OBJECTIVES:A UK EQ-5D-5L value set is urgently required to enable the latest version of EQ-5D to inform policy, including evidence submitted to the National Institute for Health and Care Excellence as part of health technology appraisals. This paper presents the EQ-5D-5L UK value set generated from preference data elicited using the time trade-off (TTO) technique with a representative sample of the UK public. METHODS:In-person and videoconference interviews were undertaken using the composite TTO method for 102 health states with a representative sample of UK adults (age 18 years and older) across England, Wales, Scotland, and Northern Ireland. Data quality was rigorously and independently assessed throughout the study. TTO data was modeled using a range of models, with the value set being selected as the preferred model using predefined criteria. RESULTS:Data quality standards were achieved. A total of 1200 interviews were conducted, 1102 (91.8%) by means of videoconference and 98 (8.2%) in person. The sample was representative of age, sex, ethnicity, and socioeconomic groups and proportionally representative for the 4 nations: England, Scotland, Wales, and Northern Ireland. TTO values highlighted by participants as ones they would reconsider were excluded. The value set was generated using a random effects Tobit model. The dimensions of anxiety/depression and usual activities have a greater relative impact on utilities than in the UK EQ-5D-3L value set, though the worst state value is comparable. CONCLUSION:The study collected good-quality data from a representative sample of the UK public, modeled the data appropriately and transparently, to generate a UK EQ-5D-5L value set suitable for informing policy.

Background: Continuous Subcutaneous Insulin Infusions (open- or closed- loop insulin pumps) improve outcomes for people with type 1 diabetes. Internationally, uptake of these technologies varies between clinical teams and by patient age, sex, ethnicity, and deprivation.We evaluated the effectiveness of a quality improvement collaborative (QIC) intervention to increase insulin pump use following feedback from a national clinical audit. Methods: EQUIPD was a cluster randomised controlled trial in England and Wales. Participants were people with type 1 diabetes and an HbA1c higher than 69·0mmol/mol. Specialist diabetes teams were randomly assigned (1:1) to QIC intervention with feedback or feedback alone (control). The primary outcome was the proportion of people established on insulin pumps (having two or more prescriptions for insulin preparations suitable for pumps at least three months apart). Trial registration ISRCTN82176651. Findings: 190/6010 (3·2%) of those in the control arm and 300/11065 (2·7%) in the QIC arm were established on insulin. The odds ratio of being established on an insulin pump in the QIC intervention versus control was 0·78 (95% CI: 0·51 to 1·21, p-value: 0·276). The QIC intervention cost £9·41 ($12·57) per patient. It would have been cost-effective to invest £43 ($57) per patient to achieve a 1% increase in insulin pump use. Interpretation: We found no evidence that QIC intervention was superior to control. Recent hybrid-closed loop guidance may have changed practice across both arms. Our economic analysis supports work to test alternative implementation strategies.

Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimens (FLAIR) demonstrated improved progression-free survival for ibrutinib and rituximab (IR) compared with fludarabine, cyclophosphamide and rituximab (FCR) in previously untreated chronic lymphocytic leukaemia (CLL). This report presents the secondary end-point of health-related quality of life (HR-QoL). FLAIR was a phase 3, open-label, randomised trial across 101 hospitals. Eligible patients were aged 18-75 years, World Health Organization performance status (PS) ≤2, requiring treatment; those with >20% 17p deletion were excluded. IR was administered for up to 6 years and FCR for six cycles. Participants completed European Organisation for Research and Treatment of Cancer Quality of Life C30 Questionnaire (EORTC-QLQ-C30), QLQ CLL Module (QLQ-CLL16), three-level EQ-5D (EQ-5D-3L) and EQ5D visual analogue (EQ-VAS) at baseline and follow-up. Function and symptom trajectories were analysed using repeated-measures multilevel regression. 84.4% of participants completed baseline questionnaires and subsequent compliance was 67.6%-83.5%. Median age was 63 years; most participants were white and male. HR-QoL trajectories were similar. FCR recipients had worse scores at end of treatment but recovered thereafter. By 48 months, more FCR-treated participants showed meaningful improvements in several scales. Statistically significant differences (p < 0.05) favoured IR for physical, role and social function; emotional function favoured FCR. Diarrhoea was more common with IR; fatigue and dyspnoea were more common with FCR, though differences did not exceed minimally important thresholds. Overall, scales were comparable between treatment groups, indicating that continuous IR does not compromise HR-QoL.

