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Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration: This trial is registered as ISRCTN06473203. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients' disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient's quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible.

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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.

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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.

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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.

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BACKGROUND: 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. DATA: 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. ANALYSIS: 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. RESULTS: 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. CONCLUSION: 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.

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BACKGROUND: Overall survival is the "gold standard" endpoint in cancer clinical trials. It plays a key role in determining the clinical- and cost-effectiveness of a new intervention and whether it is recommended for use in standard of care. The assessment of overall survival usually requires trial participants to be followed up for a long period of time. In this time, they may stop receiving the trial intervention and receive subsequent anti-cancer treatments, which also aim to extend survival, during trial follow-up. This can potentially change the interpretation of overall survival in the context of the clinical trial. This review aimed to determine how overall survival has been assessed in cancer clinical trials and whether subsequent anti-cancer treatments are considered. METHODS: Two searches were conducted using MEDLINE within OVID© on the 9th of November 2021. The first sought to identify papers publishing overall survival results from randomised controlled trials in eight reputable journals and the second to identify papers mentioning or considering subsequent treatments. Papers published since 2010 were included if presenting or discussing overall survival in the context of treating cancer. RESULTS: One hundred and thirty-four papers were included. The majority of these were presenting clinical trial results (98, 73%). Of these, 45 (46%) reported overall survival as a (co-) primary endpoint. A lower proportion of papers including overall survival as a (co-) primary endpoint compared to a secondary endpoint were published in recent years. The primary analysis of overall survival varied across the papers. Fifty-nine (60%) mentioned subsequent treatments. Seven papers performed additional analysis, primarily when patients in the control arm received the experimental treatment during trial follow-up (treatment switching). DISCUSSION: Overall survival has steadily moved from being the primary to a secondary endpoint. However, it is still of interest with papers presenting overall survival results with the caveat of subsequent treatments, but little or no investigation into their effect. This review shows that there is a methodological gap for what researchers should do when trial participants receive anti-cancer treatment during trial follow-up. Future research will identify the stakeholder opinions, on how this methodological gap should be addressed.

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OBJECTIVES: A high-quality and widely accepted UK EQ-5D-5L value set is urgently required to enable the latest version of EQ-5D scored using recent UK public preferences to inform policy including health technology assessments submitted to the National Institute for Health and Care Excellence. This article outlines the study protocol for the generation of a new EQ-5D-5L UK value set. METHODS: Twelve hundred interviews will be undertaken using the composite time trade-off elicitation technique for 102 health states (86 from the international EQ-5D-5L valuation protocol, plus 16 with best predictive performance in an extended design used in the Native American EQ-5D-5L valuation). The sample will be UK adults (age ≥18 years) proportionately representative across England, Wales, Scotland, and Northern Ireland, representative for age, sex, ethnicity, and socioeconomic group, with inclusion of participants with/without health problems. Participants will choose to be interviewed via videoconference (by Zoom) or in-person in a central venue. Data quality will be rigorously assessed. RESULTS: The value set will be generated using tobit random effects and heteroscedastic tobit models (with censoring at -1) using all data, excluding time trade-off values highlighted by participants as ones they would reconsider and data from interviewers failing protocol compliance. Quality and acceptance will be achieved by public involvement, regular Steering Group meetings, independent assessment of data quality at 4 time points, and final endorsement of data and analyses. CONCLUSION: This study will produce a UK value set for the EQ-5D-5L for use in prospective and retrospective data sets containing EQ-5D-5L data.

