade III or IV toxicities for iDEB-TACE were abdominal pain (n= 7), hepatic abscess (n= 1), pleural empyema due to biliary leakage (n= 1), and one death due to cholangitis with hepatic failure in a patient with liver cirrhosis. No hematological side-effects were observed. Almost every patient experienced a 'postembolization syndrome' with low-grade fever, nausea, and abdominal pain for up to 2 weeks. Conclusion This is the first study demonstrating that treatment of patients suffering from intrahepatic CCC with iDE…","author":[{"dropping-particle":"","family":"J.B.","given":"Kuhlmann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"W.","given":"Euringer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"H.C.","given":"Spangenberg","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"M.","given":"Breidert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"H.E.","given":"Blum","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J.","given":"Harder","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"R.","given":"Fischer","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Gastroenterology and Hepatology","id":"ITEM-1","issued":{"date-parts":[["2012"]]},"page":"437–443","title":"Treatment of unresectable cholangiocarcinoma: Conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(108)","plainTextFormattedCitation":"(108)","previouslyFormattedCitation":"(108)"},"properties":{"noteIndex":0},"schema":""}(108) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/ijc.26407","ISBN":"1097-0215 (Electronic)\\r0020-7136 (Linking)","ISSN":"00207136","PMID":"21976289","abstract":"The aim of the study was to evaluate the effectiveness of transarterial chemoembolization (TACE) with four chemotherapeutic protocols in terms of local tumor control and survival of patients with unresectable cholangiocarcinoma (CCC) and to identify the prognostic factors governing treatment success. In the single-centre study, 115 patients (mean ages = 60.4 years) with unresectable CCC were repeatedly treated with TACE. In total, 819 chemoembolization sessions were performed in 4 week intervals with a mean of 7.1 (range, 3-30) sessions per patient. The chemotherapeutic used was Mitomycin C only in 20.9% of patients, Gemcitabine only in 7%, Mitomycin C with Gemcitabine in 47% and combination of Gemcitabine, Mitomycin C and Cisplatin in 25.1%. Local tumor response was evaluated by MRI according to RECIST. Survival data were calculated according to the Kaplan-Meier method. Prognostic factors for patient's survival were evaluated using log-rank-test. The local tumor controls were: partial response 8.7%, stable disease 57.4% and progressive disease 33.9% of patients. The median and mean survival times from the start of TACE were 13 and 20.8 months. Survival rate from the start of TACE was 52% after 1-year, 29% after 2-years and 10% after 3-years. Initial tumor response, high tumor vascularity and Child-Pugh class A were statistically significant factors for patient's survival. No statistically significant difference between patients treated with different chemotherapy protocols was noted. In conclusion, TACE is a palliative and safe treatment option for patients with unresectable CCC. Child Pugh class B, tumor hypovascularity and initially progressive disease were poor prognostic factors for patient survival.","author":[{"dropping-particle":"","family":"Vogl","given":"Thomas J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Naguib","given":"Nagy N.N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nour-Eldin","given":"Nour Eldin A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bechstein","given":"Wolf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zeuzem","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trojan","given":"J?rg","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gruber-Rouh","given":"Tatjana","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Cancer","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2012"]]},"page":"733-740","title":"Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma: Results and prognostic factors governing treatment success","type":"article-journal","volume":"131"},"uris":[""]}],"mendeley":{"formattedCitation":"(109)","plainTextFormattedCitation":"(109)","previouslyFormattedCitation":"(109)"},"properties":{"noteIndex":0},"schema":""}(109) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.21873/anticanres.11522","ISSN":"02507005","PMID":"28373452","abstract":"AIM To report clinical outcomes of transarterial chemoembolization (TACE) using drug-eluting beads (DEBs) loaded with doxorubicin for the treatment of unresectable intrahepatic cholangiocarcinoma (CCA). PATIENTS AND METHODS We treated 127 patients with doxorubicin via TACE. Inclusion criteria were: diagnosis of unresectable CCA; indication for TACE, performance status (PS) 0-2, >3 months of life expectancy, >18 years old, written consent. TACE was performed using DEBs for 109 (86%) patients and polythylene glycol drug-elutable microspheres (PEG) loaded with doxorubicin for 18 (14%) patients. RESULTS Tumor response of the whole sample of 127 patients was partial response (PR) in 19 (15%) patients, stable disease (SD) in 101 (80%) and progressive disease (PD) in seven (5%) 3 months after therapy, with no complete responses. There were differences between type of embolics: PR was 7% and 77%, SD was 88% and 8%, and PD was 5% and 15%, and the disease control rate was 95% and 85% in the DEB and PEG groups, respectively. Most frequent side-effects were: abdominal pain, fever, nausea, and transaminase rise. CONCLUSION TACE was effective and safe for CCA treatment, with a high disease control rate. The best response of PEG-TACE was PR, whereas it was SD for DEB-TACE.","author":[{"dropping-particle":"","family":"Aliberti C, Carandina R","given":"Sarti D et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Anticancer research","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1859-1863","title":"Chemoembolization with Drug-eluting Microspheres Loaded with Doxorubicin for the Treatment of Cholangiocarcinoma.","type":"article-journal","volume":"37"},"uris":[""]}],"mendeley":{"formattedCitation":"(110)","plainTextFormattedCitation":"(110)","previouslyFormattedCitation":"(110)"},"properties":{"noteIndex":0},"schema":""}(110) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00270-011-0142-x","ISBN":"1432-086X (Electronic)\\r0174-1551 (Linking)","ISSN":"01741551","PMID":"21431970","abstract":"INTRODUCTION: In unresectable intrahepatic cholangiocarcinoma (ICC), systemic chemotherapy often is viewed as the only option, although efficacy is limited. Radioembolization (RE) using yttrium-90 ((90)Y) microspheres is an accepted therapy for patients with hepatocellular-carcinoma or metastatic liver tumors. However, there are limited data on the value of RE in patients with ICC and few data on factors influencing prognosis. The purpose of our retrospective analysis was to establish which factors influenced time-to-progression (TTP) and overall survival (OS).\\n\\nMETHODS: Patients with unresectable ICC were treated with (90)Y resin-microspheres and assessed at 3-monthly intervals. Radiologic response was evaluated by using Response Criteria in Solid Tumors (RECIST). Baseline characteristics, biochemical/clinical toxicities, and response were examined for impact on TTP and OS.\\n\\nRESULTS: Thirty-four treatments were administered to 33 patients without major complications. By RECIST, 12 patients had a partial response, 17 had stable disease, and 5 had progressive disease after 3 months. The median OS was 22 months posttreatment and 43.7 months postdiagnosis. Median TTP was 9.8 months. Survival and TTP were significantly prolonged in patients with ECOG 0 (vs. ECOG 1 or 2; median OS: 29.4, 10, and 5.1 months; TTP: 17.5, 6.9, and 2.4 months), tumor burden ≤25% (OS: 26.7 vs. 6 months; TTP: 17.5 vs. 2.3 months), or tumor response (PR or SD vs. PD; OS: 35.5, 17.7 vs. 5.7 months; TTP: 31.9, 9.8 vs. 2.5 months), respectively (P < 0.001).\\n\\nCONCLUSIONS: Radioembolization is an effective and safe option for patients with unresectable ICC. Predictors for prolonged survival are performance status, tumor burden, and RECIST response.","author":[{"dropping-particle":"","family":"Hoffmann","given":"Ralf T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paprottka","given":"Philipp M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sch?n","given":"Agnes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bamberg","given":"Fabian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haug","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dürr","given":"Eva Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rauch","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trumm","given":"Christoph T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jakobs","given":"Tobias F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Helmberger","given":"Thomas K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reiser","given":"Maximilian F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolligs","given":"Frank T.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"CardioVascular and Interventional Radiology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2012"]]},"page":"105-116","title":"Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: Factors associated with prolonged survival","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"(111)","plainTextFormattedCitation":"(111)","previouslyFormattedCitation":"(111)"},"properties":{"noteIndex":0},"schema":""}(111) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00259-018-4199-5","ISSN":"16197089","author":[{"dropping-particle":"al","family":"Bourien H, Palard X","given":"Rolland Y et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Nuclear Medicine and Molecular Imaging","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"title":"Yttrium-90 glass microspheres radioembolization (RE) for biliary tract cancer: a large single-center experience","type":"article-newspaper"},"uris":[""]}],"mendeley":{"formattedCitation":"(112)","plainTextFormattedCitation":"(112)","previouslyFormattedCitation":"(112)"},"properties":{"noteIndex":0},"schema":""}(112) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jvir.2018.04.001","ISSN":"15357732","PMID":"30042074","abstract":"Purpose: To evaluate the efficacy and safety of transarterial yttrium-90 glass microsphere radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). Materials and Methods: Retrospective review of 85 consecutive patients (41 men and 44 women; age, 73.4 ± 9.3 years) was performed. Survival data were analyzed by the Kaplan-Meier method, Cox regression models, and the log-rank test. Results: Median overall survival (OS) from diagnosis was 21.4 months (95% confidence interval [CI]: 16.6–28.4); median OS from radioembolization was 12.0 months (95% CI: 8.0–15.2). Seven episodes of severe toxicity occurred. At 3 months, 6.2% of patients had partial response, 64.2% had stable disease, and 29.6% had progressive disease. Median OS from radioembolization was significantly longer in patients with Eastern Cooperative Oncology Group (ECOG) scores of 0 and 1 than patients with an