The Core Outcome measures in Squamous Intraepithelial precursor lesions of the Anus (COrSIcA) study: A protocol for the development of a core outcome set for future anal high-grade squamous intraepithelial lesion (aHSIL) treatment trials

The Core Outcome measures in Squamous Intraepithelial precursor lesions of the Anus (COrSIcA) study: A protocol for the development of a core outcome set for future anal high-grade squamous intraepithelial lesion (aHSIL) treatment trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Method Article The Core Outcome measures in Squamous Intraepithelial precursor lesions of the Anus (COrSIcA) study: A protocol for the development of a core outcome set for future anal high-grade squamous intraepithelial lesion (aHSIL) treatment trials David A. Finch, Rebecca Morris, Edward Parkin, Peter Mitchell, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6949923/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction There are multiple treatments for anal high-grade squamous intraepithelial lesion (aHSIL). The evidence for aHSIL treatments is scarce and of poor quality, such that the optimal approach cannot be defined. Existing trials in aHSIL have used different ways of measuring the effects of treatment. This makes comparing the results of trials very difficult. Trials are also likely to have been poor at reporting treatment effects important to patients. Treatment trials are needed to determine optimal approaches. Key to the quality of these trials is consistent and meaningful outcome measurement and reporting. Methods and Analysis The Core Outcome measures in Squamous Intraepithelial precursor lesions of the Anus (COrSIcA) study aims to develop a core outcome set (COS) for use in future late-phase aHSIL treatment trials. This is a standardised set of outcomes deemed most important by key stakeholders, which should be measured and reported in all future treatment trials for the condition. Systematic review of current treatment studies, and interviews with patients who have lived experience of aHSIL, will determine a longlist of potentially important outcomes. Consensus methods (an international Delphi survey and consensus meeting), taking into account the views of key stakeholders (patients, healthcare professionals and clinician trialists) with experience of the condition, will determine which outcomes from the longlist are most important and subsequently be included in the COS. Ethics and Dissemination Utilisation of the COS in future treatment trials will ensure outcomes reported are consistent and meaningful. NHS/HRA research ethics committee approval has been granted. The study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative and is listed in their database (Study ID 2511, https://www.comet-initiative.org/Studies/Details/2511). Gastrointestinal Surgery Anal neoplasms Outcome Studies Outcome Measures Figures Figure 1 Figure 2 Introduction Background Anal squamous cell carcinoma (ASCC) is a Human Papilloma Virus (HPV)-associated cancer, the incidence of which has increased globally over the past three decades. This rise being particularly notable in western populations, such as the United States and United Kingdom, where the standardised incidence is now 1.9 and 2.5 per 100,00 people, respectively[ 1 , 2 ]. Initial treatment is chemoradiotherapy which is associated with considerable morbidity, including early side effects such as radiotherapy-related dermatitis and later side effects such as faecal urgency and incontinence, sexual and bladder dysfunction and permanent colostomy. Compounding this, 15–18% of cases relapse locally[ 3 ]. Prevention through the detection and treatment of the precursor lesion, anal intraepithelial neoplasia (AIN) (specifically the high-grade subtype, now termed anal high-grade squamous intraepithelial lesion (aHSIL)[ 4 ]) is thus an attractive strategy to prevent the increasing clinical burden of ASCC. Furthermore, several subpopulations have been identified as being at increased risk of developing ASCC, with risk ranging from 1.7 per 100,000 person-years in the general population to > 100 per 100,000 in HIV subpopulations[ 5 , 6 ]. The improved understanding of lesion and subpopulation risk allows for better-informed cancer prevention and early detection strategies. In 2022, the ANCHOR trial[ 7 ] reported a large, multi-centre, phase III randomised-controlled trial (RCT) of aHSIL treatment versus active monitoring without treatment in people living with HIV (PLWH) and showed significantly lower risk of progression to ASCC with aHSIL treatment (principally ablation). The evidence for treatment benefit provided by ANCHOR, when coupled with the recent publication of international consensus guidelines for screening of high-risk populations[ 8 ] is anticipated to lead to a significant increase in the number of patients requiring treatment for aHSIL. There are multiple treatments for aHSIL, broadly categorised into medical and surgical therapies. Medical treatments include patient-applied, field-based options such as imiquimod cream, topical 5-fluorouracil and cidofovir ointment, as well as clinician-applied, lesion-targeted treatments such as trichloroacetic acid and cryotherapy. Surgical treatments are clinician-directed and lesion-targeted, and include local or wide local excision with or without skin graft/flap reconstruction, as well as ablative methods such as laser, electrocautery, infrared coagulation, radiofrequency ablation, photocoagulation, and argon plasma beam coagulation. Vaccination is a possible third management strategy. The evidence base underpinning these treatments is scarce and generally of poor quality. A recent systematic review evaluating the efficacy of treatment options for AIN identified only four RCTs [ 9 ]. Inconsistent outcome measurement was identified as a major contributory factor hindering comparison of studies. There are few data on the impacts of treatments on quality of life. Optimal treatment approaches need to be defined through well-designed, high-quality interventional studies that measure clinically meaningful outcomes. We are developing a ‘core outcome set’ (COS) for future aHSIL treatment trials through the COrSIcA ( C ore O utcome measu r es in S quamous I ntraepithelial precursor lesions of the A nus) study. A COS is defined as an agreed minimum set of outcomes that should be measured and reported in all trials in a specific condition[ 10 ]. COSs include outcomes deemed most important by key stakeholders and, when used, standardise outcome measurement and reporting across trials. COSs can improve the quality of evidence through reduction in outcome heterogeneity, reduction in outcome reporting bias, and use of outcomes relevant to all stakeholders[ 11 ]. Currently, there is no COS for treatment trials in patients with aHSIL. The COrSIcA COS will be developed using methodological approaches recognised by the COMET (Core Outcome Measures in Effectiveness Trials) initiative[ 12 ]. The COMET Initiative ( https://www.comet-initiative.org ) is a guidance body for developing and reporting COSs. COMET recommend COS developers first identify ‘what’ outcomes to include in a COS and then determine ‘how’ those outcomes should be measured. Our research group have previously published a COS for ASCC chemoradiotherapy treatment trials (CORMAC and CORMAC-2)[ 13 , 14 ]. COrSIcA will determine ‘what’ outcomes should be measured in future aHSIL treatment trials. Further work will be necessary to determine ‘how’ the included outcomes be measured. Study aims and objectives The aim of COrSIcA is to develop a COS for use in all future late-phase trials investigating therapeutic interventions for aHSIL which reflects the interests of key stakeholders (patients, healthcare professionals and clinician trialists). Specific objectives are to: Determine the degree and nature of variation in the reporting of outcomes in aHSIL treatment studies to date. Formulate a list of potentially important outcomes from published studies. Identify a list of outcomes potentially important to patients, through semi-structured interviews with patients who have experienced treatment for aHSIL. Reach consensus agreement on the most important outcomes to be measured and reported in all future aHSIL treatment trials. Scope This COS is intended for: Health condition : Anal high-grade squamous intraepithelial lesion (P16 positive AIN2 and/or AIN3) affecting one or both of the perianus or anal canal. Population : Adults > 18 years of age, either screened and/or symptomatic for aHSIL. Intervention : Any direct intervention for aHSIL (e.g., surgical excision, electrocautery/laser ablation, topicals) and/or indirect interventions for aHSIL (e.g., targeting high-risk HPV (hrHPV)). Setting/context of use : Later phase trials that will inform clinical decision making. METHODS AND ANALYSIS This protocol has been developed in accordance with COMET guidance, specifically the Core Outcome