Thulium laser transurethral vaporesection of the prostate versus transurethral resection of the prostate for men with lower urinary tract symptoms or urinary retention (UNBLOCS): a randomised controlled trial.

BACKGROUND: Transurethral resection of the prostate (TURP) is the standard operation for benign prostatic obstruction. Thulium laser transurethral vaporesection of the prostate (ThuVARP) is a technique with suggested advantages over TURP, including reduced complications and hospital stay. We aimed to investigate TURP versus ThuVARP in men with lower urinary tract symptoms or urinary retention secondary to benign prostatic obstruction. METHODS: In this randomised, blinded, parallel-group, pragmatic equivalence trial, men in seven UK hospitals with bothersome lower urinary tract symptoms or urinary retention secondary to benign prostatic obstruction were randomly assigned (1:1) at the point of surgery to receive ThuVARP or TURP. Patients were masked until follow-up completion. Centres used their usual TURP procedure (monopolar or bipolar). All trial surgeons underwent training on the ThuVARP technique. Co-primary outcomes were maximum urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS) at 12-months post-surgery. Equivalence was defined as a difference of 2·5 points or less for IPSS and 4 mL per s or less for Qmax. Analysis was done according to the intention-to-treat principle. The trial is registered with the ISRCTN Registry, ISRCTN00788389. FINDINGS: Between July 23, 2014, and Dec 30, 2016, 410 men were randomly assigned to ThuVARP or TURP, 205 per study group. TURP was superior for Qmax (mean 23·2 mL per s for TURP and 20·2 mL per s for ThuVARP; adjusted difference in means -3·12, 95% CI -5·79 to -0·45). Equivalence was shown for IPSS (mean 6·3 for TURP and 6·4 for ThuVARP; adjusted difference in means 0·28, -0·92 to 1·49). Mean hospital stay was 48 h in both study groups. 91 (45%) of 204 patients in the TURP group and 96 (47%) of 203 patients in the ThuVARP group had at least one complication. INTERPRETATION: TURP and ThuVARP were equivalent for urinary symptom improvement (IPSS) 12-months post-surgery, and TURP was superior for Qmax. Anticipated laser benefits for ThuVARP of reduced hospital stay and complications were not observed. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Content of Health Economics Analysis Plans (HEAPs) for Trial-Based Economic Evaluations: Expert Delphi Consensus Survey.

OBJECTIVES: Health economics analysis plans (HEAPs) currently lack consistency, with uncertainty surrounding appropriate content. We aimed to develop a list of essential items that should be included in HEAPs for economic evaluations conducted alongside randomized trials. METHODS: A list of potential items for inclusion was developed by examining existing HEAPs. An electronic Delphi survey was conducted among professional health economists. Respondents were asked to rate potential items from 1 (least important) to 9 (most important), suggest additional items, and comment on proposed items (round 1). A second survey (round 2) was emailed to participants, including the participant's own scores from round 1 along with summary results from the whole panel; participants were asked to rerate each item. Consensus criteria for inclusion in the final list were predefined as >70% of participants rating an item 7-9 and <15% rating it 1-3 after round 2. A final item selection meeting was held to scrutinize the results and adjudicate on items lacking consensus. RESULTS: 62 participants completed round 1 of the survey. The initial list included 72 potential items; all 72 were carried forward to round 2, and no new items were added. 48 round 1 respondents (77.4%) completed round 2 and reached consensus on 53 items. At the final meeting, the expert panel (n = 9) agreed that 58 items should be included in the essential list, moved 9 items to an optional list, and dropped 5 items. CONCLUSIONS: Via expert consensus opinion, this study identified 58 items that are considered essential in a HEAP.

Development of a Core Outcome Set for Clinical Effectiveness Trials in Esophageal Cancer Resection Surgery.

OBJECTIVE: Development of a core outcome set (COS) for clinical effectiveness trials in esophageal cancer resection surgery. BACKGROUND: Inconsistency and heterogeneity in outcome reporting after esophageal cancer resection surgery hampers comparison of trial results and undermines evidence synthesis. COSs provide an evidence-based approach to these challenges. METHODS: A long list of clinical and patient-reported outcomes was identified and categorized into outcome domains. Domains were operationalized into a questionnaire and patients and health professionals rated the importance of items from 1 (not important) to 9 (extremely important) in 2 Delphi survey rounds. Retained items were discussed at a consensus meeting and a final COS proposed. Professionals were surveyed to request endorsement of the COS. RESULTS: A total of 68 outcome domains were identified and operationalized into a questionnaire; 116 (91%) of consenting patients and 72 (77%) of health professionals completed round 1. Round 2 response rates remained high (87% patients, 93% professionals). Rounds 1 and 2 prioritized 43 and 19 items, respectively. Retained items were discussed at a patient consensus meeting and a final 10-item COS proposed, endorsed by 61/67 (91%) professionals and including: overall survival; in-hospital mortality; inoperability; need for another operation; respiratory complications; conduit necrosis and anastomotic leak; severe nutritional problems; ability to eat/drink; problems with acid indigestion or heartburn; and overall quality of life. CONCLUSIONS: The COS is recommended for all pragmatic clinical effectiveness trials in esophageal cancer resection surgery. Further work is needed to delineate the definitions and parameters and explore best methods for measuring the individual outcomes.

