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Purpose: The BILCAP study described a modest benefit for capecitabine as adjuvant therapy for curatively resected biliary tract cancer (BTC), and capecitabine has become the standard of care. We present the long-term data and novel exploratory subgroup analyses., Methods: This randomized, controlled, multicenter, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an Eastern Cooperative Oncology Group performance status of < 2. Patients were randomly assigned 1:1 to receive oral capecitabine (1,250 mg/m 2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation. The primary outcome was overall survival (OS). This study is registered with EudraCT 2005-003318-13., Results: Between March 15, 2006, and December 4, 2014, 447 patients were enrolled; 223 patients with BTC resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cutoff of January 21, 2021, the median follow-up for all patients was 106 months (95% CI, 98 to 108). In the intention-to-treat analysis, the median OS was 49.6 months (95% CI, 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI, 29.7 to 44.2) in the observation group (adjusted hazard ratio 0.84; 95% CI, 0.67 to 1.06). In a protocol-specified sensitivity analysis, adjusting for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59 to 0.94). We further describe the prognostic impact of R status, grade, nodal status, and sex., Conclusion: This long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected BTC when used as adjuvant chemotherapy after surgery and should be considered as the standard of care., Competing Interests: John BridgewaterHonoraria: Merck Serono, ServierConsulting or Advisory Role: Merck Serono, Servier, Roche, Bayer, AstraZeneca, Incyte, Basilea, Taiho OncologySpeakers' Bureau: Celgene, Amgen, Bristol Myers SquibbResearch Funding: Amgen, Incyte (Inst)Travel, Accommodations, Expenses: MSD Oncology, Merck Serono, Servier, Bristol Myers Squibb/Medarex, Bristol Myers Squibb Daniel H. PalmerConsulting or Advisory Role: BMS (Inst), MSD, AstraZeneca, Eisai, Sirtex Medical, Roche, Boston Scientific, ViatrisResearch Funding: BMS, Bayer, Sirtex Medical, AstraZeneca, NuCana Darius MirzaStock and Other Ownership Interests: OrganOx Ltd Pippa CorrieHonoraria: Novartis, Merck Sharp & Dohme, Pierre Fabre, Bristol Myers SquibbConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Incyte, Pierre Fabre, Roche, MicrobioticaSpeakers' Bureau: Merck Sharp & Dohme, Novartis, Bristol Myers SquibbResearch Funding: MSD (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Array BioPharma (Inst), Celgene (Inst), Halozyme (Inst), Iovance Biotherapeutics (Inst), Lilly (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme Stephen FalkStock and Other Ownership Interests: GlaxoSmithKlineConsulting or Advisory Role: BMSSpeakers' Bureau: Merck Serono, Servier, AmgenResearch Funding: Gilead Sciences (Inst), AstraZeneca (Inst), Novartis (Inst)Travel, Accommodations, Expenses: CelgeneOther Relationship: Servier Harpreet WasanHonoraria: Merck KGaA, Celgene, Sirtex Medical, Servier, Array BioPharma, Roche/Genentech, ERYTECH Pharma, Incyte, ZymeworksConsulting or Advisory Role: Roche Pharma AG, ERYTECH Pharma, Shire, Incyte, Sirtex medical, Pierre Fabre, Pfizer, BayerSpeakers' Bureau: Sirtex Medical, Celgene, Merck KGaA, Servier, IncyteResearch Funding: Sirtex Medical (Inst), Merck KGaA (Inst), Pfizer (Inst), Merck Sharp & Dohme (Inst) Paul