Development and pilot testing of a patient-reported outcome measure to assess symptoms of parastomal hernia.

AIM: The aim was to develop and pilot a patient-reported outcome measure (PROM) to assess symptoms of parastomal hernia (PSH). METHODS: Standard questionnaire development was undertaken (phases 1-3). An initial list of questionnaire domains was identified from validated colorectal cancer PROMs and from semi-structured interviews with patients with a PSH and health professionals (phase 1). Domains were operationalized into items in a provisional questionnaire, and 'think-aloud' patient interviews explored face validity and acceptability (phase 2). The updated questionnaire was piloted in patients with a stoma who had undergone colorectal surgery and had a computed tomography scan available for review. Patient-reported symptoms were examined in relation to PSH (phase 3). Three sources determined PSH presence: (i) data about PSH presence recorded in hospital notes, (ii) independent expert review of the computed tomography scan and (iii) patient report of being informed of a PSH by a health professional. RESULTS: For phase 1, 169 and 127 domains were identified from 70 PROMs and 29 interviews respectively. In phase 2, 14 domains specific to PSH were identified and operationalized into questionnaire items. Think-aloud interviews led to three minor modifications. In phase 3, 44 completed questionnaires were obtained. Missing data were few: 5/660 items. PSH symptom scores associated with PSH presence varied between different data sources. The scale with the most consistent differences between PSH presence and absence and all data sources was the stoma appearance scale. CONCLUSION: A PROM to examine the symptoms of PSH has been developed from the literature and views of key informants. Although preliminary testing shows it to be understandable and acceptable it is uncertain if it is sensitive to PSH-specific symptoms and further psychometric testing is needed.

Access to publicly funded weight management services in England using routine data from primary and secondary care (2007-2020): An observational cohort study.

BACKGROUND: Adults living with overweight/obesity are eligible for publicly funded weight management (WM) programmes according to national guidance. People with the most severe and complex obesity are eligible for bariatric surgery. Primary care plays a key role in identifying overweight/obesity and referring to WM interventions. This study aimed to (1) describe the primary care population in England who (a) are referred for WM interventions and (b) undergo bariatric surgery and (2) determine the patient and GP practice characteristics associated with both. METHODS AND FINDINGS: An observational cohort study was undertaken using routinely collected primary care data in England from the Clinical Practice Research Datalink linked with Hospital Episode Statistics. During the study period (January 2007 to June 2020), 1,811,587 adults met the inclusion criteria of a recording of overweight/obesity in primary care, of which 54.62% were female and 20.10% aged 45 to 54. Only 56,783 (3.13%) were referred to WM, and 3,701 (1.09% of those with severe and complex obesity) underwent bariatric surgery. Multivariable Poisson regression examined the associations of demographic, clinical, and regional characteristics on the likelihood of WM referral and bariatric surgery. Higher body mass index (BMI) and practice region had the strongest associations with both outcomes. People with BMI ≥40 kg/m2 were more than 6 times as likely to be referred for WM (10.05% of individuals) than BMI 25.0 to 29.9 kg/m2 (1.34%) (rate ratio (RR) 6.19, 95% confidence interval (CI) [5.99,6.40], p < 0.001). They were more than 5 times as likely to undergo bariatric surgery (3.98%) than BMI 35.0 to 40.0 kg/m2 with a comorbidity (0.53%) (RR 5.52, 95% CI [5.07,6.02], p < 0.001). Patients from practices in the West Midlands were the most likely to have a WM referral (5.40%) (RR 2.17, 95% CI [2.10,2.24], p < 0.001, compared with the North West, 2.89%), and practices from the East of England least likely (1.04%) (RR 0.43, 95% CI [0.41,0.46], p < 0.001, compared with North West). Patients from practices in London were the most likely to undergo bariatric surgery (2.15%), and practices in the North West the least likely (0.68%) (RR 3.29, 95% CI [2.88,3.76], p < 0.001, London compared with North West). Longer duration since diagnosis with severe and complex obesity (e.g., 1.67% of individuals diagnosed in 2007 versus 0.34% in 2015, RR 0.20, 95% CI [0.12,0.32], p < 0.001), and increasing comorbidities (e.g., 2.26% of individuals with 6+ comorbidities versus 1.39% with none (RR 8.79, 95% CI [7.16,10.79], p < 0.001) were also strongly associated with bariatric surgery. The main limitation is the reliance on overweight/obesity being recorded within primary care records to identify the study population. CONCLUSIONS: Between 2007 and 2020, a very small percentage of the primary care population eligible for WM referral or bariatric surgery according to national guidance received either. Higher BMI and GP practice region had the strongest associations with both. Regional inequalities may reflect differences in commissioning and provision of WM services across the country. Multi-stakeholder qualitative research is ongoing to understand the barriers to accessing WM services and potential solutions. Together with population-wide prevention strategies, improved access to WM interventions is needed to reduce obesity levels.