ECOG score of 2 (18.5 vs 5.5 months, P =.0012), and median OS from radioembolization was significantly longer in patients with well-differentiated histology than patients with poorly differentiated histology (18.6 vs 9.7 months, P =.012). Patients with solitary tumors had significantly longer median OS from radioembolization than patients with multifocal disease (25 vs. 6.1 months, P =.006). The absence of extrahepatic metastasis was associated with significantly increased median OS (15.2 vs. 6.8 months, P =.003). Increased time from diagnosis to radioembolization was a negative predictor of OS. The morphology of the tumor (mass-forming or infiltrative, hyper- or hypo-enhancing) had no effect on survival. Post-treatment increased cancer antigen 19-9 level, increased international normalized ratio, decreased albumin, increased bilirubin, increased aspartate aminotransferase, and increased Model for End-Stage Liver Disease score were significant predictors of decreased OS. Conclusions: These data support the therapeutic role of radioembolization for the treatment of unresectable ICC with good efficacy and an acceptable safety profile.","author":[{"dropping-particle":"","family":"Gangi","given":"Alexandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shah","given":"Jehan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hatfield","given":"Nathan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Johnna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sweeney","given":"Jennifer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Junsung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"El-Haddad","given":"Ghassan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Biebel","given":"Benjamin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parikh","given":"Nainesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arslan","given":"Bulent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoffe","given":"Sarah E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frakes","given":"Jessica M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Springett","given":"Gregory M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anaya","given":"Daniel A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Malafa","given":"Mokenge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Dung Tsa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Yunyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Richard D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shridhar","given":"Ravi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kis","given":"Bela","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Vascular and Interventional Radiology","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2018"]]},"page":"1101-1108","title":"Intrahepatic Cholangiocarcinoma Treated with Transarterial Yttrium-90 Glass Microsphere Radioembolization: Results of a Single Institution Retrospective Study","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"(113)","plainTextFormattedCitation":"(113)","previouslyFormattedCitation":"(113)"},"properties":{"noteIndex":0},"schema":""}(113) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/RLU.0000000000000904","ISBN":"0000000000000","ISSN":"15360229","PMID":"26204219","abstract":"PURPOSE OF THE REPORT: Intrahepatic cholangiocarcinoma's incidence is increasing. We studied the efficacy of Y selective internal radiation therapy (SIRT) as first-line treatment, with chemotherapy, and compared with the results of chemotherapy alone., PATIENTS AND METHODS: We retrospectively studied data from patients treated at our institution with glass microspheres SIRT for intrahepatic cholangiocarcinoma as part of first-line treatment in combination with chemotherapy. We compared results with those of similar patients treated in the ABC-02 study (a study in advanced biliary tract cancer that defined the current standard chemotherapy), assessed as not progressing after the first evaluation. We assessed progression-free survival (PFS) and overall survival (OS)., RESULTS: Twenty-four patients were treated with SIRT. Chemotherapy was given concomitantly in 10 (42%), as induction before SIRT in 13 (54%) or after SIRT in 1 (4%). Grade 3 adverse events were reported in 1 (4%). Median PFS after SIRT was 10.3 months. Longer PFS was observed when chemotherapy was given concomitantly than when chemotherapy was given before SIRT, with respective median of 20.0 versus 8.8 months (P = 0.001). Median OS after SIRT was not reached. Eleven patients went to surgery (46%). Thirty-three patients in ABC-02 had locally advanced nonextrahepatic cholangiocarcinoma, not progressing after first evaluation. From the start of any treatment, the median PFS was 16.0 months in our cohort versus 11.3 months in ABC-02 (P = 0.25), whereas the median OS was significantly higher in our cohort, not reached versus 17.9 months, respectively (P = 0.026)., CONCLUSIONS: Selective internal radiation therapy combined with concomitant chemotherapy seems a promising strategy as first-line treatment for unresectable intrahepatic cholangiocarcinoma.","author":[{"dropping-particle":"","family":"Edeline","given":"Julien","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Le","family":"Du","given":"Fanny","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rayar","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rolland","given":"Yan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beuzit","given":"Luc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boudjema","given":"Karim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rohou","given":"Tanguy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Latournerie","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Campillo-Gimenez","given":"Boris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garin","given":"Etienne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boucher","given":"Eveline","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Nuclear Medicine","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2015"]]},"page":"851-855","title":"Glass microspheres 90Y selective internal radiation therapy and chemotherapy as first-line treatment of intrahepatic cholangiocarcinoma","type":"article-journal","volume":"40"},"uris":[""]}],"mendeley":{"formattedCitation":"(114)","plainTextFormattedCitation":"(114)","previouslyFormattedCitation":"(114)"},"properties":{"noteIndex":0},"schema":""}(114) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejso.2014.09.007","ISBN":"1532-2157 (Electronic) 0748-7983 (Linking)","ISSN":"15322157","PMID":"25449754","abstract":"Radioembolization with yttrium-90 microspheres offers an alternative treatment option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, the rarity and heterogeneity of ICC makes it difficult to draw firm conclusions about treatment efficacy. Therefore, the goal of the current study is to systematically review the existing literature surrounding treatment of unresectable ICCs with yttrium-90 microspheres and provide a comprehensive review of the current experience and clinical outcome of this treatment modality. We performed a comprehensive search of electronic databases for ICC treatment and identified 12 studies with relevant data regarding radioembolization therapy with yttrium-90 microspheres. Based on pooled analysis, the overall weighted median survival was 15.5 months. Tumour response based on radiological studies demonstrated a partial response in 28% and stable disease in 54% of patients at three months. Seven patients were able to be downstaged to surgical resection. The complication profile of radioembolization is similar to that of other intra-arterial treatment modalities. Overall survival of patients with ICC after treatment with yttrium-90 microspheres is higher than historical survival rates and shows similar survival to those patients treated with systemic chemotherapy and/or trans-arterial chemoembolization therapy. Therefore, the use of yttrium-90 microspheres should be considered in the list of available treatment options for ICC. However, future randomized trials comparing systemic chemotherapy, TACE and local radiation will be required to identify the optimal treatment modality for unresectable ICC.","author":[{"dropping-particle":"","family":"Al-Adra D, Gill R","given":"Axford S et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Surgical Oncology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015"]]},"page":"120-127","title":"Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: A systematic review and pooled analysis","type":"article-journal","volume":"41"},"uris":[""]}],"mendeley":{"formattedCitation":"(115)","plainTextFormattedCitation":"(115)","previouslyFormattedCitation":"(115)"},"properties":{"noteIndex":0},"schema":""}(115) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"","ISSN":"1569-8041","abstract":"Background: Patients with non-resectable intra-hepatic cholangiocarcinoma (ICC) have a bad prognosis, and the efficacy of chemotherapy is limited. SIRT is a promising treatment option in hepatic tumors. In ICC there is no prospective studies of combination SIRT with chemotherapy. Methods: This phase II single-arm study prospectively included patients with nonresectable ICC (liver-only or limited extra-hepatic disease) in 7 centers. Patients received Cisplatin 25mg/m2 and Gemcitabine 1000mg/m2 (reduced to 300mg/m2 the cycles just before and following SIRT) day 1 and 8 of a 21-days cycles. SIRT was delivered during cycle 1 (unilobar disease), or cycles 1 and 3 (bilobar disease). Primary objective was response rate (RR) at 3 months according to RECIST 1.1, with the objective to show a RR>22%. Secondary objectives were toxicity, Progression-Free Survival (PFS), Overall Survival (OS), disease control rate (DCR) and RR according to Choi criteria. Results: 45 patients met clinical inclusion criteria, and 41 were deemed treatable with SIRT after pretreatment angiography and included in the study. 34% of patients had abdominal extrahepatic lesions, 17% had thoracic lesions, tumor was unilobar in 66%, and median CA19.9 was 1499 UI/L. Grade 3 or more hematological toxicities were seen in 27 (66%) patients, and grade 3 ormore non-hematological toxicities in 21 (49%). Median number of chemotherapy cycles were 6 (range 1-15). RECIST RR was 39% [90% CI: 26-53], and DCR was 98% (all 40 evaluable patients had disease control). In the 29 patients evaluated with Choi criteria, RR was 86%. 