RossStock and Other Ownership Interests: Perci HealthHonoraria: Sirtex Medical, Roche, AstraZeneca, MerckConsulting or Advisory Role: Sirtex Medical, Roche, AstraZeneca, Amgen, Boston ScientificSpeakers' Bureau: Amgen, Merck, Servier, Boston Scientific, Roche, EisaiResearch Funding: Sanofi (Inst), Bayer (Inst)Travel, Accommodations, Expenses: Roche, Ipsen Lucy WallResearch Funding: Merck Serono Jonathan WadsleyConsulting or Advisory Role: Lilly (Inst), Novartis (Inst), Roche (Inst), Ipsen (Inst), Bayer (Inst)Speakers' Bureau: Genzyme, EisaiResearch Funding: AstraZeneca, Genzyme Thomas R. EvansHonoraria: Eisai (Inst), Merck Sharp & Dohme (Inst), Bristol Myers Squibb (Inst), NuCana (Inst), Roche/Genentech (Inst), Ascelia (Inst), AstraZeneca (Inst), Bicycle Therapeutics (Inst), Medivir (Inst)Consulting or Advisory Role: Karus Therapeutics (Inst)Speakers' Bureau: Eisai (Inst), Bristol Myers Squibb (Inst), Merck Sharp & Dohme (Inst), NuCana (Inst), United Medical (Inst), AstraZeneca (Inst), Roche/Genentech (Inst), Medivir (Inst)Research Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), BeiGene (Inst), Basilea (Inst), Celgene (Inst), Eisai (Inst), Merck Sharp & Dohme (Inst), MiNA Therapeutics (Inst), Bicycle Therapeutics (Inst), Lilly (Inst), Merck Serono (Inst), Janssen (Inst), Johnson & Johnson (Inst), Verastem (Inst), Roche/Genentech (Inst), Novartis (Inst), Iovance Biotherapeutics (Inst), Medivir (Inst), Sanofi/Aventis (Inst), Clovis Oncology (Inst), Plexxikon (Inst), NuCana (Inst), Sierra Pharma (Inst), GlaxoSmithKline (Inst), Halozyme (Inst), CytomX Therapeutics (Inst), Vertex (Inst), Athenex (Inst), Adaptimmune (Inst), Immunocore (Inst), Modulate Pharma (Inst), Berg Pharma (Inst), Starpharma (Inst), BiolineRx (Inst), iOnctura (Inst), UCB (Inst), Sapience Therapeutics (Inst), Astellas Pharma (Inst), Boehringer Ingelheim (Inst), Seattle Genetics (Inst)Expert Testimony: Medivir (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Eisai, NuCanaOther Relationship: Genmab (Inst) Deborah StockenResearch Funding: Abbott Diabetes (Inst) Yuk Ting MaHonoraria: Boston ScientificConsulting or Advisory Role: Eisai, Roche, AstraZeneca/MedImmune, Ipsen, Faron PharmaceuticalsResearch Funding: Eisai (Inst), AstraZeneca/Merck (Inst), Faron Pharmaceuticals (Inst), MINA Therapeutics (Inst) John NeoptolemosResearch Funding: Dietmar Hopp Stiftung (Inst), Stiftung Deutsche Krebshilfe (Inst), Heidelberger Stiftung Chirurgie (Inst) Timothy IvesonHonoraria: Servier, AmgenConsulting or Advisory Role: Servier, Bristol Myers Squibb, Pierre Fabre, MSD Oncology David CunninghamStock and Other Ownership Interests: OVIBIOConsulting or Advisory Role: OVIBIOResearch Funding: Celgene (Inst), MedImmune (Inst), Bayer (Inst), 4SC (Inst), Clovis Oncology (Inst), Lilly (Inst), Roche (Inst), Leap Oncology (Inst) Juan W. ValleHonoraria: IpsenConsulting or Advisory Role: Ipsen, Novartis, AstraZeneca, Merck, Agios, Pfizer, PCI Biotech, Incyte, Keocyt, QED Therapeutics, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma EDO GmbH, Wren Laboratories, NuCana, SERVIER, Debiopharm Group, Imaging Equipment Limited, Hutchison MediPharma, Zymeworks, Aptitude Health, Sirtex Medical, Baxter, Medivir, Cantargia ABSpeakers' Bureau: Novartis, Ipsen, NuCana, Imaging Equipment Limited, Mylan, Incyte, ServierTravel, Accommodations, Expenses: NuCana, Lilly, Roche, AstraZeneca/MedImmuneNo other potential conflicts of interest were reported.