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BACKGROUND: People with type 1 diabetes and raised glucose levels are at greater risk of retinopathy, nephropathy, neuropathy, cardiovascular disease, sexual health problems and foot disease. The UK National Institute for Health and Care Excellence (NICE) recommends continuous subcutaneous 'insulin pump' therapy for people with type 1 diabetes whose HbA1c is above 69 mmol/mol. Insulin pump use can improve quality of life, cut cardiovascular risk and increase treatment satisfaction. About 90,000 people in England and Wales meet NICE criteria for insulin pumps but do not use one. Insulin pump use also varies markedly by deprivation, ethnicity, sex and location. Increasing insulin pump use is a key improvement priority. Audit and feedback is a common but variably effective intervention. Limited capabilities of healthcare providers to mount effective responses to feedback from national audits, such as the National Diabetes Audit (NDA), undermines efforts to improve care. We have co-developed a theoretically and empirically informed quality improvement collaborative (QIC) to strengthen local responses to feedback with patients and carers, national audits and healthcare providers. We will evaluate whether the QIC improves the uptake of insulin pumps following NDA feedback. METHODS: We will undertake an efficient cluster randomised trial using routine data. The QIC will be delivered alongside the NDA to specialist diabetes teams in England and Wales. Our primary outcome will be the proportion of people with type 1 diabetes and an HbA1c above 69 mmol/mol who start and continue insulin pump use during the 18-month intervention period. Secondary outcomes will assess change in glucose control and duration of pump use. Subgroup analyses will explore impacts upon inequalities by ethnicity, sex, age and deprivation. A theory-informed process evaluation will explore diabetes specialist teams' engagement, implementation, fidelity and tailoring through observations, interviews, surveys and documentary analysis. An economic evaluation will micro-cost the QIC, estimate cost-effectiveness of NDA feedback with QIC and estimate the budget impact of NHS-wide QIC roll out. DISCUSSION: Our study responds to a need for more head-to-head trials of different ways of reinforcing feedback delivery. Our findings will have implications for other large-scale audit and feedback programmes. TRIAL REGISTRATION: ISRCTN82176651 Registered 18 October 2022.

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BACKGROUND: Postoperative complications are common, but there are limited data regarding their implications on patients' quality of life. This study aimed to address this gap in the literature by analysing the impact of postoperative complications on patients' health-related quality of life. METHODS: Data from the Perioperative Quality Improvement Programme were analysed, and included patient-level data for 19 685 adults who underwent elective major abdominal procedures in England since 2016. Postoperative complications were graded using the Clavien-Dindo classification. Quality of life was assessed by responses to the EuroQol five-dimension five-levels-of-response (EQ-5D-5L™) questionnaire before surgery, and at 6 and 12 months after operation. Ordinal logistic regression was used to estimate the association between Clavien-Dindo grades and quality of life. Tobit and ordinary least squares regression analyses were used to estimate the quality-adjusted life-year (QALY) loss resulting from postoperative complications between admission and 12 months after surgery. RESULTS: At 6 and 12 months after surgery, increasingly severe postoperative complications were significantly associated with poorer health-related quality of life. The effect of postoperative complications on quality of life was sustained until at least 12 months after operation. Between admission and 12 months after surgery, 0.012, 0.026, 0.033, and 0.086 QALYs were lost for those experiencing a grade I, II, III, or IV postoperative complication respectively. CONCLUSION: Postoperative complications have a significant and sustained effect on patients' quality of life after surgery; this effect worsens as the severity of the complications increases.

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Little is known about what features of AAC systems are regarded by AAC professionals as more suitable for children with different characteristics. A survey was conducted in which participants rated the suitability of hypothetical AAC systems on a Likert scale from 1 (very unsuitable) to 7 (very suitable) alongside a discrete choice experiment. The survey was administered online to 155 AAC professionals in the United Kingdom of Great Britain and Northern Ireland. Statistical modeling was used to estimate how suitable 274 hypothetical AAC systems were for each of 36 child vignettes. The proportion of AAC systems rated at least 5 out of 7 for suitability varied from 51.1% to 98.5% for different child vignettes. Only 12 out of 36 child vignettes had any AAC systems rated at least 6 out of 7 for suitability. The features of the most suitable AAC system depended on the characteristics of the child vignette. The results show that, while every child vignette had several systems that had a good suitability rating, there were variations, that could potentially lead to inequalities in provision.

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BACKGROUND: People with relapsing-remitting multiple sclerosis can benefit from disease-modifying treatments (DMTs). Several DMTs are available that vary in their efficacy, side-effect profile and mode of administration. OBJECTIVE: We aimed to measure the preferences of people with relapsing-remitting multiple sclerosis for DMTs using a discrete choice experiment and to assess which stated preference attributes correlate with the attributes of the DMTs they take in the real world. METHODS: Discrete choice experiment attributes were developed from literature reviews, interviews and focus groups. In a discrete choice experiment, participants were shown two hypothetical DMTs, then chose whether they preferred one of the DMTs or no treatment. A mixed logit model was estimated from responses and individual-level estimates of participants' preferences conditional on their discrete choice experiment choices calculated. Logit models were estimated with stated preferences predicting current real-world on-treatment status, DMT mode of administration and current DMT. RESULTS: A stated intrinsic preference for taking a DMT was correlated with currently taking a DMT, and stated preferences for mode of administration were correlated with the modes of administration of the DMTs participants were currently taking. Stated preferences for treatment effectiveness and adverse effects were not correlated with real-world behaviour. CONCLUSIONS: There was variation in which discrete choice experiment attributes correlated with participants' real-world DMT choices. This may indicate patient preferences for treatment efficacy/risk are not adequately taken account of in prescribing. Treatment guidelines must ensure they take into consideration patients' preferences and improve communication around treatment efficacy/risk.