Core Items for a Standardized Resource Use Measure: Expert Delphi Consensus Survey.

BACKGROUND: Resource use measurement by patient recall is characterized by inconsistent methods and a lack of validation. A validated standardized resource use measure could increase data quality, improve comparability between studies, and reduce research burden. OBJECTIVES: To identify a minimum set of core resource use items that should be included in a standardized adult instrument for UK health economic evaluation from a provider perspective. METHODS: Health economists with experience of UK-based economic evaluations were recruited to participate in an electronic Delphi survey. Respondents were asked to rate 60 resource use items (e.g., medication names) on a scale of 1 to 9 according to the importance of the item in a generic context. Items considered less important according to predefined consensus criteria were dropped and a second survey was developed. In the second round, respondents received the median score and their own score from round 1 for each item alongside summarized comments and were asked to rerate items. A final project team meeting was held to determine the recommended core set. RESULTS: Forty-five participants completed round 1. Twenty-six items were considered less important and were dropped, 34 items were retained for the second round, and no new items were added. Forty-two respondents (93.3%) completed round 2, and greater consensus was observed. After the final meeting, 10 core items were selected, with further items identified as suitable for "bolt-on" questionnaire modules. CONCLUSIONS: The consensus on 10 items considered important in a generic context suggests that a standardized instrument for core resource use items is feasible.

Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection: A Randomized Clinical Trial.

Importance: Acute lower respiratory tract infection is common and often treated inappropriately in primary care with antibiotics. Corticosteroids are increasingly used but without sufficient evidence. Objective: To assess the effects of oral corticosteroids for acute lower respiratory tract infection in adults without asthma. Design, Setting, and Participants: Multicenter, placebo-controlled, randomized trial (July 2013 to final follow-up October 2014) conducted in 54 family practices in England among 401 adults with acute cough and at least 1 lower respiratory tract symptom not requiring immediate antibiotic treatment and with no history of chronic pulmonary disease or use of asthma medication in the past 5 years. Interventions: Two 20-mg prednisolone tablets (n = 199) or matched placebo (n = 202) once daily for 5 days. Main Outcomes and Measures: The primary outcomes were duration of moderately bad or worse cough (0 to 28 days; minimal clinically important difference, 3.79 days) and mean severity of symptoms on days 2 to 4 (scored from 0 [not affected] to 6 [as bad as it could be]; minimal clinically important difference, 1.66 units). Secondary outcomes were duration and severity of acute lower respiratory tract infection symptoms, duration of abnormal peak flow, antibiotic use, and adverse events. Results: Among 401 randomized patients, 2 withdrew immediately after randomization, and 1 duplicate patient was identified. Among the 398 patients with baseline data (mean age, 47 [SD, 16.0] years; 63% women; 17% smokers; 77% phlegm; 70% shortness of breath; 47% wheezing; 46% chest pain; 42% abnormal peak flow), 334 (84%) provided cough duration and 369 (93%) symptom severity data. Median cough duration was 5 days (interquartile range [IQR], 3-8 days) in the prednisolone group and 5 days (IQR, 3-10 days) in the placebo group (adjusted hazard ratio, 1.11; 95% CI, 0.89-1.39; P = .36 at an α = .05). Mean symptom severity was 1.99 points in the prednisolone group and 2.16 points in the placebo group (adjusted difference, -0.20; 95% CI, -0.40 to 0.00; P = .05 at an α = .001). No significant treatment effects were observed for duration or severity of other acute lower respiratory tract infection symptoms, duration of abnormal peak flow, antibiotic use, or nonserious adverse events. There were no serious adverse events. Conclusions and Relevance: Oral corticosteroids should not be used for acute lower respiratory tract infection symptoms in adults without asthma because they do not reduce symptom duration or severity. Trial Registration: ISRCTN.com Identifier: ISRCTN57309858.

A Core Outcome Set for the Benefits and Adverse Events of Bariatric and Metabolic Surgery: The BARIACT Project.