BACKGROUND:Androgen deprivation therapy (ADT) for prostate cancer causes substantial adverse effects. Despite consistent national and international guideline recommendations, supervised exercise is rarely integrated into care. We aimed to determine whether the STAMINA lifestyle intervention, embedded into cancer care, would improve cancer-specific quality of life and fatigue versus behaviourally Optimised Usual Care in men with prostate cancer in England. METHODS:STAMINA was a multicentre, randomised trial done across 15 UK National Health Service (NHS) trusts in England. Men on ADT for prostate cancer were eligible. Participants were randomly assigned (5:4) via computer-generated minimisation, stratified by age, ADT duration, chemotherapy or androgen receptor pathway inhibitor therapy, and radiotherapy, to the STAMINA lifestyle intervention or to Optimised Usual Care. Participants were aware of treatment allocation. The STAMINA lifestyle intervention comprised supervised aerobic and resistance exercise for 12 months, dietary advice, behavioural support, and complimentary gym membership. Optimised Usual Care comprised clinician training, educational materials, behavioural prompts, and safety-to-exercise checks. Primary outcomes were the Functional Assessment of Cancer Therapy-prostate (FACT-P) and the Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F) subscale at 12 months, analysed by intention to treat (according to randomised treatment). This trial is registered with ISRCTN (ISRCTN46385239), and recruitment is complete. FINDINGS:Between Jan 20, 2022, and June 12, 2023, 700 men were randomly assigned to STAMINA lifestyle intervention (n=389) or Optimised Usual Care (n=311). Median age was 71·6 years (IQR 66·3-76·0), and 680 (97%) of 700 participants were White. Primary outcome data were available for 345 (89%) of 389 participants in the STAMINA lifestyle intervention group and 251 (81%) of 311 in the Optimised Usual Care group. The STAMINA lifestyle intervention was superior to Optimised Usual Care in terms of FACT-P score (adjusted mean difference 4·5, 97·232% CI 1·7-7·2; p=0·0004) and FACIT-F score (1·9, 0·4-3·4; p=0·0068). Three intervention-related serious adverse events occurred in the STAMINA lifestyle intervention group (transient loss of consciousness, leg pain or weakness, and back pain); all participants recovered. No treatment-related deaths occurred. INTERPRETATION:The STAMINA lifestyle intervention meets best practice guidelines, can be implemented in NHS trusts in England, and offers clinicians a clear basis for identification and prescription of a supervised exercise and dietary advice intervention to mitigate negative effects associated with ADT. FUNDING:National Institute for Health Research.

Introduction Frail myeloma (MM) patients remain at risk of greater toxicity and shorter survival outcomes. Approaches to improve this by therapy adaptation include delivering different therapeutic combinations or dose adjusting components of therapy. Understanding which of these approaches to adopt is timely as 4-drug combinations are now approved for transplant ineligible (TNE) patients but were only trialled in non-frail patients. Methods The UK-MRA, Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed TNE MM patients. The primary objectives are to compare standard and frailty-score adapted (FA) induction therapy with an oral PI/IMiD combination (ixazomib, lenalidomide, dexamethasone, IRD) for 12 cycles and, after a second randomisation (R2), to compare maintenance R to IR. Frailty status was assessed using the full IMWG frailty score. The primary endpoint, early treatment cessation (ETC) in UNFIT/FRAIL patients within 60 days of R1, was reported at ASH 2024 with no significant difference, but there was significant heterogeneity in this outcome with UNFIT patients having a benefit from FA treatment (OR 0.34 [0.16,0.72])​ not seen in FRAIL patients (OR 1.33 [0.79,2.25]). With longer follow-up we now present data exploring the pathway and outcomes of UNFIT and FRAIL patients, including updated analysis of EFS, PFS and OS. Results The FiTNEss trial randomised 733 patients from 04/AUG/20 - 01/MAR/24 at 84 UK sites. 239 (32.6%) were UNFIT and 296 (40.4%) FRAIL. In the UNFIT group the median (IQR) age was 77 years (75-78), 56.9% were male, ISS was I in 25.9%, II 43.9% and III 30.1%, 13% had ECOG >=2. In the FRAIL group the median age was 81 years (78-84), 55.4% were male, ISS was I in 14.2%, II 48.6% and III 36.8%, 43.2% had ECOG >=2. Across the primary endpoint population (UNFIT/FRAIL combined) after median follow up of 26 (IQR 16,38) months (m) median EFS was not significantly different between FA and standard dosing (FA 2m [95% CI 1,3] vs standard 1m [1,2]). PFS and OS also appeared similar (median PFS: FA 23m [19,34] vs standard 27m [21,36] HR 1.12 [0.87,1.43], p=0.372; 3yr OS: FA 69.5% [61.9,75.9] vs standard 66.4% [59.2,72.7], HR 0.87 [0.63,1.20], p=0.399). Due to the heterogeneity in the ETC primary endpoint we performed subset analysis in UNFIT and FRAIL patients for EFS, PFS and OS. In UNFIT patients FA therapy was associated with improved EFS and OS (median EFS FA 5m [95% CI 3,9] vs standard 2m [1,4]; median PFS FA 34m [20,46] vs standard 37m [26,NR]; 3yr OS: FA 84.9% [75.4,91.0] vs standard 75.2% [65.1,82.7]). FRAIL patients had inferior outcomes across all endpoints compared to UNFIT patients and did not appear to gain any benefit from FA dosing (median EFS FA 1m [0,1] vs standard 1m [0,1]; median PFS FA 19m [14,26] vs standard 21m [16,33]; 3yr OS: FA 55.2% [43.6,65.3] vs standard 58.7% [48.1, 67.8]). Most EFS events were >=G3 non-haematological toxicities (most frequently infections and skin/subcutaneous disorders). These comprised a lower proportion of events in the FA group (UNFIT 70/104, 67.3%; FRAIL 92/138, 66.7%) compared to standard (UNFIT 78/104, 75.0%; FRAIL 105/140, 75.0%). FRAIL patients were more likely to have >=G4 haem toxicity, withdrawn or died as their EFS event, and these comprised a slightly higher proportion of events in the FA group, leading to the similar EFS in this group. FRAIL patients had a shorter median duration of induction therapy even with FA dosing (UNFIT: FA 12 cycles [95% CI NR] vs standard 12 [10,NR]; FRAIL: FA 7 [4,10] vs standard 9 [6,11]). FRAIL patients in both arms were much less likely to reach R2 (UNFIT: FA 55%, standard 46%; FRAIL: FA 29%, standard 30%). Unacceptable toxicity was the most reported reason for withdrawal from treatment. Conclusions Results from FiTNEss suggest that ETC, EFS and OS were improved by FA dosing in UNFIT but not FRAIL patients. In FRAIL patients, shorter durations of treatment and shorter EFS/PFS/OS persist with PI/IMiD combinations even with prospective treatment modifications. Data from other trials suggest anti-CD38/IMiD combinations may be better tolerated in FRAIL patients, with improved outcomes. Our data suggest the recently approved anti-CD38/IMiD/PI combinations should be used cautiously in FRAIL patients even with FA dosing strategies. Future studies should explore other approaches such as treatment switching for FRAIL patients with a suboptimal response.