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BACKGROUND: Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. METHODS: This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. FINDINGS: Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). INTERPRETATION: Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. FUNDING: UK National Institute for Health and Care Research.

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BACKGROUND: Undertaking randomized clinical trials (RCTs) in emergency surgical settings is associated with methodological and practical challenges. This study explored patients' and clinicians' perspectives associated with the conduct of an RCT comparing laparoscopic and open colorectal surgery in the acute setting. METHODS: All eligible patients screened and enrolled for the 'Laparoscopic versus open colorectal surgery in the acute setting (LaCeS)' multicentre, randomized clinical feasibility trial in five UK NHS Trusts were invited to respond to a survey. Patients and healthcare professionals were also invited to take part in semi-structured interviews. Survey and interviews explored the acceptability of the feasibility trial. Interviews were audio recorded, transcribed verbatim, and analysed using thematic analysis. Survey data were analysed descriptively to assess patient views of the trial and intervention. RESULTS: Out of 72 patients enrolled for the LaCeS RCT, survey data were collected from 28 patients (38.9 per cent), and interviews were conducted with 16 patients and 14 healthcare professionals. Thirteen out of 28 patients (46 per cent) had treatment preferences but these were not strong enough to deter participation. Twelve of the patients interviewed believed that their surgeon preferred laparoscopic surgery, but this did not deter them from participating in the trial. Half of the surgeons interviewed expressed the view that laparoscopic surgery was of benefit in this setting, but recognized that the need for research evidence outweighed their personal treatment preferences. Eight of the 14 recruiters reported that the emergency setting affected recruitment, especially in centres with fewer recruiting surgeons. Interviewees reported that recruitment was helped significantly by using surgical trainees to consent patients. CONCLUSION: This study identified specific challenges for the LaCeS trial design to address and adds significant insights to our understanding of recruiting to emergency surgical trials more broadly.

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INTRODUCTION: Multiple myeloma is a plasma cell malignancy that accounts for 1%-2% of newly diagnosed cancers.At diagnosis, approximately 20% of patients can be identified, using cytogenetics, to have inferior survival (high-risk). Additionally, standard-risk patients, with detectable disease (minimal residual disease (MRD)-positive) postautologus stem cell transplant (ASCT), fare worse compared with those who do not (MRD-negative). Research is required to determine whether a risk-adapted approach post-ASCT could further improve patient outcomes. METHODS: RADAR is a UK, multicentre, risk-adapted, response-guided, open-label, randomised controlled trial for transplant-eligible newly diagnosed multiple myeloma patients, using combinations of lenalidomide (R), cyclophosphamide (Cy), bortezomib (Bor), dexamethasone (D) and isatuximab (Isa).Participants receive RCyBorD(x4) induction therapy, followed by high-dose melphalan and ASCT. Post-ASCT, there are three pathways as follows:A phase III discontinuation design to assess de-escalating therapy in standard-risk MRD-negative patients. Participants receive 12 cycles of Isa maintenance. Those who remain MRD-negative are randomised to either continue or stop treatment.A phase II/III multiarm multistage design to test treatment strategies for treatment escalation in standard-risk MRD-positive patients. Participants are randomised to either; R, RBorD(x4) +R, RIsa, or RBorIsaD(x4) + RIsa.A phase II design to assess the activity of intensive treatment strategies in high-risk patients. Participants are randomised to RBorD(x4) +R or RBorIsaD(x4) + RIsa.1400 participants will be registered to allow for 500, 450 and 172 participants in each pathway. Randomisations are equal and treatment is given until disease progression or intolerance. ETHICS AND DISSEMINATION: Ethical approval was granted by the London-Central Research Ethics Committee (20/LO/0238) and capacity and capability confirmed by the appropriate local research and development department for each participating centre prior to opening recruitment. Participant informed consent is required before trial registration and reconfirmed post-ASCT. Results will be disseminated by conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISCRTN46841867.