BACKGROUND: Bariatric and metabolic surgery is used as a treatment for patients with severe and complex obesity. However, there is a need to improve outcome selection and reporting in bariatric surgery trials. A Core Outcome Set (COS), an agreed minimum set of outcomes reported in all studies of a specific condition, may achieve this. Here, we present the development of a COS for BARIAtric and metabolic surgery Clinical Trials-the BARIACT Study. METHODS AND FINDINGS: Outcomes identified from systematic reviews and patient interviews informed a questionnaire survey. Patients and health professionals were surveyed three times and asked to rate the importance of each item on a 1-9 scale. Delphi methods provided anonymised feedback to participants. Items not meeting predefined criteria were discarded between rounds. Remaining items were discussed at consensus meetings, held separately with patients and professionals, where the COS was agreed. Data sources identified 2,990 outcomes, which were used to develop a 130-item questionnaire. Round 1 response rates were moderate but subsequently improved to above 75% for other rounds. After rounds 2 and 3, 81 and 14 items were discarded, respectively, leaving 35 items for discussion at consensus meetings. The final COS included nine items: "weight," "diabetes status," "cardiovascular risk," "overall quality of life (QOL)," "mortality," "technical complications of the specific operation," "any re-operation/re-intervention," "dysphagia/regurgitation," and "micronutrient status." The main limitation of this study was that it was based in the United Kingdom only. CONCLUSIONS: The COS is recommended to be used as a minimum in all trials of bariatric and metabolic surgery. Adoption of the COS will improve data synthesis and the value of research data. Future work will establish methods for the measurement of the outcomes in the COS.

Core Outcomes for Colorectal Cancer Surgery: A Consensus Study.

BACKGROUND: Colorectal cancer (CRC) is a major cause of worldwide morbidity and mortality. Surgical treatment is common, and there is a great need to improve the delivery of such care. The gold standard for evaluating surgery is within well-designed randomized controlled trials (RCTs); however, the impact of RCTs is diminished by a lack of coordinated outcome measurement and reporting. A solution to these issues is to develop an agreed standard "core" set of outcomes to be measured in all trials to facilitate cross-study comparisons, meta-analysis, and minimize outcome reporting bias. This study defines a core outcome set for CRC surgery. METHODS AND FINDINGS: The scope of this COS includes clinical effectiveness trials of surgical interventions for colorectal cancer. Excluded were nonsurgical oncological interventions. Potential outcomes of importance to patients and professionals were identified through systematic literature reviews and patient interviews. All outcomes were transcribed verbatim and categorized into domains by two independent researchers. This informed a questionnaire survey that asked stakeholders (patients and professionals) from United Kingdom CRC centers to rate the importance of each domain. Respondents were resurveyed following group feedback (Delphi methods). Outcomes rated as less important were discarded after each survey round according to predefined criteria, and remaining outcomes were considered at three consensus meetings; two involving international professionals and a separate one with patients. A modified nominal group technique was used to gain the final consensus. Data sources identified 1,216 outcomes of CRC surgery that informed a 91 domain questionnaire. First round questionnaires were returned from 63 out of 81 (78%) centers, including 90 professionals, and 97 out of 267 (35%) patients. Second round response rates were high for all stakeholders (>80%). Analysis of responses lead to 45 and 23 outcome domains being retained after the first and second surveys, respectively. Consensus meetings generated agreement on a 12 domain COS. This constituted five perioperative outcome domains (including anastomotic leak), four quality of life outcome domains (including fecal urgency and incontinence), and three oncological outcome domains (including long-term survival). CONCLUSION: This study used robust consensus methodology to develop a core outcome set for use in colorectal cancer surgical trials. It is now necessary to validate the use of this set in research practice.

Reporting of short-term clinical outcomes after esophagectomy: a systematic review.

OBJECTIVE: This review summarizes reporting of complications of esophageal cancer surgery. BACKGROUND: Accurate assessment of morbidity and mortality after surgery for cancer is essential to compare centers, allow data synthesis, and inform clinical decision-making. A lack of defined standards may distort clinically relevant treatment effects. METHODS: Systematic literature searches identified articles published between 2005 and 2009 reporting morbidity and mortality after esophagectomy for cancer. Data were analyzed for frequency of complication reporting and to check whether outcomes were defined and classified for severity and whether a validated system for grading complications was used. Information about reporting outcomes adjusting for baseline risk factors was collated, and a descriptive summary of the results of included outcomes was undertaken. RESULTS: Of 3458 abstracts, 224 full papers were reviewed and 122 were included (17 randomized trials and 105 observational studies), reporting outcomes of 57,299 esophagectomies. No single complication was reported in all papers, and 60 (60.6%) did not define any of the measured complications. Anastomotic leak was the most commonly reported morbidity, assessed in 80 (80.1%) articles, defined in 28 (28.3%), but 22 different descriptions were used. Five papers (5.1%) categorized morbidity with a validated grading system. One hundred fifteen papers reported postoperative mortality rates, 25 defining the term using 10 different definitions. In-hospital mortality was the most commonly used term for postoperative death, with 6 different interpretations of this phrase. Eighteen papers adjusted outcomes for baseline risk factors and 60 presented baseline measures of comorbidity. CONCLUSIONS: Outcome reporting after esophageal cancer surgery is heterogeneous and inconsistent, and it lacks methodological rigor. A consensus approach to reporting clinical outcomes should be considered, and at the minimum it is recommended that a "core outcome set" is defined and used in all studies reporting outcomes of esophageal cancer surgery. This will allow meaningful cross study comparisons and analyses to evaluate surgery.