9 patients (22%) were downstaged to surgery, with 8 (20%) achieving R0 resection. Median PFS was 13 months [95% CI: 7-NR], with 12- and 24-months PFS rates of 51% and 37%, respectively. Median OS was 21 months [95% CI: 14-NR], with 12- and 24-months OS rates of 73% and 36%, respectively. Conclusions: Combination of chemotherapy and SIRT achieved promising activity in first-line treatment of inoperable ICC,withmedian PFS andOS comparing favorably with chemotherapy-only historical data, and a significant proportion of patients downstaged to surgery. Toxicity wasmanageable. Further studies of SIRT in ICC are warranted.","author":[{"dropping-particle":"","family":"J.","given":"Edeline","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Y.","given":"Touchefeu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"B.","given":"Guiu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O.","given":"Farges","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D.","given":"Tougeron","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"P.","given":"Compagnon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"L.","given":"Chone","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"B.","given":"Campillo-Gimenez","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"M.","given":"Pracht","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"A.","given":"Lievre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"S.","given":"Le Sourd","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"K.","given":"Boudjema","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"E.","given":"Garin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"(Supplement 5)","issued":{"date-parts":[["2017"]]},"page":"v242","title":"Selective Internal Radiation Therapy (SIRT) with Yttrium-90-glassmicrospheres plus chemotherapy in first-line treatment of advanced cholangiocarcinoma (MISPHEC study)","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"(116)","plainTextFormattedCitation":"(116)","previouslyFormattedCitation":"(116)"},"properties":{"noteIndex":0},"schema":""}(116)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"1068-9265","abstract":"Background: Many patients with intrahepatic cholangiocarcinoma (ICC) present with advanced and inoperable disease. Data on the safety and efficacy of intra-arterial therapy (IAT) for ICC are limited. Methods: Between 1992 and 2012, a total of 198 patients with advanced ICC treated with IAT were retrospectively identified from the databases of five major hepatobiliary institutions. Data on clinicopathological factors, morbidity, response rates, and overall survival were collected and analyzed. Results: Median patient age was 61 years. Median tumor size was 8.1 cm, and 47.5 % patients had a solitary lesion. IAT consisted of conventional transarterial chemoembolization (cTACE) (64.7 %), drug-eluting beads (DEB) (5.6 %), bland embolization (TAE) (6.6 %), or yttrium-90 radioembolization (23.2 %). Median number of IAT sessions was 2 (range 1-8). The median time between IAT sessions was 48 days. The periprocedural morbidity was 29.8 %; most complications were minor (n = 43); however, 16 patients had a grade 3-4 complication. Assessment of tumor response revealed complete or partial response in 25.5 % patients, while 61.5 % had stable disease; 13.0 % had progressive disease. Median overall survival was 13.2 months and did not differ on the basis of the type of IAT (cTACE, 13.4 months vs. DEB 10.5 months vs. TAE, 14.3 months vs. yttrium-90, 11.3 months; P = 0.46). IAT response on modified response evaluation criteria in solid tumors (mRECIST; hazard ratio for complete-partial response 0.49, 95 % confidence interval 0.30-0.81; P < 0.001) was independently associated with better survival. Conclusions: IAT for ICC was safe and led to stable disease or partial to complete response in up to three-quarters of patients. Among patients with an IAT response, overall survival was prolonged. The role of IAT therapy for ICC warrants further prospective evaluation in clinical trials. (copyright) 2013 Society of Surgical Oncology.","author":[{"dropping-particle":"al","family":"Hyder O, Cosgrove D","given":"Liapi E et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Surgical Oncology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"S7","title":"Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: A multi-institutional analysis","type":"article-journal","volume":"20"},"uris":[""]}],"mendeley":{"formattedCitation":"(117)","plainTextFormattedCitation":"(117)","previouslyFormattedCitation":"(117)"},"properties":{"noteIndex":0},"schema":""}(117) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jso.23781","ISSN":"10969098","PMID":"25176325","abstract":"BACKGROUND: Hepatic artery based therapies (HAT) are offered for patients with unresectable intrahepatic cholangiocarcinoma (ICC). We aimed to evaluate the comparative effectiveness of HAT -hepatic arterial infusion (HAI), transcatheter arterial chemoembolization (TACE), drug-eluting bead TACE (DEB-TACE), and Yttrium(90) radioembolization (Y-90) for unresectable ICC. METHODS: A meta-analysis was performed using a prospectively registered search strategy at PROSPERO (CRD42013004830) that utilized PubMed (2003-2013). Primary outcome was median overall survival (OS), and secondary outcomes were tumor response to therapy and toxicity. RESULTS: A total of 20 articles (of 793, n=657 patients) were selected for data extraction. Highest Median OS was observed for HAI (22.8, 95% CI 9.8-35.8) months versus Y90 (13.9, 9.5-18.3) months versus TACE (12.4, 10.9-13.9) months versus DEB-TACE (12.3, 11-13.5) months. Response to therapy (complete and partial) was highest for HAI (56.9%, 95%CI 41.0-72.8) versus Y90 (27.4%, 17.4-37.5) versus TACE (17.3%, 6.8-27.8). The grade III/IV toxicity (Events per patient) was highest for HAI (0.35, 95% CI 0.22-0.48) versus TACE (0.26, 0.21-0.32) versus DEB-TACE (0.32, 0.17-0.48). CONCLUSION: For patients with unresectable ICC treated with HAT, HAI offered the best outcomes in terms of tumor response and survival but may be limited by toxicity.","author":[{"dropping-particle":"al","family":"Boehm L, Jayakrishnan T","given":"Miura J et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Surgical Oncology","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"213-220","title":"Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(118)","plainTextFormattedCitation":"(118)","previouslyFormattedCitation":"(118)"},"properties":{"noteIndex":0},"schema":""}(118). The analysis is a difficult one because very few studies are prospective or comparative, while most have a low number of patients and describe single-center experience. Moreover, there is a high heterogeneity in terms of patient population within and across studies that limits the interpretability of data. For example, a meta-analysis compared patients treated with HAI mostly as first-line and patients receiving SIRT mostly when they were chemo-refractory ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jso.23781","ISSN":"10969098","PMID":"25176325","abstract":"BACKGROUND: Hepatic artery based therapies (HAT) are offered for patients with unresectable intrahepatic cholangiocarcinoma (ICC). We aimed to evaluate the comparative effectiveness of HAT -hepatic arterial infusion (HAI), transcatheter arterial chemoembolization (TACE), drug-eluting bead TACE (DEB-TACE), and Yttrium(90) radioembolization (Y-90) for unresectable ICC. METHODS: A meta-analysis was performed using a prospectively registered search strategy at PROSPERO (CRD42013004830) that utilized PubMed (2003-2013). Primary outcome was median overall survival (OS), and secondary outcomes were tumor response to therapy and toxicity. RESULTS: A total of 20 articles (of 793, n=657 patients) were selected for data extraction. Highest Median OS was observed for HAI (22.8, 95% CI 9.8-35.8) months versus Y90 (13.9, 9.5-18.3) months versus TACE (12.4, 10.9-13.9) months versus DEB-TACE (12.3, 11-13.5) months. Response to therapy (complete and partial) was highest for HAI (56.9%, 95%CI 41.0-72.8) versus Y90 (27.4%, 17.4-37.5) versus TACE (17.3%, 6.8-27.8). The grade III/IV toxicity (Events per patient) was highest for HAI (0.35, 95% CI 0.22-0.48) versus TACE (0.26, 0.21-0.32) versus DEB-TACE (0.32, 0.17-0.48). CONCLUSION: For patients with unresectable ICC treated with HAT, HAI offered the best outcomes in terms of tumor response and survival but may be limited by toxicity.","author":[{"dropping-particle":"al","family":"Boehm L, Jayakrishnan T","given":"Miura J et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Surgical Oncology","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"213-220","title":"Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(118)","plainTextFormattedCitation":"(118)","previouslyFormattedCitation":"(118)"},"properties":{"noteIndex":0},"schema":""}(118). Moreover, the outcomes of patients with locally-advanced iCCA receiving first-line chemotherapy may already be better than those of all-comers with advanced biliary tract cancers, and this needs to be taken into account when interpreting historical data ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Lamarca","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"ILCA meeting.","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"O-014","title":"Survival Data for Advanced Intrahepatic Cholangiocarcinoma from the ABC-01, -02 And -03 Clinical Studies.","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(119)","plainTextFormattedCitation":"(119)"},"properties":{"noteIndex":0},"schema":""}(119).The available evidence clearly indicates some activity of intra-arterial hepatic therapy in iCCA at least in terms of response rate ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1245/s10434-014-4365-3","ISSN":"15344681","PMID":"25623598","abstract":"PURPOSE: To evaluate the downstaging efficacy of yttrium-90 radioembolization (Ytt-90)-associated with chemotherapy and the results of surgery for initially unresectable huge intrahepatic cholangiocarcinoma (ICC)., METHODS: Between January 2008 and October 2013, unresectable ICC were treated with chemotherapy and Ytt-90. Patients with unique tumors localized to noncirrhotic livers and without extrahepatic metastasis were considered to be potentially resectable and were evaluated every 2 months for possible secondary resection., RESULTS: Forty-five patients were treated for unresectable ICCs; ten had potentially resectable tumors, and eight underwent surgery. Initial unresectability was due to the involvement of the hepatic veins or portal vein of the future liver remnant in seven and one cases, respectively. Preoperative treatment induced significant decreases in tumor volume (295 vs. 168 ml, p = 0.02) and allowed for R0 resection in all cases. Three patients (37.5 %) had Clavien-Dindo grade three or higher complications, including two postoperative deaths. The median follow-ups were 15.6 [range 4-40.7] months after medical treatment initiation and 7.2 [0.13-36.4] months after surgery. At the end of the study period, five patients were still alive, with one patient still alive 40 months after medical treatment initiation (36.4 months after surgery); two patients experienced recurrences., CONCLUSIONS: For initially unresectable huge ICCs, chemotherapy with Ytt-90 radioembolization is an effective downstaging method that allows for secondary resectability.","author":[{"dropping-particle":"","family":"Rayar","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sulpice","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Edeline","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garin","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levi Sandri","given":"G. B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meunier","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boucher","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boudjema","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Surgical Oncology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2015"]]},"page":"3102-3108","title":"Intra-arterial Yttrium-90 Radioembolization Combined with Systemic Chemotherapy is a Promising Method for Downstaging Unresectable Huge Intrahepatic Cholangiocarcinoma to Surgical Treatment","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(120)","plainTextFormattedCitation":"(120)","previouslyFormattedCitation":"(119)"},"properties":{"noteIndex":0},"schema":""}(120). Several studies have reported cases of patients with initially unresectable disease that could be downstaged to surgery following treatment, especially with SIRT. These observations have supported the incorporation of intra-arterial therapies in the treatment algorithms of scientific societies ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jhep.2014.01.021","ISBN":"doi:10.1016/j.jhep.2014.01.021","ISSN":"16000641","PMID":"24681130","abstract":"Cholangiocarcinoma (CCA) comprises a heterogeneous group of\\r\\ncancers with pathologic features of biliary tract differentiation,\\r\\nand is presumed to arise from the intra- or extrahepatic biliary\\r\\ntract. Two recent papers suggest these cancers may also arise\\r\\ndirectly from transdifferentiation of hepatocytes [1,2]. Gallbladder\\r\\ncancer is distinct from cholangiocarcinoma in epidemiology,\\r\\npathobiology, clinical presentation and management, and should\\r\\nbe considered a different form of biliary tract cancer [3]. On the\\r\\nbasis of its anatomical origin, CCA is best classified anatomically\\r\\nas intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA) CCA [4].