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This study examines the comparative equivalence, feasibility and acceptability of video and in-person interviews in generating time trade-off (TTO) values. Sample participants in England were recruited using a blended approach of different methods and sampled based on age, gender, ethnicity, and index of multiple deprivation. Participants were randomly allocated to be interviewed either via video or in-person. Participants completed TTO tasks for the same block of 10 EQ-5D-5L health states using the EQ-VTv2 software. Feasibility, acceptability and equivalence was assessed across mode using: sample representativeness; participant understanding, engagement and feedback; participant preferred mode of interview; data quality; mean utility and distribution of values for each health state; and regression analyses assessing the impact of mode whilst controlling for participant characteristics. The video and in-person samples had statistically significant differences in ethnicity and income but were otherwise broadly similar. Video interviews generated marginally lower quality data across some criteria. Participant understanding and feedback was positive and similar across modes. TTO values were similar across modes; whilst mean in-person TTO values were lower for the more severe states, mode was insignificant in most regression analyses. There was no clear preference of mode across all participants, though the characteristics of participants preferring to be interviewed in-person or by video differs. Video and in-person TTO interviews were feasible, acceptable and generated good-quality data, though video interviews had lower quality data across some criteria. Whilst TTO values differed across modes for the more severe states, mode does not appear to be the cause. The study found that the characteristics of people preferring each mode differed, and this should be taken into account in future valuation studies since sample representativeness for some characteristics, and therefore potentially TTO values, could be affected by the choice of mode.

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AIM: The global burden of colorectal cancer (CRC) is set to increase by 60% by 2030. An aging population and increasing treatment complexity add difficulties for patients and clinicians in CRC management. Patient preferences can be investigated using attribute-based stated preference (AbSP) techniques to explore trade-offs between different treatments. These techniques include discrete-choice experiments (DCEs), conjoint analysis and time-trade off (TTO) methods. This systematic review with a narrative synthesis aimed to determine the use and design of AbSP studies in CRC treatment and to identify patient choice themes. METHODS: The searches were performed using MEDLINE, Embase, PsycInfo and Cochrane Library in March 2021. All manuscripts featuring the use of AbSP techniques in CRC treatment were included. Data synthesis was performed using a narrative approach. RESULTS: The search strategy returned 271 articles. Eighteen AbSP studies were included featuring 1890 patients and 296 clinicians. AbSP techniques compromised DCE (38.9%, n = 7), TTO (38.9%, n = 7) and conjoint analysis (22.2%, n = 4). Eleven studies (61.1%) involved piloting of tasks and the average task completion rate was 75%. CRC treatments included chemotherapy (33%, n = 6), combined treatments (33%, n = 6), surgery (17%, n = 3), targeted therapy (11%, n = 2) and radiotherapy (6%, n = 1). The most examined domain was physical health, investigated with 49 (59.8%) attributes. CONCLUSIONS: Life expectancy was the main attribute in chemotherapy treatment. With surgery, patients were willing to trade life-expectancy to avoid adverse outcomes or a permanent stoma. Communication skills, treatment cost, and clinicians' views were important attributes for patients in cancer services. Further research in the elderly population, and other quality of life domains, are needed to deliver patient-centred CRC care.

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INTRODUCTION: Multiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have improved. However, this is less apparent in older, less fit patients, who are ineligible for stem cell transplant. Research is required in this patient group, taking into account frailty and aiming to improve: treatment tolerability, clinical outcomes and quality of life. METHODS AND ANALYSIS: Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma is a national, phase III, multicentre, randomised controlled trial comparing standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide to lenalidomide+ixazomib, in patients with newly diagnosed multiple myeloma not suitable for stem cell transplant. Overall, 740 participants will be registered into the trial to allow 720 and 478 to be randomised at induction and maintenance, respectively.All participants will receive IRD induction with the dosing strategy randomised (1:1) at trial entry. Patients randomised to the standard, reactive arm will commence at the full dose followed by toxicity dependent reactive modifications. Patients randomised to the adaptive arm will commence at a dose level determined by their International Myeloma Working Group frailty score. Following 12 cycles of induction treatment, participants alive and progression free will undergo a second (double-blind) randomisation on a 1:1 basis to maintenance treatment with lenalidomide+placebo versus lenalidomide+ixazomib until disease progression or intolerance. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the North East-Tyne & Wear South Research Ethics Committee (19/NE/0125) and capacity and capability confirmed by local research and development departments for each participating centre prior to opening to recruitment. Participants are required to provide written informed consent prior to trial registration. Trial results will be disseminated by conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN17973108, NCT03720041.