LBA9508 Background: Optimal first line therapy for patients with metastatic melanoma is an immunotherapy regimen containing an anti-PD1 antibody, regardless of tumour BRAF mutation status. Anti-PD1 antibodies are licensed for use until disease progression. Recurrence rarely occurs in responding patients after 2 years of treatment. Optimal duration of anti-PD1-based immunotherapy has not been established. Reduced treatment duration may reduce the risk of long-term side-effects and generate cost savings for healthcare systems. Methods: DANTE (ISRCTN15837212) was a UK academic multi-centre parallel group non inferiority trial. Adults with unresectable stage III/IV melanoma receiving first line anti-PD1 +/- anti-CTLA-4 antibody immunotherapy were eligible. Patients who were progression-free after 1 year of treatment were randomised (1:1) to stop treatment (with the option of restarting on progression) or to continue treatment to at least 2 years in the absence of disease progression / unacceptable toxicity (control). The primary endpoint was progression-free survival (PFS) at 1 year post-randomization. Secondary endpoints included quality of life, best objective response, overall survival, toxicity and cost-effectiveness. A qualitative study explored patient acceptance of randomization. Follow-up to 4-years was planned for PFS with secondary outcomes collected up to 18-months post-randomization. Assuming a 2-year PFS rate in the control arm of 86% and defining non-inferiority (NI) as a reduction in PFS of no more than 6%, a sample size of 1208 patients (604 per arm) was required (80% power, 5% significance, 5% drop-out). DANTE closed early due to slow patient enrolment. PFS was compared between arms using Cox’s proportional hazards model, adjusting for stratification factors. Results: Between September 2018 and March 2023, 415 patients were registered from 36 UK hospitals and 166 patients (65.6% male, median age 74, BRAF mutant 25.9%) were randomised. Patient characteristics were broadly balanced. As of 27 th January 2025, with a median follow-up of 29.1 (IQR 17.9-39.3) months, there were 53 PFS events in total: 18 in the control arm (15 progressions+3 deaths) versus 35 in the stop arm (29 progressions+6 deaths). PFS rates at 1-year were 87.6% in the control arm and 80.2% in the stop arm (HR 1.76; 90% CI 1.03-3.03), with an absolute difference of -7.4% and 90% two-sided CI -17.1-2.32, which is within the pre-defined NI margin of 6%. Analyses are ongoing, results for secondary endpoints will be presented. Conclusions: DANTE is the largest prospective melanoma trial evaluating immunotherapy duration completed to date. Although results suggest stopping immunotherapy at 1 year was non-inferior compared to at least 2 years of treatment, the trial was underpowered due to early closure. Continuing immunotherapy for at least 2 years should remain as standard treatment. Clinical trial information: 15837212 .

INTRODUCTION:In the UK National Health Service (NHS), most people with cancer are cared for at oncology outpatient services, where there are no standardised procedures for managing pain. As a result, patients with cancer may receive inadequate care for pain. The Cancer Pain-assessment Toolkit for Use in RoutinE oncology outpatient services aims to assess the feasibility of conducting a multicentre cluster-randomised trial of a systematic pain assessment and management programme integrated within routine care at UK NHS oncology outpatient services. This protocol describes an embedded process evaluation that aims to evaluate the acceptability, fidelity and implementation of the intervention and trial procedures. METHODS AND ANALYSIS:A combination of methods will be used in the process evaluation. Quantitative data on fidelity and intervention implementation will be collected using case report forms completed at sites, capturing details on training, intervention delivery and adherence. Qualitative data on acceptability and trial experience will be collected through semistructured interviews with intervention recipients (participants), intervention deliverers (healthcare professionals), research nurses and intervention champions. Researcher fieldnotes will also document trial acceptability throughout the trial. Quantitative data will be summarised descriptively. Qualitative data will be analysed using thematic analysis, guided by the framework of acceptability. ETHICS AND DISSEMINATION:The trial received ethical approval from South Yorkshire Research Ethics Committee and Health Research Authority (21/HRA/5245). Site-specific approvals were obtained from the research and innovation offices at Leeds Teaching Hospital and Hull Teaching Hospital. Trial findings will be disseminated through peer-reviewed publications and via participating sites. TRIAL REGISTRATION NUMBER:ISRCTN86926298.