Standards of outcome reporting in surgical oncology: a case study in esophageal cancer.

BACKGROUND: Multimodal strategies before surgery are often used to improve outcomes, but disease progression (precluding surgical resection) and inoperability at planned surgery still occur following neoadjuvant treatment. The standards of reporting of these outcomes have not previously been considered. This study examined reporting of rates of progression to surgical resection and inoperability at planned surgery following neoadjuvant treatment in surgical oncology, using esophageal cancer as a case study. METHODS: A systematic review identified randomized trials and prospective nonrandomized studies reporting short-term outcomes of neoadjuvant treatment and surgery for esophageal cancer. RESULTS: Of 4,763 abstracts, 224 papers were retrieved and 76 studies included (8 randomized trials and 68 cohort studies of 19,441 esophagectomies). Articles reported outcomes of preoperative chemotherapy (n = 33, 43.4 %), chemoradiotherapy (n = 13, 17.1 %), or both within one paper (n = 18, 23.7 %) and 12 (15.8 %) did not specify the type of neoadjuvant treatment. Also, 20 papers (26.3 %) reported numbers of patients not progressing to surgery after neoadjuvant treatment (with rates of nonprogression ranging between 2.0 and 35.3 %). In addition, 24 papers (31.6 %) reported rates of inoperability at planned surgery (with inoperability rates ranging between 0 and 26.2 %). More randomized controlled trials (RCTs) than observational studies reported nonprogression (4 randomized and 16 nonrandomized studies, 95 % CI -9.6 to 62.6 %, p = 0.108) and inoperability (6 randomized trials and 18 observational studies, 95 % CI 16.8-80.3 %, p = 0.005). Some 17 and 10 articles provided reasons for the observed rates of nonprogression and inoperability, respectively. CONCLUSIONS: Reporting rates of progression to surgery after neoadjuvant treatment and inoperability at planned surgery for esophageal cancer were poor, limiting data synthesis and comparisons. It is suggested that core outcome sets for trials in surgical oncology are developed with inclusion of these important endpoints. Collaboration between medical and surgical oncologists is necessary to achieve this.

Thulium laser transurethral vaporesection versus transurethral resection of the prostate for benign prostatic obstruction: the UNBLOCS RCT.

BACKGROUND: Transurethral resection of the prostate (TURP) is the standard operation for benign prostatic obstruction (BPO). Thulium laser transurethral vaporesection of the prostate (ThuVARP) vaporises and resects the prostate using a technique similar to TURP. The small amount of existing literature suggests that there may be potential advantages of ThuVARP over TURP. OBJECTIVE: To determine whether or not the outcomes from ThuVARP are equivalent to the outcomes from TURP in men with BPO treated in the NHS. DESIGN: A multicentre, pragmatic, randomised controlled parallel-group trial, with an embedded qualitative study and economic evaluation. SETTING: Seven UK centres - four university teaching hospitals and three district general hospitals. PARTICIPANTS: Men aged ≥ 18 years who were suitable to undergo TURP, presenting with bothersome lower urinary tract symptoms (LUTS) or urinary retention secondary to BPO. INTERVENTIONS: Patients were randomised 1 : 1 to receive TURP or ThuVARP and remained blinded. MAIN OUTCOME MEASURES: Two co-primary outcomes - patient-reported International Prostate Symptom Score (IPSS) and clinical measure of maximum urine flow rate (Qmax) at 12 months post surgery. RESULTS: In total, 410 men were randomised, 205 to each arm. The two procedures were equivalent in terms of IPSS [adjusted mean difference 0.28 points higher for ThuVARP (favouring TURP), 95% confidence interval (CI) -0.92 to 1.49 points]. The two procedures were not equivalent in terms of Qmax (adjusted mean difference 3.12 ml/second in favour of TURP, 95% CI 0.45 to 5.79 ml/second), with TURP deemed superior. Surgical outcomes, such as complications and blood transfusion rates, and hospital stay were similar for both procedures. Patient-reported urinary and sexual symptoms were also similar between the arms. Qualitative interviews indicated similar patient experiences with both procedures. However, 25% of participants in the ThuVARP arm did not undergo their randomised allocation, compared with 2% of participants in the TURP arm. Prostate cancer was also detected less frequently from routine histology after ThuVARP (65% lower odds of detection) in an exploratory analysis. The adjusted mean differences between the arms were similar for secondary care NHS costs (£9 higher for ThuVARP, 95% CI -£359 to £376) and quality-adjusted life-years (0.01 favouring TURP, 95% CI -0.04 to 0.01). LIMITATIONS: Complications were recorded in prespecified categories; those not prespecified were excluded owing to variable reporting. Preoperative Qmax and IPSS data could not be collected for participants with indwelling catheters, making adjustment for baseline status difficult. CONCLUSIONS: TURP was superior to ThuVARP in terms of Qmax, although both operations resulted in a Qmax considered clinically successful. ThuVARP also potentially resulted in lower detection rates of prostate cancer as a result of the smaller volume of tissue available for histology. Length of hospital stay after ThuVARP, anticipated to be a key benefit, was equal to that after TURP in this trial. Overall, both ThuVARP and TURP were effective procedures for BPO, with minor benefits in favour of TURP. Therefore, the results suggest that it may be appropriate that new treatment alternatives continue to be compared with TURP. FUTURE WORK: Longer-term follow-up to assess reoperation rates over time, and research into the comparative effectiveness of ThuVARP and TURP in large prostates. TRIAL REGISTRATION: Current Controlled Trials ISRCTN00788389. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 41. See the NIHR Journals Library website for further project information.