Set-Standards for Development (COS-STAD) recommendations[ 15 ] and the Core outcome Set-Standardised Protocol Items (COS-STAP) statement[ 16 ] which outline the minimum standards and essential items for COS development and documentation. Mixed-methods will be employed to maximise stakeholder involvement and granularity. Summarised in Fig. 1 , the COS will be developed in two phases over four distinct stages. Phase one involving identifying a ‘longlist’ of potentially important outcomes, and Phase two involving determining which outcomes from the longlist are ‘core’ (i.e., outcomes deemed so important that they should be measured and reported in all future treatment trials). Stakeholders Stakeholder involvement in the COS development process has been considered from both the research team perspective and that of the study participants. Patient and Public Involvement and Engagement A patient and public involvement and engagement (PPIE) group has been established comprising patients with lived experience of aHSIL. The group will help inform the study from design, commenting on patient-focused information (e.g., adverts, patient information sheets, consent forms), wording of interview and survey questions, through to dissemination and wider public engagement. Study Steering Group A study steering group (SSG) has been assembled to oversee the project. Members include, trialists with leading roles in past or current aHSIL clinical trials, clinicians with experience in aHSIL from the fields of colorectal surgery, gynaecology and sexual health, a COS methodological expert, a qualitative methodology expert and have patient representation. The SSG will meet at key stages during the course of the project and ensure that key stakeholder opinion is represented at every stage of the COS development. Study participants Study participants comprise three main stakeholder groups: Patients : Any person who has received or is receiving treatment for aHSIL will be invited to participate. Healthcare professionals (HCPs) : HCPs from any speciality managing (assessing, treating or reviewing) patients for their aHSIL will be invited to participate. Clinician trialists : Corresponding authors of published/proposed phase III RCT’s in aHSIL will be invited to participate as will those of any non-randomised trials or large observational studies. Other stakeholder groups, including healthcare regulators, industry representatives, and policymakers, have been considered. Taking into account practical constraints on the project and recent evidence suggesting overlap in outcomes suggested in COSs and those suggested by healthcare regulators[ 17 ] the decision was made not to include these groups. Importantly, if an outcome is not included in a COS, it does not mean that it cannot be measured. Therefore, should any other stakeholder group suggest additional outcomes to those included in the final COS, they can still be measured. Study design Phase one – Identifying potential outcomes Phase one comprises two stages and is concerned with identifying an exhaustive list of potentially important outcomes. Stage 1. A systematic review of academic literature – Identifying existing knowledge about outcomes A systematic review of the literature will be performed to identify a comprehensive list of all outcome measures used in studies investigating the effect of treatments in patients with aHSIL. The outcomes identified in this stage will be taken to represent the views of the HCPs and clinician trialists. Given the lack of published late phase trials for the treatment of aHSIL, limiting the systematic review to only these studies risks missing important outcomes. To ensure the breadth of treatment outcomes are explored, analysis will be extended to include published early phase trials and observational studies. The full protocol for the systematic review, including the search strategy and study selection criteria, is available online via the PROSPERO database (CRD42023429661). Stage 2. A series of semi-structured interviews with patients with experience of aHSIL treatment – Filling in the gaps COMET emphasise the importance of including patient relevant outcomes within COS[ 12 ]. Patient participation is vital because it is the patients themselves who are subject to the benefits and potential risks of treatments for their condition. A qualitative approach, involving in-depth semi-structured interviews with individuals who have or have had aHSIL, will enable a full exploration of patients’ perceptions of and priorities about outcomes in aHSIL ensuring outcomes most important to patients are considered for the final COS. Study participants Inclusion and exclusion criteria based on types of participant, pathology and intervention is detailed in Table 1 . Table 1 Inclusion and Exclusion criteria for semi-structured interviews Inclusion Exclusion Participants •Adults > 18 years of age. •Patients who have completed or are receiving treatment for aHSIL. •Unable to give informed consent. •Too unwell to comfortably participate in an interview lasting approximately 30–60 minutes. •Untreated patients Pathology •High-grade squamous intraepithelial neoplasia of the anal canal, perianus or both. •Low-grade anal squamous intraepithelial neoplasia (aLSIL) only. Intervention Any intervention for the treatment of aHSIL. •No specific treatment exclusions. Recruitment and sampling Purposive sampling will be used to maximise the diversity of the interviewed patient population[ 18 ]. Criteria have been selected to ensure that subsets within the study population, which may express a wide variety and potentially contrasting views and experiences are included. Examples include: High-risk groups : Individuals with recognised high-risk of malignant transformation, such as PLWH, men who have sex with men (MSM), individuals with a history of intraepithelial neoplasia or invasive SCC in adjacent anogenital sites, and the immunosuppressed, whether due to solid organ transplantation or autoimmune conditions[ 5 ]. Symptomatic vs. asymptomatic individuals : Those with troublesome symptoms attributable to aHSIL, such as itching, discomfort and bleeding, compared asymptomatic individuals diagnosed through screening or incidentally. Concurrent conditions : Patients with concurrent intraepithelial neoplasia in affecting genital sites adjacent to the anus (multizone intraepithelial neoplasia) who require concurrent assessment and treatment. Different treatment experiences : Patients with experience of various treatment types, such as self-applied topical medical treatments (e.g., Imiquimod, 5-fluorouracil, Cidofovir) administered over several weeks, versus clinician-administered surgical options (e.g., laser, electrocautery ablation, surgical excision) delivered as single or staged treatment episodes. The key criteria for identifying difference is shown in the sampling matrix in Table 2 : Table 2 Purposive sampling matrix for semi-structured interview participants Key criteria Target number of participants Age at diagnosis 18–35 2–4 36–65 6–8 65+ 6–8 Gender Male 6–8 Female 6–8 Transgender 1–2 Sexuality Heterosexual 10–12 Homosexual 3–4 Socioeconomic status* Most deprived 5–6 Least deprived 3–4 Ethnicity White 10–12 Black 1–2 Asian 1–2 HIV status Positive 2–4 History of intraepithelial neoplasia/invasive SCC in adjacent genital sites Present 2–4 History of multizone disease** Present 2–4 Solid organ transplant Present 1–2 Non-HIV/Solid organ transplant recipient immunosuppressed Present 1–2 Symptoms attributed to aHSIL Yes 5–6 No 5–6 Time since initial diagnosis Less than 1 year 5–7 1–3 years 5–7 Greater than 3 years 5–7 Treatment type(s) experienced*** Medical 6–8 Surgical 6–8 Target total**** 20 * Socioeconomic status (based on English indices of deprivation) **People with concurrent intraepithelial neoplasia affecting sites in addition to the anus (e.g., cervix, vulva, vagina, penis, scrotum). ***Medical treatments including patient-applied, field-based options such as imiquimod cream, topical 5-fluorouracil, antiviral agents like cidofovir ointment, and clinician-applied treatments such as trichloroacetic acid and cryotherapy. Surgical treatments including local or wide local excision with or without skin graft/flap reconstruction or ablative methods such as laser, electrocautery, infrared coagulation, radiofrequency ablation, photocoagulation, and argon plasma beam coagulation. ****Many participants will fall into several categories. The ‘target total’ refers to the number of participants, not the sum of the individual criteria. Recruitment Recruitment for patient interviews will come from three primary sources; regional treatments centres, patient groups, and via snowball sampling. Suitable participants will be identified from clinic lists, multidisciplinary team (MDT) meeting lists, and patient records at The Christie NHS Foundation Trust and Lancashire Teaching Hospitals NHS Foundation Trust (LTHTR). A database