Access to safe, timely and affordable surgical care is lacking globally. Less than 6

There is limited evidence on the optimal frequency of mammogram surveillance. At 5-year follow-up, the Mammo-50 trial found that, in patients aged 50+ and 3 years post diagnosis, less frequent mammograms were non-inferior to annual mammograms for breast-cancer-specific-survival, recurrence-free interval and overall survival. A within-trial cost-effectiveness analysis compared annual versus less frequent mammogram surveillance over 5 years from healthcare and societal perspectives. Hospital Episodes Statistics captured hospital-based resource use. Health-related quality of life and other cost data were obtained via questionnaires at surveillance mammograms. A budget impact analysis estimated NHS savings. Less frequent surveillance led to cost savings of −£543.88 (−£1116; £26) and a small reduction in quality-adjusted life years (QALYs) of −0.02 (−0.095; 0.06) per patient. The incremental net monetary benefit at a £20,000/QALY threshold was £187 (−£1574; £2027). Including societal costs increased savings to £1543 per person (−£2416; −£669), and cost-effectiveness. Projected NHS savings were £185.87 million over 6 years. Less frequent mammogram surveillance is cost-effective. Uncertainty remains due to variability in costs and quality of life estimates, and missing data in the less frequent arm due to study design. Given the trial’s non-inferiority findings, this strategy is recommended from healthcare and societal perspectives.

Overall survival is used to assess clinical effectiveness in cancer clinical trials. In practice, it may be influenced by intercurrent events post-randomisation. The decisions made on how to address intercurrent events, change the interpretation of the results. An example is when participants stop their trial intervention and start subsequent anti-cancer interventions (treatment lines) during trial follow-up. At present, there is no evidence on the views of all stakeholders about this intercurrent event or consensus on how it should be addressed. The aim of this work was to understand the perspectives of all stakeholders and to obtain consensus through a qualitative study to guide future methodological work. A modified Rand/UCLA appropriateness method was implemented. Stakeholder views were collected using an online questionnaire and discussed at a focus group. The questionnaire included items on, the different methods for addressing an intercurrent event, data collection following an intercurrent event, statistical assumptions, and data presentation. Analysis was descriptive incorporating a conventional content approach. Consensus was defined a priori. One hundred three stakeholders (30 statisticians or other data analysts, 6 payers or industry partners, 22 healthcare professionals and 45 patient, carer or members of the public) completed the questionnaire between 3/8/2022 and 30/9/2022. Seventy-nine percent of respondents thought it important to consider the potential effect of subsequent treatment lines. Consensus was reached on most questionnaire items. Stakeholders agreed that statistical assumptions were applicable only in “Some Scenarios” and that results should be presented using both a visual and summary measure. The focus group discussed different methods for addressing an intercurrent event and items around data collection where consensus was unclear. Seven participants attended (two patients/carers, one healthcare professional, three statisticians and one payer) with K-LR and PW. Attendees agreed that the treatment policy approach should be considered in future work as it was the most realistic, and that data collection was acceptable with informed consent. This work demonstrates that all stakeholder groups are interested in how subsequent treatment lines may impact overall survival and provides evidence on what future methodological work in the area should consider. The next step of this work will investigate whether it is possible to estimate the overall survival treatment effect in a hypothetical scenario where participants who received second-line therapy all received the same second-line therapy. This will aim to complement the existing treatment policy approach and quantify the impact of subsequent treatments.

Anastomotic leakage (AL) following resection for rectal cancer has a significant negative impact on patients and represents a substantial economic burden. Intraoperative fluorescence angiography using indocyanine green (ICG+) is a potential strategy to reduce ALs. Findings from recent randomized controlled trials were positive; however, no full economic evaluations of ICG+ have been conducted to date. We conducted a cost-utility analysis of the ICG+ vs standard surgeon assessment (ICG-) using the IntAct trial data. We took the perspective of the UK NHS over a 90-day post procedure horizon. EQ-5D-5L and resource use data were collected at baseline, 30 and 90 days in the UK trial sub-sample to enable estimation of quality-adjusted life years (QALYs) and costs. Incremental cost-effectiveness ratios (ICERs) were estimated using generalised linear regression models. We analysed data from n=345 UK patients finding negligible adjusted differences in QALYs (−0.001 in the primary multiply imputed analysis) at 90 days but modest cost savings (£73 [95% CI −£78, −£67] for the primary and £140 [95% CI −£150, −£129] for the secondary complete case analyses) per patient for ICG+. The ICER primary analysis indicated ICG+ was cost effective. Simulations indicated ICG+ had a 60% chance of being the optimal strategy in the primary analysis. This research represents a novel contribution on the value of ICG+ for preventing ALs. Results indicate that ICG+ leads to modest cost savings. Together with the clinical effectiveness results, and the potential positive budget impact, the current results indicate ICG+ is likely to provide net health benefit.