An enlarged prostate can make it difficult, or even impossible, for a man to pass urine by blocking the urine flow from the bladder. This can cause significant problems, and 25,000 men in the UK each year are treated with an operation to relieve their symptoms. The standard operation [transurethral resection of the prostate (TURP)], which uses electricity to shave off the enlarged prostate, is successful, but it can have some complications. There is some evidence to suggest that laser surgery can lead to less blood loss and a shorter stay in hospital, but laser operations can be difficult for surgeons to carry out. This trial has looked at a procedure using a new type of laser called thulium, which uses a very similar surgical technique to TURP and has shown promising results so far. A total of 410 men needing a prostate operation received either TURP or a laser operation. Participants were unaware of which operation they received until the end of the study to ensure a fair comparison. Seven hospitals across the UK were involved over 4 years. The trial mainly assessed the benefits of the operations using a urinary symptom questionnaire completed by participants, and by measuring the speed of passing urine after surgery. Overall, both procedures achieved positive results, and participants expressed high levels of satisfaction with the outcomes. Participants who had either operation reported a similar improvement in urinary symptoms in their questionnaires. However, although both operations did a good job of improving the speed of passing urine, TURP was better. Participants experienced few complications, and the complications that did occur were similar after both operations, including levels of bleeding and time spent in hospital. The cost of the two operations to the NHS was also similar. Overall, we concluded that both operations are suitable for patients with prostate enlargement, with TURP showing some minor additional benefits.

A systematic review of core outcome set development studies demonstrates difficulties in defining unique outcomes.

OBJECTIVES: Core outcome set (COS) development often begins with a systematic review to identify outcomes. Reviews frequently show heterogeneity in numbers of outcomes reported across trials. Contributing to this is a lack of a uniform definition for an outcome. This study proposes a first working definition for a unique trial outcome to support reporting a quantitative assessment of outcome reporting heterogeneity (ORH). STUDY DESIGN AND SETTING: Eligible COS literature (development papers, protocols, and reviews) were identified using the COMET database, Ovid MEDLINE, and PubMed. Outcome numbers, definitions, timing, and grouping methodology were examined. RESULTS: One hundred and thirty two studies were included. 82 (88.1%) studies (excluding protocols) reported a total number of unique outcomes (median, 82; range, 12-5776; IQR, 261). Timing of assessment was reported in 32 (31.4%) studies. Methods to group similar outcomes were reported in 8 (7.8%) articles. No study defined how outcomes were agreed as different and how final numbers of unique outcomes were determined. It is proposed that a unique outcome requires original meaning and context. Thus ORH is suggested to be the reporting of multiple unique outcomes across trials related to one health care condition. CONCLUSION: This review identified inconsistencies in how authors define, extract, group, and count trial outcomes. Further work is needed to refine our proposed definitions to optimize COS development and allow a quantifiable measure of ORH.

Relationship between lower urinary tract symptoms and erectile dysfunction: results from the Boston Area Community Health Survey.

PURPOSE: We explored the association of lower urinary tract symptoms and erectile dysfunction in a racially and ethnically diverse random sample of men. MATERIALS AND METHODS: The Boston Area Community Health Survey used a stratified, 2-stage cluster sample to recruit 2,301 men representative of Boston. Data were obtained on symptoms suggestive of a number of urogynecologic conditions, comorbidities, and lifestyle and psychosocial factors. RESULTS: The percent of men reporting moderate/severe lower urinary tract symptoms, as measured by the American Urological Association symptom index, ranged from 8% in those 30 to 39 years old to 26% in those 70 to 79 years old. The prevalence of erectile dysfunction was high and it increased dramatically with age with 10% of 30 to 39-year-old and 59% of 70 to 79-year-old men reporting mild-moderate/moderate/severe symptoms. A strong association was observed between the American Urological Association symptom index and erectile dysfunction after adjusting for age. However, after adjusting for other symptoms and comorbidities evidence of this association became weak. Much stronger associations were seen with incontinence, which is not included in the American Urological Association symptom index, and symptoms suggestive of prostatitis. When considering the American Urological Association symptom index symptoms separately, only nocturia increased the severity of erectile dysfunction. Stratified analyses demonstrated similar associations across race/ethnicity groups. CONCLUSIONS: Lower urinary tract symptoms and erectile dysfunction are common conditions in older men in the community. This study provides evidence to suggest that the previously observed association between erectile dysfunction and lower urinary tract symptoms may be primarily due to nocturia, incontinence and symptoms suggestive of prostatitis.