\\r\\nThe incidence of iCCA appears to be increasing and may be as\\r\\nhigh as 2.1 per 100,000 person years in Western Countries [5].\\r\\niCCA may occur in patients with normal liver or with underlying\\r\\nliver disease, and in either clinical context usually is classified\\r\\npathologically as an adenocarcinoma, although mixed hepatocellular\\r\\n– cholangiocarcinomas also occur, especially in chronic liver\\r\\ndisease [6].\\r\\nGiven the increasing incidence of this complex and fatal disease,\\r\\nthe growing recognition of iCCA as a distinct cancer, and\\r\\nthe large number of recent publications on this disease, the International\\r\\nLiver Cancer Association (ILCA) governing board noted it\\r\\nwas both timely and topical to develop practice guidelines on\\r\\niCCA. These guidelines are largely based on a consensus of a multidisciplinary,\\r\\ngeographically diverse writing committee using a\\r\\ndata-supported approach, and subsequently reviewed by a separate\\r\\nPractice Guidelines committee of ILCA. The ILCA guidelines\\r\\ncommittee employed an extensive PubMed search to broadly\\r\\ncanvas the existing literature. Each author then wrote different\\r\\nsections of the manuscript relative to their expertise. All authors\\r\\nthen reviewed and edited the manuscript to ensure objectivity\\r\\nand evidence-based recommendations. Finally an ILCA oversight\\r\\ncommittee reviewed the document, provided recommendations,\\r\\nand then additional edits were made to the document. Thus, a\\r\\ntwo-tiered integrated and interactive process was employed to\\r\\ngenerate the guidelines. These recommendations suggest preferred\\r\\napproaches to the diagnostic and therapeutic aspects of\\r\\ncare, and are intended to be flexible, in contrast to standards of\\r\\ncare, which should be supported by robust evidence-based data.\\r\\nThus, the guidelin…","author":[{"dropping-particle":"","family":"Bridgewater","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galle","given":"Peter R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khan","given":"Shahid A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Llovet","given":"Josep M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Joong-Won","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patel","given":"Tushar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pawlik","given":"Timothy M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gores","given":"Gregory J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2014"]]},"page":"1268-1289","title":"Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma","type":"article-journal","volume":"60"},"uris":[""]}],"mendeley":{"formattedCitation":"(121)","plainTextFormattedCitation":"(121)","previouslyFormattedCitation":"(120)"},"properties":{"noteIndex":0},"schema":""}(121) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdw324","ISBN":"3512104800","ISSN":"15698041","PMID":"26314782","abstract":"Galectin-3 (Gal3) plays diverse roles in cancer initiation, progression, and drug resistance depending on tumor type characteristics that are also associated with cancer stem cells (CSCs). Recurrence of breast carcinomas may be attributed to the presence of breast CSCs (BCSCs). BCSCs exist in mesenchymal-like or epithelial-like states and the transition between these states endows BCSCs with the capacity for tumor progression. The discovery of a feedback loop with galectins during epithelial-to-mesenchymal transition (EMT) prompted us to investigate its role in breast cancer stemness. To elucidate the role of Gal3 in BCSCs, we performed various in vitro and in vivo studies such as sphere-formation assays, Western blotting, flow cytometric apoptosis assays, and limited dilution xenotransplant models. Histological staining for Gal3 in tissue microarrays of breast cancer patients was performed to analyze the relationship of clinical outcome and Gal3 expression. Here, we show in a cohort of 87 node-positive breast cancer patients treated with doxorubicin-based chemotherapy that low Gal3 was associated with increased lymphovascular invasion and reduced overall survival. Analysis of in vitro BCSC models demonstrated that Gal3 knockdown by small hairpin RNA (shRNA) interference in epithelial-like mammary spheres leads to EMT, increased sphere-formation ability, drug-resistance, and heightened aldefluor activity. Furthermore, Gal3negative BCSCs were associated with enhanced tumorigenicity in orthotopic mouse models. Thus, in at least some breast cancers, loss of Gal3 might be associated with EMT and cancer stemness-associated traits, predicts poor response to chemotherapy, and poor prognosis.","author":[{"dropping-particle":"","family":"Valle","given":"J. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borbath","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khan","given":"S. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huguet","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gruenberger","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnold","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"(suppl_5)","issued":{"date-parts":[["2016"]]},"page":"v28-v37","title":"Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up?","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(122)","plainTextFormattedCitation":"(122)","previouslyFormattedCitation":"(121)"},"properties":{"noteIndex":0},"schema":""}(122), either as first-line or in chemo-refractory patients.Unquestionably, multicenter prospective randomized studies are required to assess the benefit of intra-arterial hepatic therapies better in iCCA. The SIRCCA randomized phase II trial ( identifier NCT02807181) is currently randomizing patients with non-resectable iCCA to either chemotherapy alone or SIRT followed by chemotherapy. Another study is comparing SIRT with transarterial chemoembolization ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1186/1745-6215-15-311","ISSN":"17456215","PMID":"25095718","abstract":"BACKGROUND: Cholangiocellular carcinoma is the second most common primary liver cancer after hepatocellular carcinoma. Over the last 30 years, the incidence of intrahepatic cholangiocellular carcinoma has risen continuously worldwide. Meanwhile, the intrahepatic cholangiocellular carcinoma has become more common than the extrahepatic growth type and currently accounts for 10-15% of all primary hepatic malignancies. Intrahepatic cholangiocellular carcinoma is typically diagnosed in advanced stages due to late clinical symptoms and an absence of classic risk factors. A late diagnosis precludes curative surgical resection. There is evidence that transarterial chemoembolization leads to better local tumor control and prolongs survival compared to systemic chemotherapy. New data indicates that selective internal radiotherapy, also referred to as radioembolization, provides promising results for treating intrahepatic cholangiocellular carcinoma.\\n\\nMETHODS/DESIGN: This pilot study is a randomized, controlled, single center, phase II trial. Twenty-four patients with intrahepatic cholangiocellular carcinoma will be randomized in a 1:1 ratio to receive either chemoembolization or radioembolization. Randomization will be stratified according to tumor load. Progression-free survival is the primary endpoint; overall survival and time to progression are secondary endpoints. To evaluate treatment success, patients will receive contrast enhanced magnetic resonance imaging every 3 months.\\n\\nDISCUSSION: Currently, chemoembolization is routinely performed in many centers instead of systemic chemotherapy for treating intrahepatic cholangiocellular carcinoma confined to the liver. Recently, radioembolization has been increasingly applied to cholangiocellular carcinoma as second line therapy after TACE failure or even as an alternative first line therapy. Nonetheless, no randomized studies have compared radioembolization and chemoembolization. Considering all this background information, we recognized a strong need for a randomized controlled trial (RCT) to compare the two treatments. Therefore, the present protocol describes the design of a RCT that compares SIRT and TACE as the first line therapy for inoperable CCC confined to the liver.