of AIN patients under surveillance at LTHTR will form another source of participants. A member of the clinical team will make initial contact with potential participants, either in person or by telephone, after which the research team will discuss and arranging participation for those who are interested. Links have been established with patient groups (International Anal Neoplasia Society, HPV and Anal Cancer Foundation and British HIV Association). A contact at each group will approach members to about participating in this research. To maximise opportunities for the inclusion of minority groups (e.g., MSM), snowball sampling will be employed by asking participants to suggest contacts who may be willing to participate. This is an established technique for research involving sensitive topics and accessing historically marginalised populations[ 19 ]. Sample size An initial sample of 20 patients will be recruited. Although the purposive sampling matrix (Table 2 ) includes many stratification factors, the anticipated overlap of factors among participants is expected to ensure that this sample size is sufficient to achieve data saturation. A stopping criterion of three will be applied. Previous studies suggest that most relevant outcomes can be identified within 17 interviews[ 13 , 20 ]. If no new outcomes emerge by interview 20, data saturation will be confirmed and recruitment will cease[ 21 , 22 ]. If new outcomes are identified in interviews 18–20, up to three additional interviews will be conducted until no new outcomes emerge or a maximum of 30 interviews is reached. Consent The researcher will obtain informed written consent from participants. Information will be provided verbally and through ethically approved information sheets. Only individuals with the capacity to give consent will be included. It will be stressed that participation is voluntary, with no obligation, and participants may withdraw at any time without affecting their medical care. The individual will be offered ample time to consider participation prior to consent (at least 24 hours). Interview location Interviews will be conducted at a time convenient to the participant in either: A clinic room at either The Christie Hospital or The Royal Preston Hospital (LTHTR) An office at the Manchester Cancer Research Centre or the NIHR Preston Clinical Research Facility The participants home Over the phone Via an online video conferencing platform Interview format Interviews will follow a semi-structured format to explore patients' perceptions, priorities, and experiences of living with and receiving treatment for aHSIL. This method involves open-ended questions to encourage a patient-led discussion, supplemented by prompts from a pre-prepared interview guide to ensure that key topics are addressed. The interview schedule may be modified iteratively using the experience yielded from successive patient interviews to ensure inclusion of items that have been raised by earlier participants are included in the interview schedule for subsequent discussions. The study can translate materials and conduct interviews in other languages using University of Manchester-approved translation services and interpreters from an approved NHS translator service. This allows inclusion of participants who do not speak or understand English. Data analysis Interviews will be audio recorded, transcribed and interrogated for outcomes which may supplement the outcomes already gathered from the systematic review of the literature. Data will be analysed through thematic analysis[ 23 , 24 ] using NVivo 12 software ( https://www.qsrinternational.com/nvivo-qualitative-data-analysis-software/home , QSR International, Burlington, MA, USA). The data will be coded to produce a matrix of themes. Themes will be derived from issues raised by participants. From these themes, outcomes of key importance to patients with aHSIL will be developed. These outcomes will be combined with the results of the systematic review to create a ‘longlist’ of potentially important outcomes. A consultation exercise with the SSG will finalise the ‘longlist’ for prioritisation in Stage 3, the Delphi survey. The consultation exercise will ensure clear and precise meanings are given to the outcomes identified and ensure there is no duplication of outcomes. Any outcomes deemed unrelated to treatment effect, such as adverse effects unrelated to treatment will be discussed with the SSG and dropped at this stage. Outcomes will be categorised into outcome domains, using COMET recommended taxonomy[ 25 ], so that similar or related outcomes are viewed together in the survey. Phase two – Determining the core outcomes Phase two comprises two further stages and uses consensus methods to determine the outcomes deemed most important for inclusion in the final COS. Figure 2 summarises the COrSIcA consensus process. Stage 3. A Delphi survey – Eliciting views about important outcomes A Delphi survey is an iterative process involving key stakeholders commonly used in COS development, to reach consensus on the most important outcomes for inclusion. The major advantage of the Delphi process is that it is anonymous and can be conducted remotely and online, thereby reaching an international audience and minimising the potential for bias toward more vocal participants or those whose views might be perceived as superior. Furthermore, it permits opportunity to suggest and include additional outcome items, and can be circulated to large numbers of potential participants. The aim of the Delphi process is to progress towards consensus for which outcomes from the longlist generated at the end of stage two should be included in the final COS. While there is no optimal methodological approach to conducting a Delphi survey, specific considerations for COrSIcA include: Participants Participants will be recruited internationally from the three main stakeholder groups. All participants must be adults > 18 years of age and able to complete a questionnaire in the English language. Given anal HSIL’s association with HPV and ‘at-risk’ populations crossing multiple medical disciplines, we will reach out to all clinical specialities likely to manage patients with aHSIL, including: Colorectal surgeons Gynaecologists Clinical oncologists Dermatologists Gastroenterologists Infectious diseases / HIV physicians Transplant physicians General practitioners / Family physicians Nurse anoscopists Specialist nurses Recruitment and sampling All UK centres managing aHSIL will be invited to become participant identification centres (PIC’s), targeting potential patient participants through their anal cancer MDTs and clinics. Centres unable to be PICs can advertise the study via posters for self-referral. International clinicians approached for the Delphi survey will also be encouraged to display the poster in relevant settings. As with the patient interviews, patient participants will also be recruited via links with patient groups and via snowball sampling. For clinicians, all UK anal cancer MDT members managing aHSIL and members of relevant international associations will be invited. Participants from the COrSIcA SSG and corresponding authors of recent phase 3 RCTs, non-randomised trials, and large observational studies on aHSIL will also be invited. Sample size There is no accepted or required ‘sample size’ requirement for a Delphi survey[ 26 ]. The key consideration with sample size is that there is good representation from key stakeholder groups comprising experts (including those with lived experience) who have a deep understanding of the issues. We aim to recruit at least 100 participants, a realistic target based on the experience of successful COSs from allied disease group and/or similar methodological approach[ 13 , 27 ]. We will keep a record of the invitations made, the number of and source of all participants per stakeholder group. This will facilitate interpretation of the results of the Delphi. No new participants will be invited after the closure of Round 1. Participant information Participant information sheets will use terminology piloted within the PPIE group to ensure comprehensibility. Instructions for how to complete the questionnaire will be included at the start of each round. Prior to commencing Round 1, patient participants will be asked to enter demographic information, and healthcare professionals/clinical trialists will be asked about their speciality and the volume of their aHSIL workload (Table 3 ). This will enable the exploration of the impact of language, cultural variation and clinical experience in relation to the Delphi survey responses. Table 3 Information specific to each stakeholder group to be gathered: Patients Healthcare professionals (including clinical trialists) • Age • Sex and Gender • Ethnicity • Country • Marital status • Sexuality • HIV status • Other immunosuppression • Any other HPV associate intraepithelial neoplasia / invasive carcinoma • Details about aHSIL diagnosis and treatment • Speciality (coloproctology, infectious diseases, gynaecology, specialist nurse, etc). • Treatments offered • Duration of practice • Country of practice • Involvement with trials Number of Rounds Delphi surveys for the development of COSs typically contain two or three rounds[ 28 – 32 ], with three iterations sufficient to reach consensus in most cases[ 33 ]. For practical purposes, COrSIcA will comprise a two-round Delphi, acknowledging that this approach may result in a higher number of outcomes for which consensus is not reached, thereby placing greater burden on the consensus meeting stage to attempt to reach consensus on these. Structure of the questionnaires and order of questionnaire items The Delphi survey will be conducted online, but participants will also have the option to complete paper versions to accommodate those with limited internet access or skills. The questionnaire will be constructed and disseminated using Qualtrics survey software (Qualtrics, Provo, UT, USA. https://www.qualtrics.com ) approved by the University of Manchester. The electronic Delphi method has been validated as a reliable approach for achieving consensus on COS for various health conditions[ 12 , 34 ]. Within the questionnaire, outcomes will be organised into domains, grouping similar or related outcomes for easier comparison. Each outcome will be described in plain language. The language used will be piloted with patients and HCPs before finalising the questionnaire. Involvement of the SSG and PPIE group will form a key element of this activity ensuring the questionnaire is accessible, comprehensible, and valid. Additional open questions At the end of Round 1 of the Delphi, participants will be asked to list any additional outcomes they feel have not been covered by the questionnaire. Any suggested outcomes deemed to represent a new outcome domain by the SSG (following discussion and a majority decision) will be included in Round 2 of the Delphi. Scoring system Participants will be asked to rate the importance of each outcome based a Likert scoring system as recommended by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working group for assessing the level of importance about research evidence[ 10 , 35 ]. Outcomes are graded in accordance to their level of importance on a 9-point scale. Scores of, 1 to 3 signify an outcome is of limited importance (‘unimportant’), 4 to 6 ‘important but not critical’, and scores of 7 to 9 are considered ‘critically important’ outcomes [ 36 – 38 ]. An ‘unable to score’ category will be included to allow for the fact that some stakeholder group members may not have the expertise to score certain outcomes. Feedback between rounds Descriptive statistics will be used and presented to participants to summarise the scores from each round. For each outcome, participants will see their individual score, the median score of each stakeholder group (HCPs and clinician trialists being combined at this stage into a single stakeholder group) and the overall median for all stakeholder groups combined. Histograms showing the number of people choosing a particular rating (1–9) for each outcome will be presented, again broken down by stakeholder group. Retaining or dropping items between rounds All items in addition to new outcomes identified by participants in Round 1 will be carried forward for consideration in Round 2. Attrition (between rounds) and attrition bias Based on previous studies of similar design [ 13 , 27 ] we anticipate attrition of up to 30% between rounds. In the study by Fish et al, attrition rates were found to be higher in those recruited through online routes than in those identified through in person approach[ 13 ]. To minimise attrition, personalised reminder emails will be sent to participants (including updates on Delphi response rates). If a participant does not complete the second round of the Delphi survey, their scores from the previous round will be counted as valid and retained in the study. Similarly, if a participant fails to score a specific item during a survey round, the answers to other items will be held as valid and retained. The rate of missing responses will be reported with the results of the Delphi survey. The views of those who complete all rounds of the Delphi will be compared with those who drop out before completion to elicit any differences. Missing data We do not anticipate any missing data from participants in the online Delphi, participants will be unable to submit their scores if there are any blanks. Any participants completing paper versions whom miss questions will be contacted and asked to rescore questions for which missing data exists. Should they be uncontactable only the data that is missing will be excluded from the analysis. Consensus definitions Consensus can be considered to have been reached if the majority of participants rank an outcome similarly. The thresholds defined below are based on the thresholds adopted in multiple previous similar studies[ 13 , 27 , 39 , 40 ]. After the final round, for each stakeholder group, we will assign each outcome to one of three categories: Consensus in : 70% or more respondents within ALL stakeholder groups rate the outcome as critically important (7–9) AND 15% or fewer rate the outcome as limited importance (1–3). Consensus out : 50% or less of respondents within ALL stakeholder groups rate the outcome as of critical importance (7–9) OR 50% or more rate the outcome as limited importance (1–3). No consensus : Neither of the above criteria are met. Stage 4. A consensus meeting to approve the final COS. The results of the Delphi process will be discussed at an online consensus meeting via Zoom involving an invited sample of Delphi participants from all stakeholder groups. This modality will allow for break out rooms should it become apparent that the views of individuals or particular stakeholder groups dominate. An independent facilitator will be used. All participants registering to complete the Delphi process will be offered participation in the consensus meeting. A sample of participants from each stakeholder group, who have indicated ‘yes’ to this question and have completed all rounds of the Delphi, will be invited to attend the consensus meeting. At the meeting, it will be proposed that any outcome categorised as ‘consensus in’ by all stakeholder groups be included in the final COS and any outcome categorised as ‘consensus out’ across all stakeholder groups be excluded. Attendees will vote electronically (using Mentimeter (2024). Mentimeter (Version 3.4.1) [Software]. Retrieved from https://www.mentimeter.com ) to accept this proposal or suggest outcomes from this group that warrant further discussion. All other outcomes, including those categorised as ‘consensus in’ or ‘consensus out’ by one or two stakeholder groups, and those categorised as ‘no-consensus’ will then be discussed and further rounds of voting will be used to agree the final COS. If a final COS is not agreed at the end of the first consensus meeting, subsequent meetings will be considered. Declarations ETHICS AND DISSEMINATION The study will be conducted in full conformance with all relevant legal requirements and the principles of the Declaration of Helsinki, Good Clinical Practice (GCP) and the UK Policy Framework for Health and Social Care Research 2017. Research ethics committee approval for the patient interviews was granted on 1st June 2023 by the Yorkshire & The Humber - South Yorkshire Research Ethics Committee, NHS/HRA REC reference 23/YH/0115 (IRAS ID 321687). Research ethics committee approval for the Delphi survey and Consensus meeting was granted on 16th July 2024 by the London - South East Research Ethics Committee, NHS/HRA REC reference 24/PR/0715 (IRAS ID 339389). COrSIcA is registered with COMET and listed on the COMET searchable database of COS development projects. https://www.comet-initiative.org/Studies/Details/2511 The final COS will be reported using Core Outcome Set-STAndards for Reporting: The COS-STAR Statement (COS-STAR) guidance[41] to ensure clarity for utilisation. It is anticipated that the COS will feed directly into future aHSIL trials in development from 2025. To facilitate adoption, the final COS will be available via the COMET database, submitted for publication in peer reviewed medical journals, presented at professional conferences and publicised through social media channels. Plain English summaries will be created for public contributors. PATIENT AND PUBLIC INVOLVEMENT Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details. DATA AVAILABILITY STATEMENT Data are available upon reasonable request. All data relevant to the study are included in the article. AUTHOR CONTRIBUTIONS DAF planned and designed the study. RF, RM, EP, PM, PMH and AGR provided advice and guidance. DAF drafted the manuscript with all authors reviewing and subsequently approving the final draft. FUNDING STATEMENT This study forms part of a 3-year PhD project funded by the Department of General Surgery at Lancashire Teaching Hospitals NHS Foundation Trust (year 1), the NIHR Manchester Biomedical Research Centre (BRC) 2022 bid ‘North West’ section (years 2 and 3), and the Rosemere Cancer Charity (years 2 and 3) (Registered Charity Number 1131583). Researcher salary and running expenses are covered by this funding. COMPETING INTEREST STATEMENT The authors declare no competing interests. References CRUK. Anal cancer incidence statistics 2017-2019 [Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/anal-cancer/incidence. NIH National Cancer Institute: Surveillance E, and End Results Program. Cancer Stat Facts: Anal Cancer 2021 [Available from: https://seer.cancer.gov/statfacts/html/anus.html. Sekhar H, Malcomson L, Kochhar R, et al. Temporal improvements in loco-regional failure and survival in patients with anal cancer treated with chemo-radiotherapy: treatment cohort study (1990-2014). Br J Cancer. 