Background: Clinical outcomes in transplant eligible (TE) newly diagnosed myeloma (NDMM) patients continue to improve, which highlight the persistent unmet need in patients with genetically high-risk disease. Recently published IMS/IMWG high risk criteria confirms poor outcomes in double-hit [2 high risk cytogenetic abnormalities (HRCA)] disease in comparison to patients with single HRCA (Avet-Loiseau JCO 2025). RADAR aimed to evaluate Isa-VRDc induction followed by single autologous stem cell transplant (ASCT), Isa-VRD consolidation and IsaR maintenance, in patients with ultra-high-risk disease. Study design/ Methods: UK-MRA RADAR is a prospective, national, multi-centre, risk-adapted, response-guided multi-arm, multi-stage (MAMS) phase II/III trial which aims to recruit 1400 patients with NDMM eligible for ASCT. Participants enter a high-risk pathway based on the presence of ≥2 HRCA (t(4;14), t(14;16), t(14:20), del(17p), del1p and gain(1q)) defined by standard-of-care cytogenetic (FISH/MLPA) testing. Participants with high-risk disease in v4 of the protocol (HRv4) received 4 x 21 day cycles of Isa-VRDc (Isa: Weekly C2, D1 and D8 C3, D1 and D15 C4; V: Weekly; R:D1-14; D:Weekly; c: D1 and D8). Participants received an ASCT followed by 4 x 21 day cycles of Isa-VRD consolidation (Isa: Weekly C1, D1 and D8 C2, D1 and D15 C3+; V: Weekly; R:D1-14; D:Weekly) and 28 day cycles of IsaR maintenance (Isa: Weekly C1, D1 and D15 C2; R: D1 – D21) until progression. Flow MRD testing (sensitivity 10-5) was done post-induction, post-transplant and 3, 6,12 and 18 months after starting consolidation. Primary endpoint was the proportion of patients alive and progression-free at 18 months. HRv4 followed a Sargent three-outcome phase II design. It was designed to test the null hypothesis (Ho) that the proportion of patients alive and progression-free at 18 months post-registration was ≤65.9% (based on data from Myeloma XI) against the alternative hypothesis of ≥81.7% (OPTIMUM, Kaiser Blood 2021). 70 patients were required for at least 80% power, testing at the 1-sided maximum 5% significance level with a 5% drop-out rate. Results: 70 participants were registered to HRv4 between 1Sept22 and 4Sept23. Median age was 60 yrs (range, 40-74). 84.3% of individuals were of white ethnicity. R-ISS staging proportions at diagnosis I/II/III/missing was 18.6%/67.1%/10.0%/4.3% respectively. All participants had 2 HRCA and 8/70 had ≥3 HRCA. Median follow up was 24 months (IQR, 21-26). 69/70 participants started induction treatment. 68/69 completed all four cycles. Adequate stem cell harvest was obtained in all eligible patients (62/68), and 61 proceeded to ASCT. 56 participants commenced post-ASCT treatment. Dose delivery was as per the protocol in >90% of all treatment cycles across the entire treatment pathway (induction, consolidation and maintenance). 67/70 participants were evaluable for primary endpoint. The cut-offs for the three-outcome design were: Red (do not reject Ho) ≤47 / 67, Amber (neither accept or reject Ho) 48 - 51 / 67, Green (reject Ho) ≥52 / 67. In total 59/67 participants were alive and progression-free at 18 months (88.1% (95%CI: 77.8-94.7)). ≥VGPR rates increased from 82.9% post induction to 87.5% post-transplant and were 96.2% and 85.7% at 6 and 12 months after starting consolidation. MRD negativity was 26.2% post-induction, 69.5% post-transplant and 69.6% and 59.5% at 6 and 12 months after starting consolidation. Of MRD negative participants post-ASCT with a sample available, 66.7% remained MRD negative 12 months after starting consolidation. A grade 3-4 adverse reaction was reported in 63.8% of participants. No treatment-related deaths have been reported. 47/69 (68.1%) participants had an SAE. Infections were the commonest SAE; 36/85 (42.4%) with 31/36 ≥G3 (86.1%).Conclusions: RADAR HRv4 pathway is the largest analysis of ultra-high risk (double hit) patients reported to date. All participants meet the new IMS/IMWG HR criteria. Isa-VRDc induction, followed by Isa-VRD consolidation post-ASCT and IsaR maintenance met the primary endpoint, with the study crossing the Green design threshold, with 88% (59/67) alive and progression-free at 18 months. These results compare favourably to the TE NDMM GMMG HD-7 trial which included standard and high-risk patients, and high-risk CONCEPT and OPTIMUM NDMM trials with extended consolidation