\\n\\nTRIAL REGISTRATION: , Identifier: NCT01798147, registered 16th of February 2013.","author":[{"dropping-particle":"","family":"Kloeckner","given":"Roman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruckes","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kronfeld","given":"Kai","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wo¨rns","given":"Marcus A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weinmann","given":"Arndt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galle","given":"Peter R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lang","given":"Hauke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Otto","given":"Gerd","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eichhorn","given":"Waltraud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schreckenberger","given":"Mathias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dueber","given":"Christoph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pitton","given":"Michael B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Trials","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"title":"Selective internal radiotherapy (SIRT) versus transarterial chemoembolization (TACE) for the treatment of intrahepatic cholangiocellular carcinoma (CCC): Study protocol for a randomized controlled trial","type":"article-journal","volume":"15"},"uris":[""]}],"mendeley":{"formattedCitation":"(123)","plainTextFormattedCitation":"(123)","previouslyFormattedCitation":"(122)"},"properties":{"noteIndex":0},"schema":""}(123). The results of these studies will help to draw appropriate conclusions.b. External beam radiation therapyExternal beam radiation therapy has been studied in the context of adjuvant treatment, mostly in retrospective studies in extrahepatic cholangiocarcinoma. A meta-analysis suggested that the combination of chemotherapy and radiotherapy might be useful ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2011.40.5381","ISBN":"1527-7755 (Electronic)\\r0732-183X (Linking)","ISSN":"0732183X","PMID":"22529261","abstract":"PURPOSE: The benefit of adjuvant therapy (AT) for biliary tract cancer (BTC) is unclear, with conflicting results from nonrandomized studies. We report a systematic review and meta-analysis to determine the impact of AT on survival. METHODS: Studies published between 1960 and November 2010, which evaluated adjuvant chemotherapy (CT), radiotherapy (RT), or both (CRT) compared with curative-intent surgery alone for resected BTC were included. Only tumors of the gallbladder and bile ducts were assessed. Published data were extracted and computed into odds ratios (ORs) for death at 5 years. Subgroup analyses of benefit based on lymph node (LN) or resection margin positivity (R1) were prespecified. Data were weighted by generic inverse variance and pooled using random-effect modeling. RESULTS: Twenty studies involving 6,712 patients were analyzed. There was a nonsignificant improvement in overall survival with any AT compared with surgery alone (pooled OR, 0.74; P = .06). There was no difference between gallbladder and bile duct tumors (P = .68). The association was significant when the two registry analyses were excluded. Those receiving CT or CRT derived statistically greater benefit than RT alone (OR, 0.39, 0.61, and 0.98, respectively; P = .02). The greatest benefit for AT was in those with LN-positive disease (OR, 0.49; P = .004) and R1 disease (OR, 0.36; P = .002). CONCLUSION: This analysis supports AT for BTC. Prospective randomized trials are needed to provide better rationale for this commonly used strategy. On the basis of our data, such trials could involve two active comparators rather than a no-treatment arm among patients with LN-positive or R1 disease.","author":[{"dropping-particle":"","family":"Horgan","given":"Anne M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amir","given":"Eitan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walter","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Knox","given":"Jennifer J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"16","issued":{"date-parts":[["2012"]]},"page":"1934-1940","title":"Adjuvant therapy in the treatment of biliary tract cancer: A systematic review and meta-analysis","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(11)","plainTextFormattedCitation":"(11)","previouslyFormattedCitation":"(11)"},"properties":{"noteIndex":0},"schema":""}(11). However, only one prospective single-arm trial is available ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2014.60.2219","ISBN":"1527-7755 (Electronic)\\r0732-183X (Linking)","ISSN":"15277755","PMID":"25964250","abstract":"PURPOSE: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.\\n\\nPATIENTS AND METHODS: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.\\n\\nRESULTS: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.\\n\\nCONCLUSION: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.","author":[{"dropping-particle":"al","family":"Ben-Josef E, Guthrie K","given":"El-Khoueiry A et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"24","issued":{"date-parts":[["2015"]]},"page":"2617-2622","title":"SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"(15)","plainTextFormattedCitation":"(15)","previouslyFormattedCitation":"(15)"},"properties":{"noteIndex":0},"schema":""}(15), discussed in the adjuvant section. Adjuvant radiation is not recommended by most European societies but it is included among available options in the American National Comprehensive Cancer Network guidelines ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdw324","ISBN":"3512104800","ISSN":"15698041","PMID":"26314782","abstract":"Galectin-3 (Gal3) plays diverse roles in cancer initiation, progression, and drug resistance depending on tumor type characteristics that are also associated with cancer stem cells (CSCs). Recurrence of breast carcinomas may be attributed to the presence of breast CSCs (BCSCs). BCSCs exist in mesenchymal-like or epithelial-like states and the transition between these states endows BCSCs with the capacity for tumor progression. The discovery of a feedback loop with galectins during epithelial-to-mesenchymal transition (EMT) prompted us to investigate its role in breast cancer stemness. To elucidate the role of Gal3 in BCSCs, we performed various in vitro and in vivo studies such as sphere-formation assays, Western blotting, flow cytometric apoptosis assays, and limited dilution xenotransplant models. Histological staining for Gal3 in tissue microarrays of breast cancer patients was performed to analyze the relationship of clinical outcome and Gal3 expression. Here, we show in a cohort of 87 node-positive breast cancer patients treated with doxorubicin-based chemotherapy that low Gal3 was associated with increased lymphovascular invasion and reduced overall survival. Analysis of in vitro BCSC models demonstrated that Gal3 knockdown by small hairpin RNA (shRNA) interference in epithelial-like mammary spheres leads to EMT, increased sphere-formation ability, drug-resistance, and heightened aldefluor activity. Furthermore, Gal3negative BCSCs were associated with enhanced tumorigenicity in orthotopic mouse models. Thus, in at least some breast cancers, loss of Gal3 might be associated with EMT and cancer stemness-associated traits, predicts poor response to chemotherapy, and poor prognosis.","author":[{"dropping-particle":"","family":"Valle","given":"J. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borbath","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khan","given":"S. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huguet","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gruenberger","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnold","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"(suppl_5)","issued":{"date-parts":[["2016"]]},"page":"v28-v37","title":"Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up?","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(122)","plainTextFormattedCitation":"(122)","previouslyFormattedCitation":"(121)"},"properties":{"noteIndex":0},"schema":""}(122). In the context of locally-advanced disease, the FFCD 9904 phase 3 trial closed early due to slow accrual, but worse results were reported for chemo-radiotherapy than for systemic chemotherapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejca.2014.08.013","ISBN":"1879-0852 (Electronic)\\r0959-8049 (Linking)","ISSN":"18790852","PMID":"25241229","abstract":"Background Chemoradiotherapy (CHRT) is often advocated for locally-advanced biliary tract cancer (LABTC). However there was not comparative study with chemotherapy alone (CH). Patients and methods Patients with hilar or extrahepatic non-metastatic, LABTC could be included in this phase II trial. The inclusion criteria required World Health Organisation (WHO) performance status ≤2, bilirubinemia ≤50 μM/L after biliary drainage if necessary, and possibility of external radiotherapy. Fluorouracil (5 FU) infusion and cisplatin, were given in association to radiotherapy (50 Gy) in the CHRT arm. Gemcitabine + oxaliplatin (GEMOX) was planned for 6 months in the CH arm. End-points were progression-free survival (PFS), overall survival (OS), toxicity and rate of biliary complications. Results The trial was closed before completion due to slow recruitment. Eighteen and 16 patients were included in the CHRT and CH arms, respectively. Median follow up was 27.9 months (±2.8). Grade III-IV toxicities were mostly haematological (23% and 25%), and gastrointestinal (11% and 6%), in the CHRT and CH arm, respectively. Biliary complications occurred in 28% of patients in the CHRT arm and 44% of patients in the CH arm (risk ratio (RR): 1.60 [0.65-3.92]). Median PFS was 5.8 months in the CHRT group and 11.0 months in the CH group (hazard ratio (HR): 0.65 [0.32-1.33]). Median OS was 13.5 months in the CHRT group and 19.9 months in the CH group (HR: 0.69 [0.31-1.55]). Conclusions Combination of gemcitabine plus cisplatin seems to be at least as efficient as chemoradiotherapy (50 Gy plus 5 FU and cisplatin) in LABTC.","author":[{"dropping-particle":"","family":"Phelip","given":"Jean Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vendrely","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rostain","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Subtil","given":"Fabien","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jouve","given":"Jean Louis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gasmi","given":"Mohamed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Michel","given":"Pierre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Malicot","given":"Karine","non-dropping-particle":"Le","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seitz","given":"Jean Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fauchart","given":"Jean Pierre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Martin","given":"Philippe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bennouna","given":"Jaafar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morin","given":"Thierry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bonnet","given":"Isabelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maingon","given":"Philippe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lepage","given":"C?me","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chauffert","given":"Bruno","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Cancer","id":"ITEM-1","issue":"17","issued":{"date-parts":[["2015"]]},"page":"2975-2982","title":"Gemcitabine plus cisplatin versus chemoradiotherapy in locally advanced biliary tract cancer: Fédération Francophone de Cancérologie Digestive 9902 phase II randomised study","type":"article-journal","volume":"50"},"uris":[""]}],"mendeley":{"formattedCitation":"(124)","plainTextFormattedCitation":"(124)","previouslyFormattedCitation":"(123)"},"properties":{"noteIndex":0},"schema":""}(124). New radiation techniques have been applied in locally-advanced iCCA that may improve the results ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2015.64.2710","ISBN":"0732-183x","ISSN":"15277755","PMID":"26668346","abstract":"PURPOSE To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.","author":[{"dropping-particle":"","family":"Hong","given":"Theodore S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wo","given":"Jennifer Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yeap","given":"Beow Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ben-Josef","given":"Edgar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McDonnell","given":"Erin I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blaszkowsky","given":"Lawrence S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwak","given":"Eunice L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allen","given":"Jill N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clark","given":"Jeffrey W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goyal","given":"Lipika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murphy","given":"Janet E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Javle","given":"Milind M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolfgang","given":"John A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drapek","given":"Lorraine C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arellano","given":"Ronald S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mamon","given":"Harvey J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullen","given":"John T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoon","given":"Sam S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanabe","given":"Kenneth K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ferrone","given":"Cristina R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryan","given":"David P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"DeLaney","given":"Thomas F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Christopher H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Andrew X.