2020;122(6):749-58. 10.1038/s41416-019-0689-x Darragh TM, Colgan TJ, Thomas Cox J, et al. The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. 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Evaluating the efficacy of treatment options for anal intraepithelial neoplasia: a systematic review. Int J Colorectal Dis. 2021;36(2):213-26. 10.1007/s00384-020-03740-6 Williamson PR, Altman DG, Blazeby JM, et al. Developing core outcome sets for clinical trials: issues to consider. Trials. 2012;13:132. 10.1186/1745-6215-13-132 COMET. Core Outcome Measures in Effectiveness Trials 2022 [Available from: https://www.comet-initiative.org. Williamson PR, Altman DG, Bagley H, et al. The COMET Handbook: version 1.0. Trials. 2017;18(Suppl 3):280. 10.1186/s13063-017-1978-4 Fish R, Sanders C, Adams R, et al. A core outcome set for clinical trials of chemoradiotherapy interventions for anal cancer (CORMAC): a patient and health-care professional consensus. Lancet Gastroenterol Hepatol. 2018;3(12):865-73. 10.1016/S2468-1253(18)30264-4 Samuel R, Knight SR, Adams R, et al. International consensus to define outcomes for trials of chemoradiotherapy for anal cancer (CORMAC-2): defining the outcomes from the CORMAC core outcome set. eClinicalMedicine. 2024;78. 10.1016/j.eclinm.2024.102939 Kirkham JJ, Davis K, Altman DG, et al. Core Outcome Set-STAndards for Development: The COS-STAD recommendations. PLoS Med. 2017;14(11):e1002447. 10.1371/journal.pmed.1002447 Kirkham JJ, Gorst S, Altman DG, et al. Core Outcome Set-STAndardised Protocol Items: the COS-STAP Statement. Trials. 2019;20(1):116. 10.1186/s13063-019-3230-x Saldanha IJ, Dodd S, Fish R, et al. Comparison of published core outcome sets with outcomes recommended in regulatory guidance from the US Food and Drug Administration and European Medicines Agency: cross sectional analysis. BMJ Med. 2022;1(1):e000233. 10.1136/bmjmed-2022-000233 Palinkas LA, Horwitz SM, Green CA, et al. Purposeful Sampling for Qualitative Data Collection and Analysis in Mixed Method Implementation Research. Adm Policy Ment Health. 2015;42(5):533-44. 10.1007/s10488-013-0528-y Lee RM. Doing research on sensitive topics. Thousand Oaks, CA, US: Sage Publications, Inc; 1993. 248- p. Alkhaffaf B, Blazeby JM, Bruce IA, et al. Patient priorities in relation to surgery for gastric cancer: qualitative interviews with gastric cancer surgery patients to inform the development of a core outcome set. BMJ Open. 2020;10(2):e034782. 10.1136/bmjopen-2019-034782 Saunders B, Sim J, Kingstone T, et al. Saturation in qualitative research: exploring its conceptualization and operationalization. Qual Quant. 2018;52(4):1893-907. 10.1007/s11135-017-0574-8 Francis JJ, Johnston M, Robertson C, et al. What is an adequate sample size? Operationalising data saturation for theory-based interview studies. Psychol Health. 2010;25(10):1229-45. 10.1080/08870440903194015 Thomas DR. A General Inductive Approach for Analyzing Qualitative Evaluation Data. American Journal of Evaluation. 2006;27(2):237-46. 10.1177/1098214005283748 Braun V, Clarke V. Using thematic analysis in psychology. Qualitative Research in Psychology. 2006;3(2):77-101. 10.1191/1478088706qp063oa Dodd S, Clarke M, Becker L, et al. A taxonomy has been developed for outcomes in medical research to help improve knowledge discovery. J Clin Epidemiol. 2018;96:84-92. 10.1016/j.jclinepi.2017.12.020 Powell C. The Delphi technique: myths and realities. J Adv Nurs. 2003;41(4):376-82. 10.1046/j.1365-2648.2003.02537.x Alkhaffaf B, Metryka A, Blazeby JM, et al. Core outcome set for surgical trials in gastric cancer (GASTROS study): international patient and healthcare professional consensus. Br J Surg. 2021. 10.1093/bjs/znab192 Gorst SL, Gargon E, Clarke M, et al. Choosing Important Health Outcomes for Comparative Effectiveness Research: An Updated Review and User Survey. PLoS One. 2016;11(1):e0146444. 10.1371/journal.pone.0146444 Gorst SL, Gargon E, Clarke M, et al. Choosing Important Health Outcomes for Comparative Effectiveness Research: An Updated Review and Identification of Gaps. PLoS One. 2016;11(12):e0168403. 10.1371/journal.pone.0168403 Davis K, Gorst SL, Harman N, et al. Choosing important health outcomes for comparative effectiveness research: An updated systematic review and involvement of low and middle income countries. PLoS One. 2018;13(2):e0190695. 10.1371/journal.pone.0190695 Gargon E, Gorst SL, Harman NL, et al. Choosing important health outcomes for comparative effectiveness research: 4th annual update to a systematic review of core outcome sets for research. PLoS One. 2018;13(12):e0209869. 10.1371/journal.pone.0209869 Gargon E, Gorst SL, Matvienko-Sikar K, et al. Choosing important health outcomes for comparative effectiveness research: 6th annual update to a systematic review of core outcome sets for research. PLoS One. 2021;16(1):e0244878. 10.1371/journal.pone.0244878 Custer RL, Scarcella JA, Stewart BR. The Modified Delphi Technique - A Rotational Modification. Journal of Career and Technical Education. 1999. 10.21061/jcte.v15i2.702 Chevance A, Tran VT, Ravaud P. Controversy and Debate Series on Core Outcome Sets. Paper 1: Improving the generalizability and credibility of core outcome sets (COS) by a large and international participation of diverse stakeholders. J Clin Epidemiol. 2020;125:206-12.e1. 10.1016/j.jclinepi.2020.01.004 GRADE. GRADE Working Group [Available from: https://www.gradeworkinggroup.org/. Harman NL, Bruce IA, Kirkham JJ, et al. The Importance of Integration of Stakeholder Views in Core Outcome Set Development: Otitis Media with Effusion in Children with Cleft Palate. PLoS One. 2015;10(6):e0129514. 10.1371/journal.pone.0129514 Bennett WL, Robinson KA, Saldanha IJ, et al. High priority research needs for gestational diabetes mellitus. J Womens Health (Larchmt). 2012;21(9):925-32. 10.1089/jwh.2011.3270 Schmitt J, Langan S, Stamm T, et al. Core outcome domains for controlled trials and clinical recordkeeping in eczema: international multiperspective Delphi consensus process. J Invest Dermatol. 2011;131(3):623-30. 10.1038/jid.2010.303 MacLennan S, Williamson PR, Bekema H, et al. A core outcome set for localised prostate cancer effectiveness trials. BJU Int. 2017;120(5B):E64-E79. 10.1111/bju.13854 Fish R, Blackwell S, Knight SR, et al. Defining standards and core outcomes for clinical trials in prehabilitation for colorectal surgery (DiSCO): modified Delphi methodology to achieve patient and healthcare professional consensus. Br J Surg. 2024;111(6). 10.1093/bjs/znae056 Kirkham JJ, Gorst S, Altman DG, et al. Core Outcome Set-STAndards for Reporting: The COS-STAR Statement. PLoS Med. 2016;13(10):e1002148. 