A Core Outcome Set for Seamless, Standardized Evaluation of Innovative Surgical Procedures and Devices (COHESIVE): A Patient and Professional Stakeholder Consensus Study.

OBJECTIVE: To develop a COS, an agreed minimum set of outcomes to measure and report in all studies evaluating the introduction and evaluation of novel surgical techniques. SUMMARY OF BACKGROUND DATA: Agreement on the key outcomes to measure and report for safe and efficient surgical innovation is lacking, hindering transparency and risking patient harm. METHODS: (I) Generation of a list of outcome domains from published innovation-specific literature, policy/regulatory body documents, and surgeon interviews; (II) Prioritization of identified outcome domains using an international, multi-stakeholder Delphi survey; (III) Consensus meeting to agree the final COS. Participants were international stakeholders, including patients/public, surgeons, device manufacturers, regulators, trialists, methodologists, and journal editors. RESULTS: A total of 7972 verbatim outcomes were identified, categorized into 32 domains, and formatted into survey items/questions. Four hundred ten international participants (220 professionals, 190 patients/public) completed at least one round 1 survey item, of which 153 (69.5%) professionals and 116 (61.1%) patients completed at least one round 2 item. Twelve outcomes were scored "consensus in" ("very important" by ≥70% of patients and professionals) and 20 "no consensus." A consensus meeting, involvingcontext: modifications, unexpected disadvantages, device problems, technical procedure completion success, patients' experience relating to the procedure being innovative, surgeons'/operators' experience. Other domains relate to intended benefits, whether the overall desired effect was achieved and expected disadvantages. CONCLUSIONS: The COS is recommended for use in all studies before definitive randomized controlled trial evaluation to promote safe, transparent, and efficient surgical innovation.

What Are Patients Told About Innovative Surgical Procedures? A Qualitative Synthesis of 7 Case Studies in the United Kingdom.

OBJECTIVES: To investigate how information about innovative surgical procedures is communicated to patients. BACKGROUND: Despite the national and international guidance that patients should be informed whether a procedure is innovative and has uncertain outcomes, little is known about current practice. METHODS: This qualitative study followed 7 "case studies" of surgical innovation in hospitals across the United Kingdom. Preoperative interviews were conducted with clinician innovators (n=9), preoperative real-time consultations between clinicians and patients were audio-recorded (n=37). Patients were interviewed postoperatively (n=30). Data were synthesized using thematic analytical methods. RESULTS: Interviews with clinicians demonstrated strong intentions to inform patients about the innovative nature of the procedure in a neutral manner, although tensions between fully informing patients and not distressing them were raised. In the consultations, only a minority of clinicians actually made explicit statements about, (1) the procedure being innovative, (2) their limited clinical experience with it, (3) the paucity of evidence, and (4) uncertainty/unknown outcomes. Discussions about risks were generalized and often did not relate to the innovative component. Instead, all clinicians optimistically presented potential benefits and many disclosed their own positive beliefs. Postoperative patient interviews revealed that many believed that the procedure was more established than it was and were unaware of the unknown risks. CONCLUSIONS: There were contradictions between clinicians' intentions to inform patients about the uncertain outcomes of innovative and their actual discussions with patients. There is a need for communication interventions and training to support clinicians to provide transparent data and shared decision-making for innovative procedures.

Remote assessment of surgical site infection (SSI) using patient-taken wound images: Development and evaluation of a method for research and routine practice.