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2016"]]},"page":"460-468","title":"Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma","type":"article-journal","volume":"34"},"uris":[""]}],"mendeley":{"formattedCitation":"(125)","plainTextFormattedCitation":"(125)","previouslyFormattedCitation":"(124)"},"properties":{"noteIndex":0},"schema":""}(125). In summary, external beam radiation therapy has not yet proven to be beneficial and more clinical trials are needed.c. Photodynamic therapyPhotodynamic therapy (PDT) refers to the administration of a photosensitizing drug that accumulates in tumor cells followed by the exposition to laser light. In cholangiocarcinoma, the technique has been mostly studied in unresectable hilar cholangiocarcinoma, using either endoscopic or percutaneous approaches, with initial promising results ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"","ISSN":"0008-543X","PMID":"12767091","abstract":"BACKGROUND. Only 20-30% of patients with hilar cholangiocarcinomas (CC) are candidates for potentially curative resection. However, even after curative (RO) resection, these patients have a disease recurrence rate of up to 76%. The current prospective Phase II study investigated photodynamic therapy (PDT) as a neoadjuvant treatment for CC. METHODS. Seven patients with advanced proximal bile duct carcinoma were evaluated. Patients were treated with PDT at the area of tumor infiltration and 2 cm beyond and underwent surgery after a median period of 6 weeks (range, 3-44 weeks). RESULTS. One patient had a Bismuth-Corlette Type II tumor, two patients had Type IIIa, one patient had Type IIIb, and three patients had Type IV. Cholestasis parameters after PDT decreased significantly. No relevant adverse events from PDT occurred except for minor intraoperative phototoxicity in one patient. Three patients underwent right-sided liver resections, two patients underwent left-sided liver resections, and one patient received a combined hilar resection with partial pancreatoduodenectomy (PD) due to tumor extension into the distal bile duct. Liver transplantation and PD were performed in another patient. In all patients, RO resection was achieved. Four patients developed minor surgical complications, even though the bilioenteric anastomoses were sewn to PDT-pretreated bile ducts. No viable tumor cells were found in the inner 4 mm layer of the surgical specimens. The PDT-pretreated epithelium of the tumor-free proximal resection margins exhibited only minimal inflammatory infiltration. Tumors recurred in 2 patients 6 and 19 months after surgery. The 1-year recurrence free survival rate was 83%. CONCLUSIONS. Neoadjuvant PDT for hilar CC is a low-risk procedure with efficient selective destruction of the superficial 4 mm layer of bile duct tumor without complications exceeding series without neoadjuvant PDT. Neoadjuvant PDT should be evaluated prospectively to determine whether it reduces the rate of local disease recurrence after potentially curative resection. ? 2003 American Cancer Society.","author":[{"dropping-particle":"","family":"M.","given":"Wiedmann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"K.","given":"Caca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"F.","given":"Berr","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"I.","given":"Schiefke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"A.","given":"Tannapfel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"C.","given":"Wittekind","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J.","given":"Mossner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J.","given":"Hauss","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wiedmann","given":"Marcus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caca","given":"Karel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berr","given":"Frieder","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schiefke","given":"Ingolf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tannapfel","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wittekind","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mossner","given":"Joachim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hauss","given":"Johann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Witzigmann","given":"Helmut","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issued":{"date-parts":[["2003"]]},"title":"Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: A phase II pilot study","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(126)","plainTextFormattedCitation":"(126)","previouslyFormattedCitation":"(125)"},"properties":{"noteIndex":0},"schema":""}(126). Many retrospective single-center studies and a meta-analysis suggested a benefit from this technique, both in terms of stent patency and overall survival ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3748/wjg.v23.i7.1278","ISSN":"22192840","PMID":"28275308","abstract":"AIM To perform a systematic review and meta-analysis on clinical outcomes of photodynamic therapy (PDT) in non-resectable cholangiocarcinoma. METHODS Included studies compared outcomes with photody-namic therapy and biliary stenting (PDT group) vs biliary stenting only (BS group) in palliation of non-resectable cholangiocarcinoma. Articles were searched in MEDLINE, PubMed, and EMBASE. Pooled proportions were calculated using fixed and random effects model. Heterogeneity among studies was assessed using the I 2 statistic. (print) ISSN 2219-2840 (online) RESULTS Ten studies (n = 402) that met inclusion criteria were included in this analysis. The P for χ 2 heterogeneity for all the pooled accuracy estimates was > 0.10. Pooled odds ratio for successful biliary drainage (decrease in bilirubin level > 50% within 7days after stenting) in PDT vs BS group was 4.39 (95%CI: 2.35-8.19). Survival period in PDT and BS groups were 413.04 d (95%CI: 349.54-476.54) and 183.41 (95%CI: 136.81-230.02) respectively. The change in Karnofsky performance scores after intervention in PDT and BS groups were +6.99 (95%CI: 4.15-9.82) and -3.93 (95%CI: -8.63-0.77) respectively. Odds ratio for post-intervention cholangitis in PDT vs BS group was 0.57 (95%CI: 0.35-0.94). In PDT group, 10.51% (95%CI: 6.94-14.72) had photosensitivity reactions that were self-limiting. Subgroup analysis of prospective studies showed similar results, except the incidence of cholangitis was comparable in both groups. CONCLUSION In palliation of unresectable cholangiocarcinoma, PDT seems to be significantly superior to BS alone. PDT should be used as an adjunct to biliary stenting in these patients. Core tip: Role of photodynamic therapy (PDT) in unresectable cholangiocarcinoma has been scarcely described in the past. However most of these studies included patients who also underwent additional palliative measures simultaneously. Hence, overall safety and efficacy of photodynamic therapy is not clear. This is the first systematic review and meta-analysis evaluating exclusively the role of PDT in these patients. PDT with biliary stenting was compared to biliary stenting (BS) alone. PDT seems to be relatively safe and significantly superior to BS alone in this patient population. Moole H, Tathireddy H, Dharmapuri S, Moole V, Boddireddy R, Yedama P, Dharmapuri S, Uppu A, Bondalapati N, Duvvuri A. Success of photodynamic therapy in palliating patients with nonresectable cholangiocarcinoma: A systematic review …","author":[{"dropping-particle":"","family":"Moole","given":"Harsha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tathireddy","given":"Harsha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dharmapuri","given":"Sirish","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moole","given":"Vishnu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boddireddy","given":"Raghuveer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yedama","given":"Pratyusha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dharmapuri","given":"Sowmya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Uppu","given":"Achuta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bondalapati","given":"Naveen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Duvvuri","given":"Abhiram","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"World Journal of Gastroenterology","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1278–1288","title":"Success of photodynamic therapy in palliating patients with nonresectable cholangiocarcinoma: A systematic review and meta-analysis","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(127)","plainTextFormattedCitation":"(127)","previouslyFormattedCitation":"(126)"},"properties":{"noteIndex":0},"schema":""}(127). However, prospective randomized studies failed to demonstrate any such benefit. In a randomized phase 2 study, Park et al compared PDT with or without chemotherapy using S1 in 43 patients. The PDT-only arm had clearly lower PFS (2 vs 10 months, p=0.009) and OS (8 vs 17 months, p=0.005), suggesting that PDT has little added value over chemotherapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"Background Hilar cholangiocarcinoma is an uncommon cancer and its overall incidence is increasing. Photodynamic therapy (PDT) has been proposed as palliative management for unresectable hilar cholangiocarcinoma (UHC). To date, little is known about the role of the addition of systemic chemotherapy to PDT for UHC. We performed a prospective, randomised, phase II trial to compare PDT plus S-1 and PDT alone for UHC. Methods Patients with UHC were randomly assigned (in a 1:1 ratio) to PDT plus S-1 or PDT alone. The primary end-point was overall survival. The secondary end-points were progression-free survival, complications, re-intervention rate and quality of life. This trial is registered