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BACKGROUND: Good patient access to medicines at home during the last 12 months of life is critical for effective symptom control, prevention of distress and avoidance of unscheduled and urgent care. OBJECTIVES: To undertake an evaluation of patient and carer access to medicines at end-of-life within the context of models of service delivery. DESIGN: Evaluative, mixed method case studies of service delivery models, including cost analysis. The unit of analysis was the service delivery model, with embedded sub-units of analysis. SETTING: (i) General Practitioner services (ii) Palliative care clinical nurse specialist prescribers (iii) a 24/7 palliative care telephone support line service. PARTICIPANTS: Healthcare professionals delivering end-of-life care; patients living at home, in the last 12 months of life, and their carers. METHODS: Within each case: Patients/carers completed a structured log on medicines access experiences over an 8-week period. Logs were used as an aide memoire to sequential, semi-structured interviews with patients/carers at study entry, and at four and eight weeks. Healthcare professionals took part in semi-structured interviews focused on their experiences of facilitating access to medicines, including barriers, and facilitating factors. Data on prescribed medicines were extracted from patient records. Detailed contextual data on each case were also collected from a range of documents. Patient, carer and healthcare professional interview data were analysed using Framework Analysis to identify main themes. We estimated prescription costs and budget impact analysis of the different service models. Data were triangulated within each case. Cross-case comparison and logic models were employed to enable systematic comparisons across service delivery types. FINDINGS: Accessing medicines is a process characterised by complexity and systems inter-dependency requiring considerable co-ordination work by patients, carers and healthcare professionals. Case studies highlighted differences in speed and ease of access to medicines across service delivery models. Key issues were diversifying the prescriber workforce, the importance of continuity of relationships and team integration, access to electronic prescribing systems, shared records and improved community pharmacy stock. Per patient prescription cost differentials between services were modest but were substantial when accounting for the eligible population over the medium term. CONCLUSIONS: Experiences of medicines access would be improved through increasing numbers of nurse and pharmacist prescribers, and improving shared inter-professional access to electronic prescribing systems and patient records, within care delivery systems that prioritise continuity of relationships. Community pharmacy stock of palliative care medicines also needs to become more reliable.

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INTRODUCTION: Unmet needs in patients with cancer and their carers are common but poorly identified and addressed. The Needs Assessment Tool-Cancer (NAT-C) is a structured consultation guide to identify and triage patient and carer unmet needs. The NAT-C is validated, but its effectiveness in reducing unmet patient and carer needs in primary care is unknown. METHODS AND ANALYSIS: Cluster randomised controlled trial with internal pilot and embedded process evaluation to test the clinical and cost effectiveness of the NAT-C in primary care for people with active cancer in reducing unmet patient and carer need, compared with usual care. We will recruit 1080 patients with active cancer (and carers if relevant) from 54 general practices in England.Participating practices will be randomised 1:1 to either deliver an NAT-guided clinical consultation plus usual care or to usual care alone. Consenting participants with active cancer and their carers (if nominated) will be asked to complete study questionnaires at baseline, 1 and 3 months for all, 6 months except for those recruited outside of the last 3 months of recruitment, and attend an NAT-C appointment if allocated to an intervention practice. An internal pilot will assess: site and participant recruitment, intervention uptake and follow-up rates. The primary outcome, the proportion of patients with an unmet need on the Supportive Care Needs Survey Short Form 34 at 3 months postregistration, will be analysed using a multilevel logistic regression. Mixed-methods process evaluation informed by Normalisation Process Theory will use quantitative survey and interview data from clinicians and key stakeholders in cancer care to develop an implementation strategy for nationwide rollout of the NAT-C if the intervention is cost-effective. ETHICS AND DISSEMINATION: Ethical approval from London-Surrey REC (20/LO/0312). Results will be peer-reviewed, published and made available to research participants. TRIAL REGISTRATION NUMBER: ISRCTN15497400.

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The all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed multiple myeloma (MM). We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with relapsed MM after prior treatment with thalidomide, lenalidomide, and a proteasome inhibitor (ISRCTN58227268), with the primary objective to test whether ICD has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in terms of progression-free survival (PFS). Between January 2016 and December 2018, 112 participants were randomised between ICD (n = 58) and CD (n = 54) in 33 UK centres. Patients had a median age of 70 years and had received a median of four prior lines of therapy. 74% were classed as frail. Median PFS in the ICD arm was 5.6 months, compared to 6.7 months with CD (hazard ratio (HR) = 1.21, 80% CI 0.9-1.6, p = 0.3634). Response rates and overall survival were not significantly different between ICD and CD. Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve outcomes in the comparatively frail patients enroled in the MUKeight trial.

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