10.1371/journal.pmed.1002148 Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6949923","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Method Article","associatedPublications":[],"authors":[{"id":474781942,"identity":"4ce99baa-f618-4c35-b699-205a5607a254","order_by":0,"name":"David A. Finch","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-2964-9906","institution":"Division of Cancer Sciences, University of Manchester, United Kingdom. Manchester Cancer Research Centre, NIHR Manchester Biomedical Research Centre, Manchester, United Kingdom.","correspondingAuthor":true,"prefix":"","firstName":"David","middleName":"A.","lastName":"Finch","suffix":""},{"id":474781976,"identity":"6ddf96ae-f07b-4b97-ae9a-449e50c5c9e1","order_by":1,"name":"Rebecca Morris","email":"","orcid":"","institution":"Division of Population Health, Health Services research and Primary Care, University of Manchester, United Kingdom.","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Morris","suffix":""},{"id":474782044,"identity":"b3a90db3-c471-43b3-9f63-74fd3eaf0fa1","order_by":2,"name":"Edward Parkin","email":"","orcid":"","institution":"Department of General and Colorectal surgery, Lancashire Teaching Hospitals NHS Foundation Trust, United Kingdom.","correspondingAuthor":false,"prefix":"","firstName":"Edward","middleName":"","lastName":"Parkin","suffix":""},{"id":474782045,"identity":"a034faf0-d506-4fd1-8486-7155d8956e3c","order_by":3,"name":"Peter Mitchell","email":"","orcid":"","institution":"Department of General and Colorectal surgery, Lancashire Teaching Hospitals NHS Foundation Trust, United Kingdom.","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Mitchell","suffix":""},{"id":474782046,"identity":"8824c796-c885-400b-b2ad-af932ef08bb5","order_by":4,"name":"Pierre Martin-Hirsch","email":"","orcid":"","institution":"Department of Gynaecological oncology, Lancashire Teaching Hospitals NHS Foundation Trust, United Kingdom.","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Martin-Hirsch","suffix":""},{"id":474782096,"identity":"f7303006-2688-41d4-a070-bcbfc4d44d64","order_by":5,"name":"Andrew G. Renehan","email":"","orcid":"","institution":"Division of Cancer Sciences, University of Manchester, United Kingdom. Manchester Cancer Research Centre, NIHR Manchester Biomedical Research Centre, Manchester, United Kingdom. Colorectal and Peritoneal Oncology Centre (CPOC), The Christie NHS Foundation Trust, United Kingdom.","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"G.","lastName":"Renehan","suffix":""},{"id":474782151,"identity":"74418336-c0c8-492f-8c48-41a3c265819c","order_by":6,"name":"Rebecca Fish","email":"","orcid":"","institution":"6Colorectal and Peritoneal Oncology Centre (CPOC), The Christie NHS Foundation Trust, United Kingdom.","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Fish","suffix":""}],"badges":[],"createdAt":"2025-06-22 14:04:22","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6949923/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6949923/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85370560,"identity":"5e99dc93-d360-4ce6-a305-c7bf724b4a51","added_by":"auto","created_at":"2025-06-25 07:25:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35076,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of phases and stages of COrSIcA COS development\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6949923/v1/205a6c024c480ccf7068763c.png"},{"id":85370605,"identity":"6af18860-261e-42bc-a144-347438971a3c","added_by":"auto","created_at":"2025-06-25 07:25:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":136611,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of the COrSIcA consensus process\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6949923/v1/1b230f69c199d583e8236179.png"},{"id":85371083,"identity":"ed705805-0dcf-42d2-890f-48550de13c4e","added_by":"auto","created_at":"2025-06-25 07:33:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1433039,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6949923/v1/cec1de83-61d6-4dd5-9214-52b6501093ec.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eThe Core Outcome measures in Squamous Intraepithelial precursor lesions of the Anus (COrSIcA) study: A protocol for the development of a core outcome set for future anal high-grade squamous intraepithelial lesion (aHSIL) treatment trials\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\n\u003ch3\u003eBackground\u003c/h3\u003e\n\u003cp\u003eAnal squamous cell carcinoma (ASCC) is a Human Papilloma Virus (HPV)-associated cancer, the incidence of which has increased globally over the past three decades. This rise being particularly notable in western populations, such as the United States and United Kingdom, where the standardised incidence is now 1.9 and 2.5 per 100,00 people, respectively[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Initial treatment is chemoradiotherapy which is associated with considerable morbidity, including early side effects such as radiotherapy-related dermatitis and later side effects such as faecal urgency and incontinence, sexual and bladder dysfunction and permanent colostomy. Compounding this, 15\u0026ndash;18% of cases relapse locally[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevention through the detection and treatment of the precursor lesion, anal intraepithelial neoplasia (AIN) (specifically the high-grade subtype, now termed anal high-grade squamous intraepithelial lesion (aHSIL)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]) is thus an attractive strategy to prevent the increasing clinical burden of ASCC. Furthermore, several subpopulations have been identified as being at increased risk of developing ASCC, with risk ranging from 1.7 per 100,000 person-years in the general population to \u0026gt;\u0026thinsp;100 per 100,000 in HIV subpopulations[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The improved understanding of lesion and subpopulation risk allows for better-informed cancer prevention and early detection strategies.\u003c/p\u003e \u003cp\u003eIn 2022, the ANCHOR trial[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] reported a large, multi-centre, phase III randomised-controlled trial (RCT) of aHSIL treatment versus active monitoring without treatment in people living with HIV (PLWH) and showed significantly lower risk of progression to ASCC with aHSIL treatment (principally ablation). The evidence for treatment benefit provided by ANCHOR, when coupled with the recent publication of international consensus guidelines for screening of high-risk populations[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] is anticipated to lead to a significant increase in the number of patients requiring treatment for aHSIL.\u003c/p\u003e \u003cp\u003eThere are multiple treatments for aHSIL, broadly categorised into medical and surgical therapies. Medical treatments include patient-applied, field-based options such as imiquimod cream, topical 5-fluorouracil and cidofovir ointment, as well as clinician-applied, lesion-targeted treatments such as trichloroacetic acid and cryotherapy. Surgical treatments are clinician-directed and lesion-targeted, and include local or wide local excision with or without skin graft/flap reconstruction, as well as ablative methods such as laser, electrocautery, infrared coagulation, radiofrequency ablation, photocoagulation, and argon plasma beam coagulation. Vaccination is a possible third management strategy. The evidence base underpinning these treatments is scarce and generally of poor quality. A recent systematic review evaluating the efficacy of treatment options for AIN identified only four RCTs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Inconsistent outcome measurement was identified as a major contributory factor hindering comparison of studies. There are few data on the impacts of treatments on quality of life.\u003c/p\u003e \u003cp\u003eOptimal treatment approaches need to be defined through well-designed, high-quality interventional studies that measure clinically meaningful outcomes. We are developing a \u0026lsquo;core outcome set\u0026rsquo; (COS) for future aHSIL treatment trials through the COrSIcA (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eC\u003c/span\u003eore \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eO\u003c/span\u003eutcome measu\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003er\u003c/span\u003ees in \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eS\u003c/span\u003equamous \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eI\u003c/span\u003entraepithelial precursor lesions of the \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eA\u003c/span\u003enus) study. A COS is defined as an agreed \u003cem\u003eminimum\u003c/em\u003e set of outcomes that should be measured and reported in all trials in a specific condition[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. COSs include outcomes deemed most important by key stakeholders and, when used, standardise outcome measurement and reporting across trials. COSs can improve the quality of evidence through reduction in outcome heterogeneity, reduction in outcome reporting bias, and use of outcomes relevant to all stakeholders[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Currently, there is no COS for treatment trials in patients with aHSIL.\u003c/p\u003e \u003cp\u003eThe COrSIcA COS will be developed using methodological approaches recognised by the COMET (Core Outcome Measures in Effectiveness Trials) initiative[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The COMET Initiative (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.comet-initiative.org\u003c/span\u003e\u003cspan address=\"https://www.comet-initiative.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a guidance body for developing and reporting COSs. COMET recommend COS developers first identify \u0026lsquo;what\u0026rsquo; outcomes to include in a COS and then determine \u0026lsquo;how\u0026rsquo; those outcomes should be measured. Our research group have previously published a COS for ASCC chemoradiotherapy treatment trials (CORMAC and CORMAC-2)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. COrSIcA will determine \u0026lsquo;what\u0026rsquo; outcomes should be measured in future aHSIL treatment trials. Further work will be necessary to determine \u0026lsquo;how\u0026rsquo; the included outcomes be measured.