Impact of question order on prioritisation of outcomes in the development of a core outcome set: a randomised controlled trial.

BACKGROUND: Core outcome set (COS) developers increasingly employ Delphi surveys to elicit stakeholders' opinions of which outcomes to measure and report in trials of a particular condition or intervention. Research outside of Delphi surveys and COS development demonstrates that question order can affect response rates and lead to 'context effects', where prior questions determine an item's meaning and influence responses. This study examined the impact of question order within a Delphi survey for a COS for oesophageal cancer surgery. METHODS: A randomised controlled trial was nested within the Delphi survey. Patients and health professionals were randomised to receive a survey including clinical and patient-reported outcomes (PROs), where the PRO section appeared first or last. Participants rated (1-9) the importance of 68 items for inclusion in a COS (ratings 7-9 considered 'essential'). Analyses considered the impact of question order on: (1) survey response rates; (2) participants' responses; and (3) items retained at end of the survey. RESULTS: In total, 116 patients and 71 professionals returned completed surveys. Question order did not affect response rates among patients, but fewer professionals responded when clinical items appeared first (difference = 31.3%, 95% confidence interval [CI] = 13.6-48.9%, P = 0.001). Question order led to different context effects within patients and professionals. While patients rated clinical items highly, irrespective of question order, more PROs were rated essential when appearing last rather than first (difference = 23.7%, 95% CI = 10.5-40.8%). Among professionals, the greatest impact was on clinical items; a higher percentage rated essential when appearing last (difference = 11.6%, 95% CI = 0.0-23.3%). An interaction between question order and the percentage of PRO/clinical items rated essential was observed for patients (P = 0.025) but not professionals (P = 0.357). Items retained for further consideration at the end of the survey were dependent on question order, with discordant items (retained by one question order group only) observed in patients (18/68 [26%]) and professionals (20/68 [29%]). CONCLUSIONS: In the development of a COS, participants' ratings of potential outcomes within a Delphi survey depend on the context (order) in which the outcomes are asked, consequently impacting on the final COS. Initial piloting is recommended with consideration of the randomisation of items in the survey to reduce potential bias. TRIAL REGISTRATION: The randomised controlled trial reported within this paper was nested within the development of a core outcome set to investigate processes in core outcome set development. Outcomes were not health-related and trial registration was not therefore applicable.

A core outcome set for clinical trials of chemoradiotherapy interventions for anal cancer (CORMAC): a patient and health-care professional consensus.

Chemoradiotherapy is the primary treatment for patients with squamous cell carcinoma of the anus, but variations in the reported outcomes have restricted between-study comparisons. Treatment-related morbidity is considerable; however, no trial has comprehensively quantified long-term side-effects or quality of life. Therefore, we established the first international health-care professional and patient consensus to develop a core outcome set, using the Core Outcome Measures in Effectiveness Trials method. We used the results from our previous systematic review and combined them in this Review with patient interviews to derive a comprehensive list of outcomes, followed by a two-round Delphi survey completed by 149 participants (55 patients and 94 health-care professionals) from 11 countries. The Delphi results were discussed at a consensus meeting of health-care professionals and patients. Agreement was reached on 19 outcomes across four domains: disease activity, survival, toxicity, and life impact. Implementation of the Core Outcome Research Measures in Anal Cancer (CORMAC) set in future trials will serve as a framework to achieve standardisation, facilitate selection of health-area-specific evaluation tools, reduce redundancy of outcome lists, allow between-study comparisons, and ultimately enhance the relevance of trial findings to health-care professionals, trialists, and patients.

Understanding usual care for patients with multimorbidity: baseline data from a cluster-randomised trial of the 3D intervention in primary care.

OBJECTIVES: Recent evidence has highlighted the high prevalence and impact of multimorbidity, but the evidence base for improving management is limited. We have tested a new complex intervention for multimorbidity (the 3D model). The paper describes the baseline characteristics of practices and patients in order to establish the external validity of trial participants. It also explores current 'usual primary care' for multimorbidity, against which the 3D intervention was tested. DESIGN: Analysis of baseline data from patients in a cluster-randomised controlled trial and additional data from practice staff. SETTING: Primary care in the UK. PARTICIPANTS: Patients with multimorbidity (n=5253) and 154 practice staff. PRIMARY AND SECONDARY OUTCOME MEASURES: Using surveys and routinely available data, we compared the characteristics of participating and non-participating practices and participating and non-participating eligible patients.Baseline questionnaire data from patient participants was used to examine participant illness burden, treatment burden and perceptions of receiving patient-centred care. We obtained data about usual care preintervention from practice staff using questionnaires and a structured pro forma. RESULTS: Participating practices were slightly larger, in less deprived areas, and with slightly higher scores for patient satisfaction compared with non-participating practices. Patients with dementia or learning difficulties were likely to be excluded by their general practitioners, but comparison of participants with non-participants identified only minor differences in characteristics, suggesting that the sample was otherwise representative. Patients reported substantial illness burden, and an important minority reported high treatment burden. Although patients reported relatively high levels of satisfaction with care, many reported not having received potentially important components of care. CONCLUSION: This trial achieved good levels of external validity. Although patients were generally satisfied with primary care services, there was significant room for improvement in important aspects of care for multimorbidity that are targeted by the 3D intervention. TRIAL REGISTRATION NUMBER: ISRCTN06180958; Post-results.

