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Liposomal daunorubicin and cytarabine (CPX-351) improves overall survival (OS) compared to 7+3 chemotherapy in older patients with secondary acute myeloid leukaemia (AML); to date there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly-diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). 189 patients were randomized (median age 56y). By clinical criteria 49% had de novo AML, 20% secondary AML and 30% high risk MDS. MDS-related cytogenetics were present in 73% of patients, with complex karyotype in 49%. TP53 was the most commonly mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 patients (44%). The overall response rate (CR + CRi) after course two was 64% and 76% for CPX-351 and FLAG-Ida (OR:0.54, 95%CI 0.28-1.04, p=0.06). There was no difference in OS (13.3 months vs 11.4 months, HR:0.78, 95%CI 0.55-1.12, p=0.17) or event-free survival (HR:0.90, 95%CI 0.64-1.27, p=0.55) in multivariable analyses. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months, HR:0.58, 95% CI 0.36-0.95, p=0.03). There was no difference between the treatment arms in patients with clinically defined secondary AML (HR:1.1, 95%CI 0.52-2.30) or those with MDS-related cytogenetic abnormalities (HR:0.94, 95%CI 0.63-1.40), however an exploratory sub-group of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months, HR:0.42, 95%CI 0.21-0.84, heterogeneity p=0.05). In conclusion, OS in younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.

BackgroundVenous thromboembolism is common in cancer patients and requires anticoagulation with low-molecular-weight heparin (LMWH). Current data recommend LMWH for anticoagulation as far as 6 months, yet guidelines recommend LMWH beyond 6 months in patients who have ongoing or active cancer. This recommendation, based on expert consensus, has not been evaluated in a clinical study.Objectives(1) To identify the most clinically and cost-effective length of anticoagulation with LMWH in the treatment of cancer-associated thrombosis (CAT); (2) to identify practicalities of conducting a full randomised controlled trial (RCT) with regard to recruitment, retention and outcome measurement; and (3) to explore the barriers for progressing to a full RCT.DesignThe Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT) trial is a randomised, multicentre, feasibility mixed-methods study with three components: (1) a RCT comparing ongoing LMWH treatment for CAT with cessation of LMWH at 6 months’ treatment (current licensed practice) in patients with locally advanced or metastatic cancer, consulted in three clinical settings (haematology outpatients, oncology outpatients and primary care); (2) a nested qualitative study, including focus groups with clinicians to investigate attitudes for recruiting to the study and identify the challenges of progressing to a full RCT, and semistructured interviews with patients and relatives to explore their attitudes towards participating in the study, and potential barriers and concerns to participation; and (3) a UK-wide survey exercise to develop a classification and enumeration system for the CAT models and pathways of care.SettingA haematology outpatients department, an oncology outpatients department and primary care.ParticipantsPatients with ongoing active or metastatic cancer who have received 6 months of LMWH for CAT.InterventionsOngoing LMWH treatment for CAT versus cessation of LMWH at 6 months’ treatment in patients with locally advanced or metastatic cancer.Main outcome measures(i) The number of eligible patients over 12 months; (ii) the number of recruited patients over 12 months (target recruitment rate of 30% of eligible patients); and (iii) the proportion of randomised participants with recurrent venous thromboembolisms (VTEs) during follow-up.ResultsFollowing several delays in setting up the RCT component of the study, 5 out of 32 eligible patients consented to be randomised to the RCT suggesting progression to a full RCT was not feasible. Reasons for non-consenting were primarily based on a fixed preference for continuing or discontinuing treatment after 6 months of anticoagulation, and a fear of randomisation to their non-preferred option. Views were largely influenced by patients’ initial experience of CAT. Focus groups with clinicians revealed that they would be reticent to recruit to such a study as they had fixed views of best management despite the lack of evidence. Patient pathway modelling suggested that there is a broad heterogeneity of practice with respect to CAT management and co-ordination, with no consensus on which specialty should best manage such cases.ConclusionsThe results of the RCT reflect recruitment from the oncology site only and provide no recruitment data from haematology centres. However, it is unlikely that these other sites would have access to more eligible patients. The management of cancer-associated thrombosis beyond 6 months will remain a clinical challenge. As it is unlikely that a prospective study will successfully recruit, other strategies to accrue relevant data are necessary. Currently the LONGHEVA (Long-term treatment for cancer patients with deep-venous thrombosis or pulmonary embolism) registry is in development to prospectively evaluate this important and common clinical scenario.Study registrationThis study is registered as clinical trials.gov number NCT01817257 and International Standard Randomised Controlled Trial Number (ISRCTN) 37913976.Funding detailsFunding for the ALICAT trial was provided by the Health Technology Assessment programme (10/145/01) in response to a themed funding call. The study was designed in accordance with the initial funding brief and feedback from the review process.