\u003c/p\u003e\n\u003ch3\u003eStudy aims and objectives\u003c/h3\u003e\n\u003cp\u003eThe aim of COrSIcA is to develop a COS for use in all future late-phase trials investigating therapeutic interventions for aHSIL which reflects the interests of key stakeholders (patients, healthcare professionals and clinician trialists).\u003c/p\u003e \u003cp\u003eSpecific objectives are to:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDetermine the degree and nature of variation in the reporting of outcomes in aHSIL treatment studies to date.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFormulate a list of potentially important outcomes from published studies.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIdentify a list of outcomes potentially important to patients, through semi-structured interviews with patients who have experienced treatment for aHSIL.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eReach consensus agreement on the most important outcomes to be measured and reported in all future aHSIL treatment trials.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eScope\u003c/h2\u003e \u003cp\u003eThis COS is intended for:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eHealth condition\u003c/b\u003e: Anal high-grade squamous intraepithelial lesion (P16 positive AIN2 and/or AIN3) affecting one or both of the perianus or anal canal.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePopulation\u003c/b\u003e: Adults\u0026thinsp;\u0026gt;\u0026thinsp;18 years of age, either screened and/or symptomatic for aHSIL.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eIntervention\u003c/b\u003e: Any direct intervention for aHSIL (e.g., surgical excision, electrocautery/laser ablation, topicals) and/or indirect interventions for aHSIL (e.g., targeting high-risk HPV (hrHPV)).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eSetting/context of use\u003c/b\u003e: Later phase trials that will inform clinical decision making.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"METHODS AND ANALYSIS","content":"\u003cp\u003eThis protocol has been developed in accordance with COMET guidance, specifically the Core Outcome Set-Standards for Development (COS-STAD) recommendations[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and the Core outcome Set-Standardised Protocol Items (COS-STAP) statement[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] which outline the minimum standards and essential items for COS development and documentation.\u003c/p\u003e \u003cp\u003eMixed-methods will be employed to maximise stakeholder involvement and granularity. Summarised in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the COS will be developed in two phases over four distinct stages. Phase one involving identifying a \u0026lsquo;longlist\u0026rsquo; of potentially important outcomes, and Phase two involving determining which outcomes from the longlist are \u0026lsquo;core\u0026rsquo; (i.e., outcomes deemed so important that they should be measured and reported in all future treatment trials).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eStakeholders\u003c/h3\u003e\n\u003cp\u003eStakeholder involvement in the COS development process has been considered from both the research team perspective and that of the study participants.\u003c/p\u003e\n\u003ch3\u003ePatient and Public Involvement and Engagement\u003c/h3\u003e\n\u003cp\u003eA patient and public involvement and engagement (PPIE) group has been established comprising patients with lived experience of aHSIL. The group will help inform the study from design, commenting on patient-focused information (e.g., adverts, patient information sheets, consent forms), wording of interview and survey questions, through to dissemination and wider public engagement.\u003c/p\u003e\n\u003ch3\u003eStudy Steering Group\u003c/h3\u003e\n\u003cp\u003eA study steering group (SSG) has been assembled to oversee the project. Members include, trialists with leading roles in past or current aHSIL clinical trials, clinicians with experience in aHSIL from the fields of colorectal surgery, gynaecology and sexual health, a COS methodological expert, a qualitative methodology expert and have patient representation. The SSG will meet at key stages during the course of the project and ensure that key stakeholder opinion is represented at every stage of the COS development.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants\u003c/h2\u003e \u003cp\u003eStudy participants comprise three main stakeholder groups:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatients\u003c/b\u003e: Any person who has received or is receiving treatment for aHSIL will be invited to participate.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eHealthcare professionals (HCPs)\u003c/b\u003e: HCPs from any speciality managing (assessing, treating or reviewing) patients for their aHSIL will be invited to participate.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eClinician trialists\u003c/b\u003e: Corresponding authors of published/proposed phase III RCT\u0026rsquo;s in aHSIL will be invited to participate as will those of any non-randomised trials or large observational studies.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eOther stakeholder groups, including healthcare regulators, industry representatives, and policymakers, have been considered. Taking into account practical constraints on the project and recent evidence suggesting overlap in outcomes suggested in COSs and those suggested by healthcare regulators[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] the decision was made not to include these groups. Importantly, if an outcome is not included in a COS, it does not mean that it cannot be measured. Therefore, should any other stakeholder group suggest additional outcomes to those included in the final COS, they can still be measured.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePhase one \u0026ndash; Identifying potential outcomes\u003c/h2\u003e \u003cp\u003ePhase one comprises two stages and is concerned with identifying an exhaustive list of potentially important outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStage 1. A systematic review of academic literature \u0026ndash; Identifying existing knowledge about outcomes\u003c/h2\u003e \u003cp\u003eA systematic review of the literature will be performed to identify a comprehensive list of all outcome measures used in studies investigating the effect of treatments in patients with aHSIL. The outcomes identified in this stage will be taken to represent the views of the HCPs and clinician trialists.\u003c/p\u003e \u003cp\u003eGiven the lack of published late phase trials for the treatment of aHSIL, limiting the systematic review to only these studies risks missing important outcomes. To ensure the breadth of treatment outcomes are explored, analysis will be extended to include published early phase trials and observational studies.\u003c/p\u003e \u003cp\u003eThe full protocol for the systematic review, including the search strategy and study selection criteria, is available online via the PROSPERO database (CRD42023429661).\u003c/p\u003e \u003cp\u003e \u003cb\u003eStage 2. A series of semi-structured interviews with patients with experience of aHSIL treatment \u0026ndash; Filling in the gaps\u003c/b\u003e \u003c/p\u003e \u003cp\u003eCOMET emphasise the importance of including patient relevant outcomes within COS[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Patient participation is vital because it is the patients themselves who are subject to the benefits and potential risks of treatments for their condition. A qualitative approach, involving in-depth semi-structured interviews with individuals who have or have had aHSIL, will enable a full exploration of patients\u0026rsquo; perceptions of and priorities about outcomes in aHSIL ensuring outcomes most important to patients are considered for the final COS.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants\u003c/h2\u003e \u003cp\u003eInclusion and exclusion criteria based on types of participant, pathology and intervention is detailed in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInclusion and Exclusion criteria for semi-structured interviews\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInclusion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExclusion\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParticipants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull;Adults\u0026thinsp;\u0026gt;\u0026thinsp;18 years of age.\u003c/p\u003e \u003cp\u003e\u0026bull;Patients who have completed or are receiving treatment for aHSIL.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull;Unable to give informed consent.