Background: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer., Methods: The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m 2 , L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m 2 [bolus], and fluorouracil 2400 mg/m 2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30., Findings: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients)., Interpretation: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials., Funding: Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research., Competing Interests: Declaration of interests AL has received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, and Incyte; advisory honoraria from EISAI, Nutricia Ipsen, QED, and Roche, outside of the submitted work. AL is also a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. DHP declares research grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Nucana, and Sirtex; and consulting or advisory roles for AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Merck Sharp & Dohme, Servier, and Roche, outside of the submitted work. HSW has participated in advisory boards for Incyte, Bayer, Roche/Genentech/Foundation Medicine, SIRTEX Medical, Celgene, and Zymeworks; has been a NICE expert for Bayer (uncompensated); and reports consultancies for ONCOSIL; speaker-related honoraria and travel support from BTG/Biocompatibles, Merck KGaA, and BMS; participation in trials steering committee for Pfizer and Zymeworks; creation of educational materials for AstraZeneca; and receipt of research funding from Sirtex, outside of the submitted work. PJR declares research grants from Sanofi and Bayer; consulting or advisory roles for Bayer, Bristol-Myers Squibb, Eisai, Sirtex, and Roche; speaker fees from Amgen, Roche, and Servier; and travel grants from Bayer, Roche, and Servier, outside of the submitted work. YTM declares speaker honoraria and advisory roles for Bayer, Eisai, and Roche, outside of the submitted work. JW declares research grants from AstraZeneca and Sanofi-Genzyme and consulting or advisory roles for Lilly, AstraZeneca, Sanofi Genyme, Eisai, AAA, Roche, Novartis, and Ipsen, outside of the submitted work. AM declares research grants from Pfizer, Bristol-Myers Squibb, and Bayer; speaker fees from Bristol-Myers Squibb, Bayer Ipsen, EUSA Pharma, Daiichi Sankyo, and Pfizer; and advisory roles for Bayer, Bristol-Myers Squibb, Leo, Pfizer, Merck, and Ipsen, outside of the submitted work. JSW has received educational support for travel and conference attendance from Mylan and Ipsen, and speaker honoraria from Mylan, outside of the submitted work. JR declares research grants, speaker fees, and advisory roles for Ipsen, Novartis, and AAA, outside of the submitted work. JAB declares consulting or advisory roles for Merck Serono, Servier, Roche, Bayer, AstraZeneca, Incyte, and Basilea; and travel support from MSD Oncology, Merck Serono, Servier, and Bristol-Myers Squibb, outside of the submitted work. JWV declares consulting or advisory roles for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED, and Wren Laboratories; speakers' bureau for Imaging Equipment, Ipsen, Novartis, and Nucana; and travel grants from Celgene and Nucana, outside of the submitted work. AAr, SF, RG, KP, AAn, TI, CH, SB, WDR, and LMD declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Cisplatin/gemcitabine is standard first-line treatment for patients with advanced biliary tract cancer (ABC). NUC-1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites., Methods: Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0-1 received NUC-1031 (625 or 725 mg/m 2 ) and cisplatin (25 mg/m 2 ) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression-free survival (PFS), and overall survival (OS)., Results: Twenty-one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC-1031 625 mg/m 2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m 2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment-emergent grade 3-4 adverse events occurring in more than one patient with 625 mg/m 2 NUC-1031 were increased gamma-glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m 2 , increased GGT, 67%, and fatigue, 33%. NUC-1031 725 mg/m 2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3-10.1), and median OS was 9.6 months (95% CI, 6.7-13.1). The median estimates of area under the plasma concentration-time curve from time 0 to last measurable time and maximum concentration were highest for NUC-1031 (218-324 μg•h/mL and 309-889 μg/mL, respectively) and lowest for di-fluoro-deoxycytidine (0.47-1.56 μg•h/mL and 0.284-0.522 μg/mL, respectively)., Conclusion: This is the first study reporting on the combination of NUC-1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m 2 NUC-1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015-000100-26)., Implications for Practice: The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first-line treatment for patients with ABC. NUC-1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC-08) demonstrated a favorable safety profile of NUC-1031 in combination with cisplatin for the first-line treatment of patients with ABC, and 725 mg/m 2 NUC-1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling., (© 2020 AlphaMed Press.)

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m 2 )/cisplatin (25 mg/m 2 ) or gemcitabine (1000 mg/m 2 )/cisplatin (25 mg/m 2 ), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. (Investigational new drug (IND) number : 139058, European Clinical Trials database : EudraCT Number 2019-001025-28, ClinicalTrials.gov identifier : NCT04163900).