BACKGROUND/AIM: Clinical assessment of wounds for surgical site infection (SSI) after hospital discharge is challenging and resource intensive. Remote assessment using digital images may be feasible and expedite SSI diagnosis. Acceptable and accurate methods for this process are needed. This study developed and evaluated the feasibility, acceptability and usability of a method for patients to capture standardised wound images for remote wound assessment to detect SSI. MATERIALS AND METHODS: The work was conducted in two phases. Phase I involved: i) a review of literature to identify key components of photography relevant to taking wound images, ii) development of wound photography instructions for patients and a secure process for transmission of images using electronic survey software and iii) pre-testing of the photography instructions and processing method with a sample of 16 patients using cognitive interviews and observations. Phase II involved a prospective cohort study of 89 patients to evaluate the feasibility, acceptability and usability of the remote method following discharge from hospital after surgery. Quality of the images was assessed by three independent clinical reviewers. RESULTS: Some 21 key components for photographing wounds were identified from 11 documents. Of these, 16 were relevant to include in instructions for patients to photograph their wounds. Pre-testing and subsequent iterations improved understanding and ease of use of the instructions and the process for transmitting images. Fifty-two of 89 (58.4%) patients testing the method remotely took an image of their wound(s) and 46/52 (88.5%) successfully transmitted images. When it was possible to ascertain a reason for not taking/transmitting images, this was primarily health problems (n = 7) or lack of time/poor engagement with the study (n = 4) rather than problems relating to technology/competency (n = 2) or practical issues relating to the wound itself (n = 2). Eighty-seven (85.3%) of the 102 images received were evaluated to be of high quality and sufficient to remotely assess SSI by at least two independent reviewers. CONCLUSION: A simple, standardised and acceptable method for patients to take and transmit wound images suitable for remote assessment of SSI has been developed and tested and is now available for use in routine clinical care and research.

Development of a Reliable Surgical Quality Assurance System for 2-stage Esophagectomy in Randomized Controlled Trials.

OBJECTIVE: The aim was to develop a reliable surgical quality assurance system for 2-stage esophagectomy. This development was conducted during the pilot phase of the multicenter ROMIO trial, collaborating with international experts. SUMMARY OF BACKGROUND DATA: There is evidence that the quality of surgical performance in randomized controlled trials influences clinical outcomes, quality of lymphadenectomy and loco-regional recurrence. METHODS: Standardization of 2-stage esophagectomy was based on structured observations, semi-structured interviews, hierarchical task analysis, and a Delphi consensus process. This standardization provided the structure for the operation manual and video and photographic assessment tools. Reliability was examined using generalizability theory. RESULTS: Hierarchical task analysis for 2-stage esophagectomy comprised fifty-four steps. Consensus (75%) agreement was reached on thirty-nine steps, whereas fifteen steps had a majority decision. An operation manual and record were created. A thirty five-item video assessment tool was developed that assessed the process (safety and efficiency) and quality of the end product (anatomy exposed and lymphadenectomy performed) of the operation. The quality of the end product section was used as a twenty seven-item photographic assessment tool. Thirty-one videos and fifty-three photographic series were submitted from the ROMIO pilot phase for assessment. The overall G-coefficient for the video assessment tool was 0.744, and for the photographic assessment tool was 0.700. CONCLUSIONS: A reliable surgical quality assurance system for 2-stage esophagectomy has been developed for surgical oncology randomized controlled trials. ETHICAL APPROVAL: 11/NW/0895 and confirmed locally as appropriate, 12/SW/0161, 16/SW/0098.Trial registration number: ISRCTN59036820, ISRCTN10386621.

Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment [ProtecT] study).

OBJECTIVE: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. PATIENTS AND METHODS: Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. RESULTS: Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. CONCLUSION: Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes.

A Systematic Review of Minimally Invasive Trans-thoracic Liver Resection to Examine Intervention Description, Governance, and Outcome Reporting of an Innovative Technique.

INTRODUCTION: The number of laparoscopic liver resections undertaken has increased. However, lesions located postero-superiorly are difficult to access. This may be overcome by the novel use of trans-thoracic port(s). Methods for the safe and transparent introduction of new and modified surgical procedures are limited and a summary of these issues, for minimally invasive trans-thoracic liver resections (MITTLR), is lacking. This study aims to understand and summarize technique description, governance procedures, and reporting of outcomes for MITTLR. METHODS: A systematic literature search to identify primary studies of all designs describing MITTLR was undertaken. How patients were selected for the new technique was examined. The technical components of MITTLR were identified and summarized to understand technique development over time. Governance arrangements (eg, Institutional Review Board approval) and steps taken to mitigate harm were recorded. Finally, specific outcomes reported across studies were documented. RESULTS: Of 2067 screened articles, 16 were included reporting data from 145 patients and 6 countries. Selection criteria for patients was explicitly stated in 2 papers. No studies fully described the technique. Five papers reported ethical approval and 3 gave details of patient consent. No study reported on steps taken to mitigate harm.Technical outcomes were commonly reported, for example, blood loss (15/16 studies), operative time (15/16), and margin status (11/16). Information on patient-reported outcomes and costs were lacking. CONCLUSIONS: Technical details and governance procedures were poorly described. Outcomes focussed on short term details alone. Transparency is needed for reporting the introduction of new surgical techniques to allow their safe dissemination.

Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines).

Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial.

Protocol for the UK cohort study to investigate the prevention of parastomal hernia (the CIPHER study).

AIM: Abdominal surgery sometimes necessitates the creation of a stoma, which can cause future complications including parastomal hernia (PSH), an incisional hernia adjacent to and related to the stoma. PSH affects approximately 40% of patients within 2 years of stoma formation. Complications of PSH reduce a patient's quality of life and can be severe (e.g. bowel obstruction). PSHs are difficult to manage and can recur after surgical repair. Therefore, it is very important to prevent a PSH. Surgeons create stomas in different ways and both patient and surgical factors are believed to influence the development of PSH. The aim of the CIPHER study is to investigate the influence of different surgical techniques on the development of PSH. METHOD: The UK cohort study to investigate the prevention of parastomal hernia (the CIPHER study) aims to recruit 4000 patients undergoing elective or expedited surgery with the intention of forming an ileostomy or colostomy, irrespective of the primary indication for the planned surgery. For each patient, surgeons will describe their methods of trephine formation, mesh reinforcement of the stoma trephine, use of the stoma as a specimen extraction site and wound closure. The primary outcome will be incident PSH during follow-up, defined as symptoms of PSH (custom-designed questionnaire) and anatomical PSH, ascertained by independent reading of usual care CT scans. Secondary outcomes will include surgical site infection, the Comprehensive Complication Index, quality of life (EQ-5D-5L and SF-12), PSH repair and use of NHS resources. RESULTS: Results of the study will be submitted for publication in peer-reviewed journals. All publications relating to the results of CIPHER will use a corporate authorship, 'The CIPHER Study Investigators' with named writing committee members. CONCLUSION: The CIPHER study will be the first to investigate detailed surgical methods of stoma formation in a large, representative cohort of patients with a range of primary indications, both cancer and noncancer.

Impact on Health-Related Quality of Life of Video-Assisted Thoracoscopic Surgery for Lung Cancer.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) approaches are increasingly used in lung cancer surgery, but little is known about their impact on patients' health-related quality of life (HRQL). This prospective study measured recovery and HRQL in the year after VATS for non-small cell lung cancer (NSCLC) and explored the feasibility of HRQL data collection in patients undergoing VATS or open lung resection. PATIENTS AND METHODS: Consecutive patients referred for surgical assessment (VATS or open surgery) for proven/suspected NSCLC completed HRQL and fatigue assessments before and 1, 3, 6 and 12 months post-surgery. Mean HRQL scores were calculated for patients who underwent VATS (segmental, wedge or lobectomy resection). Paired t-tests compared mean HRQL between baseline and expected worst (1 month), early (3 months) and longer-term (12 months) recovery time points. RESULTS: A total of 92 patients received VATS, and 18 open surgery. Questionnaire response rates were high (pre-surgery 96-100%; follow-up 67-85%). Pre-surgery, VATS patients reported mostly high (good) functional health scores [(European Organisation for Research and Treatment of Cancer) EORTC function scores > 80] and low (mild) symptom scores (EORTC symptom scores < 20). One-month post-surgery, patients reported clinically and statistically significant deterioration in overall health and physical, role and social function (19-36 points), and increased fatigue, pain, dyspnoea, appetite loss and constipation [EORTC 12-26; multidimensional fatigue inventory (MFI-20) 3-5]. HRQL had not fully recovered 12 months post-surgery, with reduced physical, role and social function (10-14) and persistent fatigue and dyspnoea (EORTC 12-22; MFI-20 2.7-3.2). CONCLUSIONS: Lung resection has a considerable detrimental impact on patients' HRQL that is not fully resolved 12 months post-surgery, despite a VATS approach.