Each year in the UK approximately 367,000 people are diagnosed with cancer of whom half will experience moderate to severe chronic pain and a third are undertreated for their pain. Most people with cancer are cared for at oncology outpatient services where there are no standardised approaches for managing pain. As a result, cancer patients are at risk of receiving inadequate care for pain. There is a need for a standardised approach to pain management within oncology outpatient services. The aim of this pilot trial is to establish the feasibility of conducting a multi-centre clustered-randomised trial of an integrated standardised pain assessment and management programme integrated within routine care at oncology outpatient services in the United Kingdom National Health Service (NHS). We will conduct a two-arm pilot cluster randomised trial with nested process evaluation to evaluate the feasibility and acceptability of trial processes, establish fidelity of intervention implementation, estimate variability in outcomes and feasibility of future economic evaluation. Twelve outpatient services (clusters) from at least two NHS tertiary oncology referral centres (sites), in the North of England will be randomised (1:1) to deliver a pain management programme plus usual care or usual care alone and will recruit a total sample of 180 participants. Adults attending a participating outpatient service who self-report a score of ≥ 3 on the 0–10 Numerical Rating Scale (NRS) for worst pain in the past 72 h in any part of their body, and will be available for 1-week follow-up will be eligible. Participant self-reported questionnaires will be collected at baseline, 1-week, 1-month, and 2-months with medical record review at 1-month and 2-months. Progression to a future trial will be based on pre-defined criteria associated with eligibility and consent rates, follow-up and intervention delivery and acceptability. Little research has described optimal ways to implement a standardised pain assessment and management programme into oncology outpatient services. The strengths of the pilot trial are its sample size, number of clusters, and planned evaluation of trial processes and intervention fidelity to provide robust trial evidence to fully inform a future definitive phase III multi-centre cluster randomised trial within the UK NHS. The CAPTURE pilot trial is registered on the ISRCTN registry (86,926,298).

Background UK national clinical guidance recommends that men with prostate cancer on androgen deprivation therapy are offered twice weekly supervised aerobic and resistance exercise to address iatrogenic harm caused by treatment. Very few NHS trusts have established adequate provision of such services. Furthermore, interventions fail to demonstrate sustained behaviour change. The STAMINA lifestyle intervention offers a system-level change to clinical care delivery addressing barriers to long-term behaviour change and implementation of new prostate cancer care pathways. This trial aims to establish whether STAMINA is clinically and cost-effective in improving cancer-specific quality of life and/or reducing fatigue compared to optimised usual care. The process evaluation aims to inform the interpretation of results and, if the intervention is shown to benefit patients, to inform the implementation of the intervention into the NHS. Methods Men with prostate cancer on androgen deprivation therapy (n = 697) will be identified from a minimum of 12 UK NHS trusts to participate in a multi-centre, two-arm, individually randomised controlled trial. Consenting men will have a 'safety to exercise' check and be randomly allocated (5:4) to the STAMINA lifestyle intervention (n = 384) or optimised usual care (n = 313). Outcomes will be collected at baseline, 3-, 6- and 12-month post-randomisation. The two primary outcomes are cancer-specific quality of life and fatigue. The parallel process evaluation will follow a mixed-methods approach to explore recruitment and aspects of the intervention including, reach, fidelity, acceptability, and implementation. An economic evaluation will estimate the cost-effectiveness of the STAMINA lifestyle intervention versus optimised usual care and a discrete choice experiment will explore patient preferences. Discussion The STAMINA lifestyle intervention has the potential to improve quality of life and reduce fatigue in men on androgen deprivation therapy for prostate cancer. Embedding supervised exercise into prostate cancer care may also support long-term positive behaviour change and reduce adverse events caused by treatment. Findings will inform future clinical care and could provide a blueprint for the integration of supervised exercise and behavioural support into other cancer and/or clinical services. Trial registration ISRCTN 46385239, registered on 30/07/2020. Cancer Research UK 17002, retrospectively registered on 24/08/2022.