A randomised controlled trial to determine the clinical and cost effectiveness of thulium laser transurethral vaporesection of the prostate (ThuVARP) versus transurethral resection of the prostate (TURP) in the National Health Service (NHS) - the UNBLOCS trial: a study protocol for a randomised controlled trial.

BACKGROUND: Transurethral resection of the prostate (TURP) has been the standard operation for benign prostatic obstruction (BPO) for 40 years, with approximately 25,000 procedures performed annually, and has remained largely unchanged. It is generally a successful operation, but has well-documented risks for the patient. Thulium laser transurethral vaporesection of the prostate (ThuVARP) vaporises and resects the prostate using a surgical technique similar to TURP. The small amount of study data currently available suggests that ThuVARP may have certain advantages over TURP, including reduced blood loss and shorter hospital stay, earlier return to normal activities, and shorter duration of catheterisation. DESIGN: A multicentre, pragmatic, randomised, controlled, parallel-group trial of ThuVARP versus standard TURP in men with BPO. Four hundred and ten men suitable for prostate surgery were randomised to receive either ThuVARP or TURP at four university teaching hospitals, and three district general hospitals. The key aim of the trial is to determine whether ThuVARP is equivalent to TURP judged on both the patient-reported International Prostate Symptom Score (IPSS) and the maximum urine flow rate (Qmax) at 12 months post-surgery. DISCUSSION: The general population has an increased life expectancy. As men get older their prostates enlarge, potentially causing BPO, which often requires surgery. Therefore, as the population ages, more prostate operations are needed to relieve obstruction. There is hence sustained interest in the condition and increasing need to find safer techniques than TURP. Various laser techniques have become available but none are widely used in the NHS because of lengthy training required for surgeons or inferior performance on clinical outcomes. Promising initial evidence from one RCT shows that ThuVARP has equivalent clinical effectiveness when compared to TURP, as well as other potential advantages. As ThuVARP uses a technique similar to that used in TURP, the learning curve is short, potentially making it also very quickly generalisable. This randomised study is designed to provide the high-quality evidence, in an NHS setting, with a range of patient-reported, clinical and cost-effectiveness outcomes, which will underpin and inform future NICE guidance. TRIAL REGISTRATION: ISRCTN registry, ISRCTN00788389 . Registered on 20 September 2013.

The COMET Handbook: version 1.0.

The selection of appropriate outcomes is crucial when designing clinical trials in order to compare the effects of different interventions directly. For the findings to influence policy and practice, the outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. It is now widely acknowledged that insufficient attention has been paid to the choice of outcomes measured in clinical trials. Researchers are increasingly addressing this issue through the development and use of a core outcome set, an agreed standardised collection of outcomes which should be measured and reported, as a minimum, in all trials for a specific clinical area.Accumulating work in this area has identified the need for guidance on the development, implementation, evaluation and updating of core outcome sets. This Handbook, developed by the COMET Initiative, brings together current thinking and methodological research regarding those issues. We recommend a four-step process to develop a core outcome set. The aim is to update the contents of the Handbook as further research is identified.

Exploring methods the for selection and integration of stakeholder views in the development of core outcome sets: a case study in reconstructive breast surgery.

BACKGROUND: The development and use of core outcome sets (COSs) in trials may improve data synthesis and reduce outcome reporting bias. The selection of outcomes in COSs is informed by views of key stakeholders, yet little is known about the role and influence of different stakeholders' views during COS development. We report an exploratory case study examining how stakeholder selection and incorporation of stakeholders' views may influence the selection of outcomes for a COS in reconstructive breast surgery (RBS). We also make recommendations for future considerations. METHODS: Key stakeholder groups and subgroups were identified from the literature and expert opinion by the COS management group. They included health care professionals, subdivided by profession (breast and plastic surgeons, specialist nurses and psychologists) and patients, subdivided according to type of surgery received, timing of reconstruction, time since surgery and patient age. All participated in a survey in which they were asked to prioritise outcomes. Outcomes were prioritised using a 9-point scale from 1 (not important) to 9 (extremely important). The proportion of (1) all participants, ignoring stakeholder group (single heterogeneous panel analysis), (2) 'professional' and 'patient' groups separately (two heterogeneous panels), ignoring prespecified subgroups and (3) each participant subgroup separately (multiple homogeneous panel analysis) rating each item 'extremely important' was summarised and compared to explore how selection and integration of stakeholder views may influence outcome prioritisation. RESULTS: There were many overlaps between items rated as most important by all groups. Specific stakeholders, however, prioritised specific concerns and a broader range of outcomes were prioritised when the subgroups were considered separately. For example, two additional outcomes were prioritised when patient and professional groups were considered separately and eight additional outcomes were identified when the views of the individual subgroups were explored. In general, patient subgroups preferentially valued additional clinical outcomes, including unplanned surgery, whereas professional subgroups prioritised additional psychosocial issues including body image. CONCLUSION: Stakeholder groups value different outcomes. Selection of groups, therefore, is important. Our recommendations for robust and transparent stakeholder selection and integration of stakeholder views may aid future COS developers in the design and conduct of their studies and improve the validity and value of future COS.