Integrating expert opinions with clinical trial data to analyse low-powered subgroup analyses: a Bayesian analysis of the VeRDiCT trial.

BACKGROUND: Typically, subgroup analyses in clinical trials are conducted by comparing the intervention effect in each subgroup by means of an interaction test. However, trials are rarely, if ever, adequately powered for interaction tests, so clinically important interactions may go undetected. We discuss the application of Bayesian methods by using expert opinions alongside the trial data. We applied this methodology to the VeRDiCT trial investigating the effect of preoperative volume replacement therapy (VRT) versus no VRT (usual care) in diabetic patients undergoing cardiac surgery. Two subgroup effects were of clinical interest, a) preoperative renal failure and b) preoperative type of antidiabetic medication. METHODS: Clinical experts were identified within the VeRDiCT trial centre in the UK. A questionnaire was designed to elicit opinions on the impact of VRT on the primary outcome of time from surgery until medically fit for hospital discharge, in the different subgroups. Prior beliefs of the subgroup effect of VRT were elicited face-to-face using two unconditional and one conditional questions per subgroup analysis. The robustness of results to the 'community of priors' was assessed. The community of priors was built using the expert priors for the mean average treatment effect, the interaction effect or both in a Bayesian Cox proportional hazards model implemented in the STAN software in R. RESULTS: Expert opinions were obtained from 7 clinicians (6 cardiac surgeons and 1 cardiac anaesthetist). Participating experts believed VRT could reduce the length of recovery compared to usual care and the greatest benefit was expected in the subgroups with the more severe comorbidity. The Bayesian posterior estimates were more precise compared to the frequentist maximum likelihood estimate and were shifted toward the overall mean treatment effect. CONCLUSIONS: In the VeRDiCT trial, the Bayesian analysis did not provide evidence of a difference in treatment effect across subgroups. However, this approach increased the precision of the estimated subgroup effects and produced more stable treatment effect point estimates than the frequentist approach. Trial methodologists are encouraged to prospectively consider Bayesian subgroup analyses when low-powered interaction tests are planned. TRIAL REGISTRATION: ISRCTN, ISRCTN02159606 . Registered 29th October 2008.

A mixed methods case study investigating how randomised controlled trials (RCTs) are reported, understood and interpreted in practice.

BACKGROUND: While randomised controlled trials (RCTs) provide high-quality evidence to guide practice, much routine care is not based upon available RCTs. This disconnect between evidence and practice is not sufficiently well understood. This case study explores this relationship using a novel approach. Better understanding may improve trial design, conduct, reporting and implementation, helping patients benefit from the best available evidence. METHODS: We employed a case-study approach, comprising mixed methods to examine the case of interest: the primary outcome paper of a surgical RCT (the TIME trial). Letters and editorials citing the TIME trial's primary report underwent qualitative thematic analysis, and the RCT was critically appraised using validated tools. These analyses were compared to provide insight into how the TIME trial findings were interpreted and appraised by the clinical community. RESULTS: 23 letters and editorials were studied. Most authorship included at least one academic (20/23) and one surgeon (21/23). Authors identified wide-ranging issues including confounding variables or outcome selection. Clear descriptions of bias or generalisability were lacking. Structured appraisal identified risks of bias. Non-RCT evidence was less critically appraised. Authors reached varying conclusions about the trial without consistent justification. Authors discussed aspects of internal and external validity covered by appraisal tools but did not use these methodological terms in their articles. CONCLUSIONS: This novel method for examining interpretation of an RCT in the clinical community showed that published responses identified limited issues with trial design. Responses did not provide coherent rationales for accepting (or not) trial results. Findings may suggest that authors lacked skills in appraisal of RCT design and conduct. Multiple case studies with cross-case analysis of other trials are needed.

Short-term safety outcomes of mastectomy and immediate implant-based breast reconstruction with and without mesh (iBRA): a multicentre, prospective cohort study.