with , number NCT00869635. Findings Between February 2009 and May 2012, we randomly assigned 21 patients to receive PDT plus S-1 and 22 to receive PDT alone. The UHC patients treated with PDT plus S-1 showed higher 1-year survival rate compared with the patients treated with PDT alone (76.2% versus 32%, P = 0.003) and prolonged overall survival (median 17 months, 95% confidence interval [CI]: 12.6-21.4, versus 8 months, 95% CI: 6-10, P = 0.005, hazard ratio [HR], 0.36; 95% CI: 0.17-0.75). Regarding the secondary end-points, PDT plus S-1 was associated with prolonged progression-free survival compared with PDT alone (median 10 months [95% CI: 4.1-16] versus 2 months [95% CI: 0.4-3.5], P = 0.009 (HR for progression 0.39, 95% CI: 0.19-0.83). There were no differences in the number of PDT sessions, the frequency of cholangitis, overall adverse events or the quality of life in either group. Interpretations PDT plus S-1 was well tolerated and was associated with a significant improvement of overall survival and progression-free survival compared with PDT alone in patients with UHC. These findings warrant further clinical investigation of PDT plus S-1 in patients with UHC. 2014 Elsevier Ltd. All rights reserved.","author":[{"dropping-particle":"al","family":"Park D, Lee S, Park S","given":"et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European journal of cancer","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2014"]]},"page":"1259-1268","title":"Randomised phase II trial of photodynamic therapy plus oral fluoropyrimidine, S-1, versus photodynamic therapy alone for unresectable hilar cholangiocarcinoma","type":"article-journal","volume":"50"},"uris":[""]}],"mendeley":{"formattedCitation":"(128)","plainTextFormattedCitation":"(128)","previouslyFormattedCitation":"(127)"},"properties":{"noteIndex":0},"schema":""}(128). More importantly, the larger PHOTOSTENT-02 phase 3 trial aimed to demonstrate an OS improvement with PDT; the study randomized 92 patients between stenting combined with PDT vs stenting alone. The median OS was significantly lower in the PDT arm (6.2 vs 9.8 months) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"","ISSN":"2059-7029","abstract":"Background: Endobiliary stenting is standard practice for palliation of obstructive jaundice due to biliary tract cancer (BTC). Photodynamic therapy (PDT) may also improve biliary drainage and previous small studies suggested survival benefit. Aims: To assess the difference in outcome between patients with BTC undergoing palliative stenting plus PDT versus stenting alone. Methods: 92 patients with confirmed locally advanced or metastatic BTC, ECOG performance status 0-3 and adequate biliary drainage were randomised (46 per group) to receive porfimer sodium PDT plus stenting or stenting alone. The primary end point was overall survival (OS). Toxicity and progression-free survival (PFS) were secondary end points. Treatment arms were well balanced for baseline factors and prior therapy. Results: No significant differences in grade 3-4 toxicities and no grade 3-4 adverse events due to PDT were observed. Thirteen (28%) PDT patients and 24 (52%) stent alone patients received subsequent palliative chemotherapy. After a median follow-up of 8.4 months, OS and PFS were worse in patients receiving PDT compared with stent alone group (OS median 6.2 vs 9.8 months (HR 1.56, 95% CI 1.00 to 2.43, p=0.048) and PFS median 3.4 vs 4.3 months (HR 1.43, 95% CI: 0.93 to 2.18, p=0.10), respectively). Conclusion: In patients with locally advanced or metastatic BTC, PDT was associated with worse outcome than stenting alone, explained only in part by the differences in chemotherapy treatments. We conclude that optimal stenting remains the treatment of choice for malignant biliary obstruction and the use of PDT for this indication cannot be recommended outside of clinical trials. Trial registration number: ISRCTN 87712758; EudraCT 2005-001173-96; UKCRN ID: 1461.","author":[{"dropping-particle":"","family":"Pereira","given":"S P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jitlal","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Duggan","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lawrie","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beare","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Donoghue","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wasan","given":"H S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valle","given":"J W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bridgewater","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Esmo Open","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2018"]]},"page":"e000379","title":"PHOTOSTENT-02: porfimer sodium photodynamic therapy plus stenting versus stenting alone in patients with locally advanced or metastatic biliary tract cancer","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"(129)","plainTextFormattedCitation":"(129)","previouslyFormattedCitation":"(128)"},"properties":{"noteIndex":0},"schema":""}(129). PDT has not been incorporated into guidelines, and cannot be recommended outside clinical trials ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdw324","ISBN":"3512104800","ISSN":"15698041","PMID":"26314782","abstract":"Galectin-3 (Gal3) plays diverse roles in cancer initiation, progression, and drug resistance depending on tumor type characteristics that are also associated with cancer stem cells (CSCs). Recurrence of breast carcinomas may be attributed to the presence of breast CSCs (BCSCs). BCSCs exist in mesenchymal-like or epithelial-like states and the transition between these states endows BCSCs with the capacity for tumor progression. The discovery of a feedback loop with galectins during epithelial-to-mesenchymal transition (EMT) prompted us to investigate its role in breast cancer stemness. To elucidate the role of Gal3 in BCSCs, we performed various in vitro and in vivo studies such as sphere-formation assays, Western blotting, flow cytometric apoptosis assays, and limited dilution xenotransplant models. Histological staining for Gal3 in tissue microarrays of breast cancer patients was performed to analyze the relationship of clinical outcome and Gal3 expression. Here, we show in a cohort of 87 node-positive breast cancer patients treated with doxorubicin-based chemotherapy that low Gal3 was associated with increased lymphovascular invasion and reduced overall survival. Analysis of in vitro BCSC models demonstrated that Gal3 knockdown by small hairpin RNA (shRNA) interference in epithelial-like mammary spheres leads to EMT, increased sphere-formation ability, drug-resistance, and heightened aldefluor activity. Furthermore, Gal3negative BCSCs were associated with enhanced tumorigenicity in orthotopic mouse models. Thus, in at least some breast cancers, loss of Gal3 might be associated with EMT and cancer stemness-associated traits, predicts poor response to chemotherapy, and poor prognosis.","author":[{"dropping-particle":"","family":"Valle","given":"J. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borbath","given":"I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khan","given":"S. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huguet","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gruenberger","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnold","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"(suppl_5)","issued":{"date-parts":[["2016"]]},"page":"v28-v37","title":"Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up?","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"(122)","plainTextFormattedCitation":"(122)","previouslyFormattedCitation":"(121)"},"properties":{"noteIndex":0},"schema":""}(122). d. Percutaneous thermal ablationFollowing the experience in hepatocellular carcinoma and liver metastasis from colorectal cancer, percutaneous thermal ablation has also been used to treat primary or relapsing ICC. Most of the experience comes from retrospective analysis of single center cohorts and there are no prospective randomized controlled trials. Radiofrequency ablation (RFA) is the most frequently used modality, although microwave ablation has also been used ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejrad.2011.01.014","ISSN":"0720048X","PMID":"21300500","abstract":"Objective: To evaluate the efficacy and safety of sonography-guided percutaneous microwave ablation of intrahepatic primary cholangiocarcinoma. Materials and methods: From May 2006 to March 2010, 15 patients (11 men, 4 women; mean age, 57.4 years) with 24 histologically proven intrahepatic primary cholangiocarcinoma lesions (mean tumor size, 3.2 ± 1.9 cm; range, 1.3-9.9 cm) were treated with microwave ablation. Results: Thirty-eight sessions were performed for 24 nodules in 15 patients. The follow-up period was 4-31 months (mean, 12.8 ± 8.0 months). The ablation success rate, the technique effectiveness rate, and the local tumor progression rate were 91.7% (22/24), 87.5% (21/24), and 25% (6/24) respectively according to the results of follow-up. The cumulative overall 6, 12, 24 month survival rates were 78.8%, 60.0%, and 60.0%, respectively. Major complication occurred including liver abscess in two patients (13.3%) and needle seeding in one patient (6.7%). Both complications were cured satisfied with antibiotic treatment combined to catheter drainage for abscess and resection for needle seeding. The minor complications and side effects were experienced by most patients which subsided with supportive treatment. Conclusion: Microwave ablation can be used as a safe and effective technique to treat intrahepatic primary cholangiocarcinoma. ? 