Introduction: Older and frailer patients with multiple myeloma (MM) are less able to tolerate some therapies which may explain the inferior health outcomes they experience. The UK Myeloma Research Alliance Myeloma XIV FiTNEss trial (NCT0372004) is a phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not eligible for stem cell transplant that compares a standard (reactive) therapeutic dosing strategy (RT) to a pre-emptive frailty-adjusted dosing strategy (FA). FA uses IMWG-based scores to determine patients' level of frailty and adapts the dosing strategy accordingly in an effort to reduce toxicity and early treatment cessation. We conducted an economic evaluation alongside the FiTNEss clinical trial to determine the value of FA vs RT in Unfit/Frail patients over 12 months. Methods: The FiTNEss trial randomised newly diagnosed MM patients to either standard reactive dose modification in light of toxicity (RT) vs upfront pre-emptive dose-modification according to IMWG FS (FA), of induction therapy comprising the oral triplet ixazomib, lenalidomide and dexamethasone (IRd). The primary end point of the first randomisation was to compare early treatment cessation of induction therapy delivery with the triplet IRd between patient cohorts. The primary endpoint of the second randomisation was to compare progression free survival for maintenance lenalidomide (R) plus placebo and lenalidomide plus ixazomib (IR). The economic evaluation adopted the cost-utility framework and presents cost per quality-adjusted life year (QALY). Health-related quality of life (HRQoL) was captured on the EQ-5D-3L measure at baseline, 2, 6 and 12 months. Health care resource use was captured using patient reported forms at the same time points, supplemented by hospital incident forms. Costs included resources required for the frailty assessment, medication costs (including second line therapies for those progressing or stopping first line therapy), primary care costs (e.g. GP visits) and secondary care costs (e.g. hospital visits and stays). We conducted a complete case (CC) analysis, using cases who had provided full cost and HRQoL follow-up data, and an intention-to-treat (ITT) analysis using multiple imputation to deal with missing data. Estimates were adjusted for trial minimisation factors. We present cost and QALYs per trial arm and incremental cost-effectiveness ratios (ICERs). Sampling uncertainty is characterised in the probability of cost-effectiveness given the UK willingness to pay for QALY gains (£20,000-£30,000). Results: The FiTNEss trial recruited 733 patients from 04/08/2020 until 01/03/2024 from 84 sites in the UK; 535 patients were Unfit/Frail. The cost of the frailty assessment was modest (£28.50 based on an assumed 30 minutes of research nurse time). A total of 163 patients were included in the CC sample. The number of treatment cycles completed was slightly higher among Unfit/Frail in the FA arm (7.84 [95%CI 7.3:8.39] vs 7.73 [95%CI 7.19:8.27], p=0.78). Mean per patient primary care costs were lower in the FA arm (£107 [95%CI £75:£138] vs £194 [95%CI £112:£276], p=0.05); but mean secondary care costs were higher in the FA arm (£3,582 [95%CI £2324:£4841] vs £2,036 [95%CI £1295:£2777], p=0.04), driven by higher unplanned hospital admitted days. The adjusted differences in costs and QALYs between trial arms for the CC analysis were £7,431 [95%CI £-3532:£18394, p=0.14] and 0.072 ([95%CI 0.022:0.141], p=0.07) (ICER = £103,208), respectively; and for the ITT analysis were £250 [95%CI £-6841:£7340, p=0.95] and 0.02 ([95%CI -0.021:0.06], p=0.35) (ICER = £12,943), respectively. Thus, FA was more costly on average when considering medication and health care use costs but offered QALY gains over RT. At the UK cost-effectiveness threshold of £20,000-30,000 FA has a 52-54% probability of cost-effectiveness. Conclusions: This preliminary analysis suggests that frailty-adjustment of induction therapy in newly diagnosed TNE MM is likely to lead to non-trivial benefits in QALYs over 12 months, but higher levels of secondary care use and medication costs compared to standard dosing. Based on the ITT analysis, the FA strategy is likely to be considered cost-effective in Unfit/Frail patients. Future planned research extrapolating HRQoL benefits over a longer time horizon, where cheaper maintenance therapies are used, may give a more accurate estimate of the value of FA.

Background Health policy promotes patient participation in decision making about service organisation. In English general practice this happens through contractually required patient participation groups (PPGs). However, there are problems with the enactment of PPGs that have not been systematically addressed. Aim To observe how a co-designed theory-informed intervention can increase representational legitimacy and facilitate power sharing to support PPGs to influence decision making about general practice service improvement. Design and setting Participatory action research to implement the intervention in two general practices in the North of England was undertaken. The intervention combined two different participatory practices: partnership working involving externally facilitated meetings with PPG members and staff; and consultation with the wider patient population using a bespoke discrete choice experiment (DCE). Method To illustrate decision making in PPGs, qualitative data are presented from participant observation notes and photographed visual data generated through participatory methods. The DCE results are summarised to illustrate how wider population priorities contributed to overall decision making. Observational data were thematically analysed using normalisation process theory with support from a multi-stakeholder co-research group. Results In both general practices, patients influenced decision making during PPG meetings and through the DCE, resulting in bespoke patient-centred action plans for service improvement. Power asymmetries were addressed through participatory methods, clarification of PPG roles in decision making, and addressing representational legitimacy through wider survey consultation. Conclusion Combining participatory practices and facilitated participatory methods enabled patients to influence decision making about general practice service improvement. The policy of mandatory PPGs needs updating to recognise the need to resource participation in a meaningful way.

We investigate whether and how general population health state values were influenced by the initial stages of the COVID-19 pandemic. Changes could have important implications, as general population values are used in health resource allocation. In Spring 2020, participants in a UK general population survey rated 2 EQ-5D-5L states, 11111 and 55555, as well as dead, using a visual analogue scale (VAS) from 100 = best imaginable health to 0 = worst imaginable health. Participants answered questions about their pandemic experiences, including COVID-19’s effect on their health and quality of life, and their subjective risk/worry about infection. VAS ratings for 55555 were transformed to the full health = 1, dead = 0 scale. Tobit models were used to analyse VAS responses, as well as multinomial propensity score matching (MNPS) to create samples balanced according to participant characteristics. Of 3021 respondents, 2599 were used for analysis. There were statistically significant, but complex associations between experiences of COVID-19 and VAS ratings. For example, in the MNPS analysis, greater subjective risk of infection implied higher VAS ratings for dead, yet worry about infection implied lower ratings. In the Tobit analysis, people whose health was affected by COVID-19 rated 55555 higher, whether the effect on health was positive or negative. The results complement previous findings that the onset of the COVID-19 pandemic may have impacted EQ-5D-5L health state valuation, and different aspects of the pandemic had different effects.