BACKGROUND: Use of biological or synthetic mesh might improve outcomes of immediate implant-based breast reconstruction-breast reconstruction with implants or expanders at the time of mastectomy-but there is a lack of high-quality evidence to support the safety or effectiveness of the technique. We aimed to establish the short-term safety of immediate implant-based breast reconstruction performed with and without mesh, to inform the feasibility of undertaking a future randomised clinical trial comparing different breast reconstruction techniques. METHODS: In this prospective, multicentre cohort study, we consecutively recruited women aged 16 years or older who had any type of immediate implant-based breast reconstruction for malignancy or risk reduction, with any technique, at 81 participating breast and plastic surgical units in the UK. Data about patient demographics and operative, oncological, and complication details were collected before and after surgery. Outcomes of interest were implant loss (defined as unplanned removal of the expander or implant), infection requiring treatment with antibiotics or surgery, unplanned return to theatre, and unplanned re-admission to hospital for complications of reconstructive surgery, up to 3 months after reconstruction and assessed by clinical review or patient self-report. Follow-up is complete. The study is registered with the ISRCTN Registry, number ISRCTN37664281. FINDINGS: Between Feb 1, 2014, and June 30, 2016, 2108 patients had 2655 mastectomies with immediate implant-based breast reconstruction at 81 units across the UK. 1650 (78%) patients had planned single-stage reconstructions (including 12 patients who had a different technique per breast). 1376 (65%) patients had reconstruction with biological (1133 [54%]) or synthetic (243 [12%]) mesh, 181 (9%) had non-mesh submuscular or subfascial implants, 440 (21%) had dermal sling implants, 42 (2%) had pre-pectoral implants, and 79 (4%) had other or a combination of implants. 3-month outcome data were available for 2081 (99%) patients. Of these patients, 182 (9%, 95% CI 8-10) experienced implant loss, 372 (18%, 16-20) required re-admission to hospital, and 370 (18%, 16-20) required return to theatre for complications within 3 months of their initial surgery. 522 (25%, 95% CI 23-27) patients required treatment for an infection. The rates of all of these complications are higher than those in the National Quality Standards (<5% for re-operation, re-admission, and implant loss, and <10% for infection). INTERPRETATION: Complications after immediate implant-based breast reconstruction are higher than recommended by national standards. A randomised clinical trial is needed to establish the optimal approach to immediate implant-based breast reconstruction. FUNDING: National Institute for Health Research, Association of Breast Surgery, and British Association of Plastic, Reconstructive and Aesthetic Surgeons.

Developing a real-time electronic symptom monitoring system for patients after discharge following cancer-related surgery.

BACKGROUND: Patients undergoing major cancer surgery frequently require post-acute care for complications and adverse effects. Enhanced recovery after surgery programmes mean that patients are increasingly discharged home earlier. Symptom/complication detection post-discharge is sub-optimal. Systematic patient monitoring post-discharge following surgery may be optimally achieved through routine electronic patient-reported outcome (ePRO) data capture. ePRO systems that employ clinical algorithms to guide management of patients and automatically alert clinicians of clinically-concerning symptoms can improve patient outcomes and decrease hospital admissions. ePRO systems that provide individually-tailored self-management advice and integrate live ePRO data into electronic health records (EHR) may also advance personalised health and patient-centred care. This study aims to develop a hospital EHR-integrated ePRO system to improve detection and management of complications post-discharge following cancer-related surgery. METHODS: The ePRO system was developed in two phases: (1) Development of a web-based ePRO symptom-report from validated European Organisation for Research and Treatment of Cancer (EORTC) questionnaires, clinical opinion and patient interviews, followed by hospital EHR integration; (2) Development of clinical algorithms triggering symptom severity-dependent patient advice and clinician alerts from: (i) prospectively-collected patient-completed ePRO symptom-report data; (ii) stakeholder meetings; (iii) patient interviews. Patient advice was developed from: (i) clinician-patient telephone consultations and patient interviews; (ii) review of hospital patient information leaflets (PIL) and patient support websites. RESULTS: Phase 1, including interviews with 18 patients, identified 35 symptom-report items. In phase 2, 130/300 (43%) screened patients were eligible. 61 (47%) consented to participate and 59 (97%) provided 444 complete self-reports. Stakeholder meetings (9 clinicians, 1 patient/public representative) and patient interviews (n = 66) refined advice/alert accuracy. 15 telephone consultations, 7 patient interviews and review of 28 PILs and 3 patient support websites identified 4 themes to inform self-management advice. Comparisons between ePRO symptom-report data, telephone consultations and clinical events/outcomes (n = 27 patients) further refined clinical algorithms. CONCLUSIONS: A hospital EHR-integrated ePRO system that alerts clinicians and provides patient self-management advice has been developed to improve the detection and management of problems and complications after discharge following surgery. An ongoing pilot study will inform a multicentre randomised trial to evaluate the effectiveness of the ePRO system compared to usual care.