BACKGROUND: Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II "pick a winner" trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK. METHODS/DESIGN: Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1-2 gastro-oesophageal junction (GOJ), ≥T3 and/or ≥ N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m(2) D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m(2) Day 1,15,29; capecitabine 625 mg/m(2) twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4-6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG. DISCUSSION: Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial. TRIAL REGISTRATION: Eudract No: 2012-000640-10. ClinicalTrials.gov: NCT01843829 .

3 Background: NEOSCOPE compared toxicity and efficacy of 2 pre-op CRT regimens. Methods: Eligibility: Resectable ACA of the oesophagus/GOJ ≥ T3 and/or ≥ N1. Randomisation: 1:1 to OXCAP-CRT (oxaliplatin 85 mg/m2 Day 1,15,29; capecitabine 625 mg/m2 bd on days of RT) or CarPac-CRT (Carboplatin AUC2; paclitaxel 50 mg/m2 Day 1,8,15,22,29); concurrent RT: 45Gy/25 fractions/5 weeks. Both arms received induction chemo: 2 cycles of OXCAP (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m2D1-21, q 3wk). Surgery: 6-8 weeks after naCRT. Detailed RT and pathology quality assurance was built into the protocol. Primary end-point: pathological complete response (pCR). Secondary: toxicity, surgical morbidity/mortality, R1 rate, OS. Statistics: A pCR of 15% would not warrant further investigation but a pCR of 35% would. 76 patients (38/arm) gave 90% power and one-sided type I error of 10% meaning that either arm having ≥10 pCR out of first 38 patients would be considered for Phase III. 85 patients to be recruited (allows 10% loss to follow up). Results: 85 patients were randomised between Oct 2013 and Feb 2015 from 17 UK centres. Patient characteristics: median age 65 yrs, Male (81%), WHO PS 0 (85%). Tumour characteristics: T3 (86%), N1 (48%), lower third/GOJ (90%), median tumour length 5.8cm. CTCAE grade 3/4 toxicity rate during CRT was OXCAP-CRT 42.1%, CarPac-CRT 52.4% (p=0.358). Protocol dose RT OXCAP-CRT 90.5%, CarPac-CRT 93%. Conclusion:Both regimens were well tolerated. CarPac-CRT passed the criteria for taking forward to a phase III study but OXCAP-RT did not. Funding: Cancer Research UK (C44694/A14614), ClinicalTrials.gov: NCT01843829, coordinated by Wales Cancer Trials Unit. Clinical trial information: NCT01843829. [Table: see text]

This research explores the links between bipolar disorder and work. It focuses on the factors that impact an individual’s ability to work and explores whether a simple intervention to support all the key stakeholders (employees with bipolar disorder, line managers and occupational health professionals) involved in the process can be effective. This thesis involved three distinct parts.\ud In the first part a qualitative focus group study explored the views and experiences of the employee, line manager and occupational health professional (OH) participants with respect to the management of bipolar disorder and work. Consensus was reached across the three groups on the main challenges to managing work and bipolar disorder and the solutions to overcome these. The three groups were in agreement on the key areas to be addressed in the intervention to meet the needs of each stakeholder group.\ud In the second part, a qualitative questionnaire study explored the employment patterns and the impact of clinical and demographic variables on the employment outcome across a large sample of participants with a diagnosis of bipolar disorder. This study identified that individuals with bipolar disorder can obtain and sustain employment for prolonged periods, with some reporting sickness absence levels that match those without a mood disorder.\ud It also identified the key clinical and demographical variablesbest associated with employment outcome, which included educational attainment, age of onset of contact with psychiatric services and length of longest psychiatric hospital admission. In the