Background Multiple myeloma (MM) predominates in the older adult with significant morbidity and mortality. Frailty (F) is increasingly recognized as a predictor for long- and short-term outcomes, with frailer patients at risk of greater toxicity, treatment discontinuation and poorer survival. Identifying and tailoring treatment for older/frail patients with MM remains an unmet need. The International Myeloma Working Group frailty score (IMWG FS) is a prognostic biomarker, but no evidence exists for it as a predictive biomarker, and hence its capability to direct therapy decision-making. This is key to its impact on clinical practice. Study Design and Methods The UK-MRA Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed patients with MM ineligible for stem cell transplant. The primary objectives of the study are 1) to compare in unfit/frail patients early treatment cessation (within 60 days of randomisation) randomised to standard (RT: reactive) and frailty-adjusted (FA: F based on IMWG FS) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) and 2) to compare progression-free survival for maintenance lenalidomide (R) and lenalidomide plus ixazomib (IR). Here we report the final analysis of the first primary objective. Results The FiTNEss trial recruited patients between 04/08/2020 and 01/03/2024 from 84 UK sites. 733 patients were randomised. Median (range) age at randomisation was 77 years (62-93) with 35.2% aged 76-80 and 23.6% over 80. 55.7% were male sex. ISS was I in 20.7%, II in 46.4% and III in 32.6% with standard risk CA in 41.3%, high risk in 19.0% and unavailable in 39.7%. WHO performance status was 0-1 in 76.5%, 2 in 15.6% and 3+ in 7.2%. IMWG FS was FIT in 27.0%, UNFIT in 32.6% and FRAIL in 40.4%. In the R1 ITT population (UNFIT and FRAIL; n=535) 115 patients stopped therapy in the first 60 days: 61/265 (23.0%) in the RT arm vs 54/270 (20%) in the FA arm (adjusted Odds Ratio [OR]: 1.21; 95%CI 0.80-1.84; p=0.368). Reasons for stopping therapy were: death (RT 29.5%, 18/61 vs FA 27.8%, 15/54), patient choice (RT 26.2%, 16/61 vs FA 25.9%, 14/54), clinician choice (RT 13.1%, 8/61 vs FA 20.4%, 11/54) and toxicity (RT 24.6%, 15/61 vs FA 20.4%, 11/54). There was a significant difference in early treatment cessation in the FRAIL (26.1%, n=295) versus the UNFIT (15.8%, n=240) group (adj. OR: 1.85; 95%CI 1.19-2.88; p=0.0061). Across all induction cycles delivered (n=5890 in 733 participants) dose modifications were higher in the RT arm vs FA (I 6.9% vs 5.8%, R 11.9% vs 10.0% and d 9.5% vs 7.2%). In the safety population (n=722), the total number of treatment emergent adverse events was similar between the arms. However, for treatment-emergent serious adverse reactions there were more infections in the RT arm (17%, 60/359 vs 13%, 47/363) and more GI toxicity in the FA arm (8%, 29/359 vs 10%, 36/363). There was no clinically significant difference in the local response rate between the arms, >=VGPR in 42.2% of RT vs 37.8% in FA. Similarly, the 6- and 12-month MRD negative rate was similar (RT 9.9% and 9.3% vs FA 6.8% and 8.2%). 1-year PFS was 73.4% (95%CI 68.1-77.9) in the RT and 76.4% (95%CI 71.3-80.7) in the FA arms (Hazard Ratio [HR] 0.95, 95%CI 0.74-1.20; p=0.657). 136 patients have died, 81 (22.2%) in the RT and 55 (14.9%) in the FA arms. Causes of death were: PD (RT 30.9%, 25/81 vs FA 38.2%, 21/55), infection (RT 19.8%, 16/81 vs FA 9.1%, 5/55), cardiac (RT 7.4%, 6/81 vs FA 12.7%, 7/55) and respiratory (RT 9.9%, 8/81 vs FA 9.1%, 5/55). The 1-year OS was 83.2% (95%CI 78.5-86.9) in RT and 88.7% (95%CI 84.7-91.7) in FA arm (HR 1.45 95%CI 1.03-2.04; p=0.035). Conclusion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. The delivery of a frailty-adjusted dosing schedule whilst not improving early treatment cessation rate, did not compromise depth or durability of response and did reduce early mortality (1-year). Subgroup analysis will investigate where the greatest benefit is achieved. This analysis highlights the potential of the IMWG FS to be both a prognostic and predictive biomarker for early mortality in newly diagnosed TNE MM patients.

BACKGROUND:Approximately 1.5 million adults in the UK have a learning disability. The difference between age at death for this group and the general population is 26 years for females and 22 years for males. The NHS Long Term Plan (January 2019) recognises learning disabilities as a clinical priority area. People with a learning disability are often excluded from research by design or lack of reasonable adjustments, and self-reported health status/health-related quality of life questionnaires such as the EQ-5D are often not appropriate for this population. Here, we systematically examine the EQ-5D-3L (its wording, content, and format) using qualitative methods to inform the adaption of the measure for use with adults with mild to moderate learning disabilities.METHODS:Think-aloud interviews with carers/advocates of learning-disabled adults were undertaken to explore the difficulties with completing the EQ-5D-3L. Alternative wording, language, structure, and images were developed using focus groups, stakeholder reference groups, and an expert panel. Data analysis followed a framework method.RESULTS:The dimensions and levels within the EQ-5D-3L were deemed appropriate for adults with mild to moderate learning disabilities. Consensus on wording, structure, and images was reached through an iterative process, and an adapted version of the EQ-5D-3L was finalised.CONCLUSION:The EQ-5D-3L adapted for adults with mild to moderate intellectual/learning disabilities can facilitate measurement of self-reported health status. Research is underway to assess the potential use of the adaptation for economic evaluation.