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.

Development of an online resource for recruitment research in clinical trials to organise and map current literature.

BACKGROUND: Recruiting the target number of participants within the pre-specified time frame agreed with funders remains a common challenge in the completion of a successful clinical trial and addressing this is an important methodological priority. While there is growing research around recruitment, navigating this literature to support an evidence-based approach remains difficult. The Online resource for Recruitment Research in Clinical triAls project aims to create an online searchable database of recruitment research to improve access to existing evidence and to identify gaps for future research. METHODS: MEDLINE (Ovid), Scopus, Cochrane Database of Systematic Reviews and Cochrane Methodology Register, Science Citation Index Expanded and Social Sciences Citation Index within the ISI Web of Science and Education Resources Information Center were searched in January 2015. Search strategy results were screened by title and abstract, and full text obtained for potentially eligible articles. Studies reporting or evaluating strategies, interventions or methods used to recruit patients were included along with case reports and studies exploring reasons for patient participation or non-participation. Eligible articles were categorised as systematic reviews, nested randomised controlled trials and other designs evaluating the effects of recruitment strategies (Level 1); studies that report the use of recruitment strategies without an evaluation of impact (Level 2); or articles reporting factors affecting recruitment without presenting a particular recruitment strategy (Level 3). Articles were also assigned to 1, or more, of 42 predefined recruitment domains grouped under 6 categories. RESULTS: More than 60,000 records were retrieved by the search, resulting in 56,030 unique titles and abstracts for screening, with a further 23 found through hand searches. A total of 4570 full text articles were checked; 2804 were eligible. Six percent of the included articles evaluated the effectiveness of a recruitment strategy (Level 1), with most of these assessing aspects of participant information, either its method of delivery (33%) or its content and format (28%). DISCUSSION: Recruitment to clinical trials remains a common challenge and an important area for future research. The online resource for Recruitment Research in Clinical triAls project provides a searchable, online database of research relevant to recruitment. The project has identified the need for researchers to evaluate their recruitment strategies to improve the evidence base and broaden the narrow focus of existing research to help meet the complex challenges faced by those recruiting to clinical trials.

Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.

BACKGROUND: Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. METHODS: OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1-4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4-6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. FINDINGS: Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6-26·3) with CF and 26·1 months (22·5-29·7) with ECX (hazard ratio 0·90 (95% CI 0·77-1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. INTERPRETATION: Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. FUNDING: Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. METHODS: In this multicentre, randomised, open-label phase 2-3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1-21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. FINDINGS: Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5-54·9) in the chemotherapy alone group and 48·1% (43·2-52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91-1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). INTERPRETATION: The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. FUNDING: Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.

Core Outcome Set-STAndards for Development: The COS-STAD recommendations.

BACKGROUND: The use of core outcome sets (COS) ensures that researchers measure and report those outcomes that are most likely to be relevant to users of their research. Several hundred COS projects have been systematically identified to date, but there has been no formal quality assessment of these studies. The Core Outcome Set-STAndards for Development (COS-STAD) project aimed to identify minimum standards for the design of a COS study agreed upon by an international group, while other specific guidance exists for the final reporting of COS development studies (Core Outcome Set-STAndards for Reporting [COS-STAR]). METHODS AND FINDINGS: An international group of experienced COS developers, methodologists, journal editors, potential users of COS (clinical trialists, systematic reviewers, and clinical guideline developers), and patient representatives produced the COS-STAD recommendations to help improve the quality of COS development and support the assessment of whether a COS had been developed using a reasonable approach. An open survey of experts generated an initial list of items, which was refined by a 2-round Delphi survey involving nearly 250 participants representing key stakeholder groups. Participants assigned importance ratings for each item using a 1-9 scale. Consensus that an item should be included in the set of minimum standards was defined as at least 70% of the voting participants from each stakeholder group providing a score between 7 and 9. The Delphi survey was followed by a consensus discussion with the study management group representing multiple stakeholder groups. COS-STAD contains 11 minimum standards that are the minimum design recommendations for all COS development projects. The recommendations focus on 3 key domains: the scope, the stakeholders, and the consensus process. CONCLUSIONS: The COS-STAD project has established 11 minimum standards to be followed by COS developers when planning their projects and by users when deciding whether a COS has been developed using reasonable methods.