'Trial Exegesis': Methods for Synthesizing Clinical and Patient Reported Outcome (PRO) Data in Trials to Inform Clinical Practice. A Systematic Review.

PURPOSE: The CONSORT extension for patient reported outcomes (PROs) aims to improve reporting, but guidance on the optimal integration with clinical data is lacking. This study examines in detail the reporting of PROs and clinical data from randomized controlled trials (RCTs) in gastro-intestinal cancer to inform design and reporting of combined PRO and clinical data from trials to improve the 'take home' message for clinicians to use in practice. MATERIALS AND METHODS: The case study was undertaken in gastro-intestinal cancer trials. Well-conducted RCTs reporting PROs with validated instruments were identified and categorized into those combining PRO and clinical data in a single paper, or those separating data into linked primary and supplemental papers. Qualitative methods were developed to examine reporting of the critical interpretation of the trial results (trial exegesis) in the papers in relation of the PRO and clinical outcomes and applied to each publication category. Results were used to inform recommendations for practice. RESULTS: From 1917 screened abstracts, 49 high quality RCTs were identified reported in 36 combined and 15 linked primary and supplemental papers. In-depth analysis of manuscript text identified three categories for understanding trial exegesis: where authors reported a "detailed", "general", or absent PRO rationale and integrated interpretation of clinical and PRO results. A total of 11 (30%) and 6 (16%) combined papers reported "detailed" PRO rationale and integrated interpretation of results although only 2 (14%) and 1 (7%) primary papers achieved the same standard respectively. Supplemental papers provide better information with 11 (73%) and 3 (20%) achieving "detailed" rationale and integrated interpretation of results. Supplemental papers, however, were published a median of 20 months after the primary RCT data in lower impact factor journals (median 16.8 versus 5.2). CONCLUSION: It is recommended that single papers, with detailed PRO rationale and integrated PRO and clinical data are published to optimize trial exegesis. Further work to examine whether this improves the use of PRO data to inform practice is needed.

Three nested randomized controlled trials of peer-only or multiple stakeholder group feedback within Delphi surveys during core outcome and information set development.

BACKGROUND: Methods for developing a core outcome or information set require involvement of key stakeholders to prioritise many items and achieve agreement as to the core set. The Delphi technique requires participants to rate the importance of items in sequential questionnaires (or rounds) with feedback provided in each subsequent round such that participants are able to consider the views of others. This study examines the impact of receiving feedback from different stakeholder groups, on the subsequent rating of items and the level of agreement between stakeholders. METHODS: Randomized controlled trials were nested within the development of three core sets each including a Delphi process with two rounds of questionnaires, completed by patients and health professionals. Participants rated items from 1 (not essential) to 9 (absolutely essential). For round 2, participants were randomized to receive feedback from their peer stakeholder group only (peer) or both stakeholder groups separately (multiple). Decisions as to which items to retain following each round were determined by pre-specified criteria. RESULTS: Whilst type of feedback did not impact on the percentage of items for which a participant subsequently changed their rating, or the magnitude of change, it did impact on items retained at the end of round 2. Each core set contained discordant items retained by one feedback group but not the other (3-22 % discordant items). Consensus between patients and professionals in items to retain was greater amongst those receiving multiple group feedback in each core set (65-82 % agreement for peer-only feedback versus 74-94 % for multiple feedback). In addition, differences in round 2 scores were smaller between stakeholder groups receiving multiple feedback than between those receiving peer group feedback only. Variability in item scores across stakeholders was reduced following any feedback but this reduction was consistently greater amongst the multiple feedback group. CONCLUSIONS: In the development of a core outcome or information set, providing feedback within Delphi questionnaires from all stakeholder groups separately may influence the final core set and improve consensus between the groups. Further work is needed to better understand how participants rate and re-rate items within a Delphi process. TRIAL REGISTRATION: The three randomized controlled trials reported here were each nested within the development of a core information or outcome set to investigate processes in core outcome and information set development. Outcomes were not health-related and therefore trial registration was not applicable.