2011 Elsevier Ireland Ltd.","author":[{"dropping-particle":"","family":"Yu","given":"Ming An","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liang","given":"Ping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Xiao Ling","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheng","given":"Zhi Gang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Han","given":"Zhi Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Fang Yi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Radiology","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"title":"Sonography-guided percutaneous microwave ablation of intrahepatic primary cholangiocarcinoma","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(130)","plainTextFormattedCitation":"(130)","previouslyFormattedCitation":"(129)"},"properties":{"noteIndex":0},"schema":""}(130). A meta-analysis including 7 studies that comprised 84 patients and 133 tumors treated with RFA has reported 3- and 5-year overall survival rates of 47 % and 24%, respectively, while major complications were reported in 3.8% of patients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jvir.2015.02.024","PMID":"25899049","author":[{"dropping-particle":"","family":"Han K, Ko HK, Kim KW","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Vasc Interv Radiol.","id":"ITEM-1","issue":"7","issued":{"date-parts":[["0"]]},"page":"943-8","title":"Radiofrequency ablation in the treatment of unresectable intrahepatic cholangiocarcinoma: systematic review and meta-analysis","type":"article-journal","volume":"Jul;26"},"uris":[""]}],"mendeley":{"formattedCitation":"(131)","plainTextFormattedCitation":"(131)","previouslyFormattedCitation":"(130)"},"properties":{"noteIndex":0},"schema":""}(131). As expected, lack of technical success and technical effectiveness occur typically in patients with tumors larger than 3-4 cm ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"02507005","PMID":"22199333","abstract":"To evaluate the usefulness and safety of radiofrequency ablation for primary and recurrent intrahepatic cholangiocarcinoma (ICC) in our single centre experience.","author":[{"dropping-particle":"","family":"Giorgio","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calisti","given":"Giorgio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stefano","given":"Giorgio","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farella","given":"Nunzia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sarno","given":"Antonella","non-dropping-particle":"Di","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amendola","given":"Ferdinando","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scognamiglio","given":"Umberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giorgio","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Anticancer Research","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"title":"Radiofrequency ablation for intrahepatic cholangiocarcinoma: Retrospective analysis of a single centre experience","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(132)","plainTextFormattedCitation":"(132)","previouslyFormattedCitation":"(131)"},"properties":{"noteIndex":0},"schema":""}(132) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00270-010-9849-3","ISSN":"01741551","abstract":"The purpose of this study was to evaluate the safety and efficacy of percutaneous ultrasound (US)-guided radiofrequency ablation (RFA) in patients with intrahepatic cholangiocarcinoma (ICCA) in a small, nonrandomized series. From February 2004 to July 2008, six patients (four men and two women; mean age 69.8 years [range 48 to 83]) with ICCA underwent percutaneous US-guided RFA. Preintervetional transarterial embolization was performed in two cases to decrease heat dispersion during RFA in order to increase the area of ablation. The efficacy of RFA was evaluated using contrast-enhanced dynamic computed tomography (CT) 1 month after treatment and then every 3 months thereafter. Nine RFA sessions were performed for six solid hepatic tumors in six patients. The duration of follow-up ranged from 13 to 21 months (mean 17.5). Posttreatment CT showed total necrosis in four of six tumors after one or two RFA sessions. Residual tumor was observed in two patients with larger tumors (5 and 5.8 cm in diameter). All patients tolerated the procedure, and there with no major complications. Only 1 patient developed post-RFA syndrome (pain, fever, malaise, and leukocytosis), which resolved with oral administration of acetaminophen. Percutaneous RFA is a safe and effective treatment for patients with hepatic tumors: It is ideally suited for those who are not eligible for surgery. Long-term follow-up data regarding local and systemic recurrence and survival are still needed.","author":[{"dropping-particle":"","family":"Carrafiello","given":"Gianpaolo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laganà","given":"Domenico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cotta","given":"Elisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mangini","given":"Monica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fontana","given":"Federico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bandiera","given":"Francesca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fugazzola","given":"Carlo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"CardioVascular and Interventional Radiology","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"title":"Radiofrequency ablation of intrahepatic cholangiocarcinoma: Preliminary experience","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(133)","plainTextFormattedCitation":"(133)","previouslyFormattedCitation":"(132)"},"properties":{"noteIndex":0},"schema":""}(133). In the same line, one study showed a significantly higher local progression-free survival for patients with tumors < 1.5 cm compared with those having tumors ≥ 1.5 cm ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejrad.2010.09.019","ISSN":"0720048X","PMID":"20950977","abstract":"Objective: Percutaneous radiofrequency ablation (RFA) has shown efficacy in patients with recurrent hepatocellular carcinoma, but has not been well documented in patients with recurrent intrahepatic cholangiocarcinoma (ICC). We therefore evaluated the long-term survival and safety of percutaneous RFA for patients with recurrent ICC after curative resection. Materials and methods: A total of 20 patients with 29 recurrent ICCs underwent ultrasound-guided percutaneous RFA. All patients had undergone curative resection of the primary ICC. Tumor size ranged from 0.7 cm to 4.4 cm in maximum dimension (mean, 1.9 cm; median, 1.5 cm). Results: The technical effectiveness rate of RFA was 97% (28/29) of recurrent ICCs. Mean local tumor progression-free survival was 39.8 months, and the cumulative local tumor progression-free 6 month and 1, 2, and 4 year survival rates were 93%, 74%, 74%, and 74%, respectively. Median overall survival after RFA was 27.4 months and the cumulative overall 6 month and 1, 2, and 4 year survival rates were 95%, 70%, 60%, and 21%, respectively. There were two major complications (one liver abscess and one biliary stricture, 7% per treatment) during the follow-up, but no procedure-related deaths. Conclusion: RFA is safe and provides successful local tumor control in patients with recurrent ICC after curative resection. RFA for recurrent ICC resulted in a median overall survival rate of 27.4 months after RFA in the present series. ? 2010 Elsevier Ireland Ltd.","author":[{"dropping-particle":"","family":"Kim","given":"Jin Hyoung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Won","given":"Hyung Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shin","given":"Yong Moon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Pyo Nyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Sung Gyu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hwang","given":"Shin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Radiology","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"title":"Radiofrequency ablation for recurrent intrahepatic cholangiocarcinoma after curative resection","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(134)","plainTextFormattedCitation":"(134)","previouslyFormattedCitation":"(133)"},"properties":{"noteIndex":0},"schema":""}(134). Accordingly, percutaneous thermal ablation could be an option for those rare selected patients with small (tumor diameter ≤ 3 cm) in whom resection is contraindicated based on the lack of an adequate liver functional reserve due to underlying cirrhosis, or because of comorbidities.ConclusionThe combination of cisplatin and gemcitabine in the first-line setting of advanced cholangiocarcinoma has been the only standard treatment option with grade 1 evidence for many years, with no other options available with proven benefit either in the second-line or in the adjuvant settings. Various other chemotherapy regimens have been used in this context with low levels of evidence. Clinical research in CCA has traditionally been very limited. The low incidence compared to other digestive tumors, heterogeneity of the disease, poor patient’s PS and recurrent episodes of biliary tract complications (requiring palliative but invasive procedures) are some of the reasons that have limited the scientific development in this field. However, this scenario is notably changing in the last few years. First, the incidence is slightly increasing in part due to advances in technology (i.e. NGS.) that have enabled more accurate diagnosis of patients with “liver metastases from unknown primary” into CCAs. In addition, advances in surgical and locoregional techniques have substantially reduced procedure morbidities and are also able to solve intercurrent biliary complications even after multiple procedures, allowing patients to reach systemic therapy with improved performance status and organ function. Lastly, the development of CCA reference teams connected by working networks, is allowing patients to access these highly-specialized centers to provide them optimal multidisciplinary care. Very recently, adjuvant capecitabine has shown a substantial numerical improvement in OS in the BILCAP phase III trial. Although this did not reach statistical significance in the ITT population, it has been accepted as standard of care in the adjuvant setting by many clinicians based on the magnitude of the effect and significance in the sensitivity analysis. Results from the randomized ATICCA-1 trial comparing capecitabine vs cisplatin and gemcitabine in this setting are awaited with great interest. Locoregional active treatments as SIRT or SBRT are challenging to test in clinical trials. However, some authors are progressively testing its efficacy and safety in these patients. Results from the ABC-07 trial assessing SBRT, and the SIRCCA study evaluating SIRT are eagerly awaited. Although they are not standard yet, they may represent a new therapeutic option in specific circumstances when performed by experts in the field. A better understanding of the molecular biology of cholangiocarcinoma has prompted, in the last few years, a notable increase in the development of preclinical and clinical research. Previous attempts to improve outcomes both in survival and tolerability by using new targeted agents such as anti-EGFR or anti-VEGFR have failed, although these trials were conducted in molecularly-unselected patient populations. Although there are many potential targets in the scope which have been mentioned along the chapter, it is worth mentioning the IDH1 and FGFR2 pathways. Both are being tested with specific inhibitors in phase III trials in selected populations (tumors with IDH1 mutations or FGFR2 fusions, respectively). Other targeted agents are in different stages of clinical development and are being tested both in specific subpopulations such as anti-HER2, NTRK or PARP inhibitors, as well as in an “all commers” fashion such as pan-EGFR inhibitors, BET inhibitors, HDACi or cell cycle inhibitors. Immunotherapy, which is being incorporated in many solid tumors, is still looking for its niche in CCA. To date, only the MSI biomarker can justify the use of an anti-PD1 therapy. PDL1 expression has been reported in up to 42% and could be potentially explored as a predictive biomarker in the future. Combination strategies of immunotherapy with other anticancer treatments such as chemotherapy are also being investigated. In conclusion, we are assisting to a new era in the medical management of cholangiocarcinoma. Results of these investigations are awaited and hopefully will increase the number of medical treatment options and the prognosis and quality of life of patients with cholangiocarcinoma. 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