Background: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer., Methods: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m 2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13., Findings: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related., Interpretation: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting., Funding: Cancer Research UK and Roche., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes., Methods: Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC)., Results: Samples were available from n = 117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P < 0.001 and P = 0.02, respectively)., Conclusions: Rising circulating VEGFA levels in patients with ABC, treated with CisGem, are associated with worse PFS and OS, not seen in patients receiving cediranib. Rising levels of markers of tumour burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation.

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/m(2) cisplatin and 1000 mg/m(2) 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 ClinicalTrials.gov, 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 12·2 months (IQR 7·3-18·5), median progression-free survival was 8·0 months (95% CI 6·5-9·3) in the cediranib group and 7·4 months (5·7-8·5) in the placebo group (HR 0·93, 80% CI 0·74-1·19, 95% CI 0·65-1·35; p=0·72). Patients who received cediranib had more grade 3-4 toxic effects than did patients who received placebo: hypertension (23 [37%] vs 13 [21%]; p=0·05), diarrhoea (eight [13%] vs two [3%]; p=0·05); platelet count decreased (ten [16%] vs four [6%]; p=0·09), white blood cell decreased (15 [24%] vs seven [11%]; p=0·06) and fatigue (16 [24%] vs seven [11%]; p=0·04)., 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 VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational., Funding: Cancer Research UK and AstraZeneca Pharmaceuticals., (Copyright © 2015 Valle et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Unlabelled: Better prognostic information for resected extrahepatic cholangiocarcinoma could guide treatment strategies and potentially improve outcome. This study performed a systematic review and meta-analysis to identify prognostic biomarkers for further investigation., Methods: Relevant literature was identified using Medline, EMBASE and Web of Science. Primary end point was overall survival assessed on univariate analysis. Log hazard ratio and variance were calculated and pooled using a random effects inverse variance approach. Hazard ratio and 95% confidence intervals were calculated., Results: Thirty-seven studies, including 2371 patients, met the inclusion criteria. Subsequently nine biomarkers predictive of OS were identified (HR, 95% CI): VEGF (2.32, 1.57-3.44), COX-2 (1.94, 1.01-3.71), GLUT-1 (2.09, 1.52-2.89), Cyclin D1 (1.96, 1.02-3.76), p16 (0.68, 0.47-0.98), p27 (0.48, 0.3-0.78), E-Cadherin (0.47, 0.35-0.63), Fascin (2.19, 1.35-3.55), and Ki-67 (1.69, 1.02-2.79)., Conclusion: Meta-analysis has identified a number of prognostic biomarkers for resected extrahepatic cholangiocarcinoma. These markers warrant further investigation as potential therapeutic targets and validation in a prospective setting.

Background: There is no established standard chemotherapy for patients with locally advanced or metastatic biliary tract cancer. We initially conducted a randomized, phase 2 study involving 86 patients to compare cisplatin plus gemcitabine with gemcitabine alone. After we found an improvement in progression-free survival, the trial was extended to the phase 3 trial reported here., Methods: We randomly assigned 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer to receive either cisplatin (25 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter on days 1 and 8, every 3 weeks for eight cycles) or gemcitabine alone (1000 mg per square meter on days 1, 8, and 15, every 4 weeks for six cycles) for up to 24 weeks. The primary end point was overall survival., Results: After a median follow-up of 8.2 months and 327 deaths, the median overall survival was 11.7 months among the 204 patients in the cisplatin-gemcitabine group and 8.1 months among the 206 patients in the gemcitabine group (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.80; P<0.001). The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group (P<0.001). In addition, the rate of tumor control among patients in the cisplatin-gemcitabine group was significantly increased (81.4% vs. 71.8%, P=0.049). Adverse events were similar in the two groups, with the exception of more neutropenia in the cisplatin-gemcitabine group; the number of neutropenia-associated infections was similar in the two groups., Conclusions: As compared with gemcitabine alone, cisplatin plus gemcitabine was associated with a significant survival advantage without the addition of substantial toxicity. Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer. (ClinicalTrials.gov number, NCT00262769.), (2010 Massachusetts Medical Society)