\u003c/p\u003e \u003cp\u003e\u0026bull;Too unwell to comfortably participate in an interview lasting approximately 30\u0026ndash;60 minutes.\u003c/p\u003e \u003cp\u003e\u0026bull;Untreated patients\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull;High-grade squamous intraepithelial neoplasia of the anal canal, perianus or both.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull;Low-grade anal squamous intraepithelial neoplasia (aLSIL) only.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny intervention for the treatment of aHSIL.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull;No specific treatment exclusions.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment and sampling\u003c/h2\u003e \u003cp\u003ePurposive sampling will be used to maximise the diversity of the interviewed patient population[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Criteria have been selected to ensure that subsets within the study population, which may express a wide variety and potentially contrasting views and experiences are included. Examples include:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eHigh-risk groups\u003c/b\u003e: Individuals with recognised high-risk of malignant transformation, such as PLWH, men who have sex with men (MSM), individuals with a history of intraepithelial neoplasia or invasive SCC in adjacent anogenital sites, and the immunosuppressed, whether due to solid organ transplantation or autoimmune conditions[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eSymptomatic vs. asymptomatic individuals\u003c/b\u003e: Those with troublesome symptoms attributable to aHSIL, such as itching, discomfort and bleeding, compared asymptomatic individuals diagnosed through screening or incidentally.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eConcurrent conditions\u003c/b\u003e: Patients with concurrent intraepithelial neoplasia in affecting genital sites adjacent to the anus (multizone intraepithelial neoplasia) who require concurrent assessment and treatment.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eDifferent treatment experiences\u003c/b\u003e: Patients with experience of various treatment types, such as self-applied topical medical treatments (e.g., Imiquimod, 5-fluorouracil, Cidofovir) administered over several weeks, versus clinician-administered surgical options (e.g., laser, electrocautery ablation, surgical excision) delivered as single or staged treatment episodes.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe key criteria for identifying difference is shown in the sampling matrix in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e:\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePurposive sampling matrix for semi-structured interview participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKey criteria\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTarget number of participants\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge at diagnosis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36\u0026ndash;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransgender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSexuality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeterosexual\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHomosexual\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSocioeconomic status*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMost deprived\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeast deprived\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEthnicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHIV status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of intraepithelial neoplasia/invasive SCC in adjacent genital sites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of multizone disease**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSolid organ transplant\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNon-HIV/Solid organ transplant recipient immunosuppressed\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSymptoms attributed to aHSIL\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime since initial diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLess than 1 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u0026ndash;7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u0026ndash;7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGreater than 3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u0026ndash;7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment type(s) experienced***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTarget total****\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e* Socioeconomic status (based on English indices of deprivation)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e**People with concurrent intraepithelial neoplasia affecting sites in addition to the anus (e.g., cervix, vulva, vagina, penis, scrotum).\u003c/p\u003e \u003cp\u003e***Medical treatments including patient-applied, field-based options such as imiquimod cream, topical 5-fluorouracil, antiviral agents like cidofovir ointment, and clinician-applied treatments such as trichloroacetic acid and cryotherapy. Surgical treatments including local or wide local excision with or without skin graft/flap reconstruction or ablative methods such as laser, electrocautery, infrared coagulation, radiofrequency ablation, photocoagulation, and argon plasma beam coagulation.\u003c/p\u003e \u003cp\u003e****Many participants will fall into several categories. The \u0026lsquo;target total\u0026rsquo; refers to the number of participants, not the sum of the individual criteria.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment\u003c/h2\u003e \u003cp\u003eRecruitment for patient interviews will come from three primary sources; regional treatments centres, patient groups, and via snowball sampling.\u003c/p\u003e \u003cp\u003e Suitable participants will be identified from clinic lists, multidisciplinary team (MDT) meeting lists, and patient records at The Christie NHS Foundation Trust and Lancashire Teaching Hospitals NHS Foundation Trust (LTHTR). A database of AIN patients under surveillance at LTHTR will form another source of participants. A member of the clinical team will make initial contact with potential participants, either in person or by telephone, after which the research team will discuss and arranging participation for those who are interested.\u003c/p\u003e \u003cp\u003eLinks have been established with patient groups (International Anal Neoplasia Society, HPV and Anal Cancer Foundation and British HIV Association). A contact at each group will approach members to about participating in this research.\u003c/p\u003e \u003cp\u003eTo maximise opportunities for the inclusion of minority groups (e.g., MSM), snowball sampling will be employed by asking participants to suggest contacts who may be willing to participate. This is an established technique for research involving sensitive topics and accessing historically marginalised populations[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eAn initial sample of 20 patients will be recruited. Although the purposive sampling matrix (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) includes many stratification factors, the anticipated overlap of factors among participants is expected to ensure that this sample size is sufficient to achieve data saturation. A stopping criterion of three will be applied. Previous studies suggest that most relevant outcomes can be identified within 17 interviews[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. If no new outcomes emerge by interview 20, data saturation will be confirmed and recruitment will cease[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. If new outcomes are identified in interviews 18\u0026ndash;20, up to three additional interviews will be conducted until no new outcomes emerge or a maximum of 30 interviews is reached.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eConsent\u003c/h2\u003e \u003cp\u003e The researcher will obtain informed written consent from participants. Information will be provided verbally and through ethically approved information sheets. Only individuals with the capacity to give consent will be included. It will be stressed that participation is voluntary, with no obligation, and participants may withdraw at any time without affecting their medical care. The individual will be offered ample time to consider participation prior to consent (at least 24 hours).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eInterview location\u003c/h2\u003e \u003cp\u003eInterviews will be conducted at a time convenient to the participant in either:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eA clinic room at either The Christie Hospital or The Royal Preston Hospital (LTHTR)\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAn office at the Manchester Cancer Research Centre or the NIHR Preston Clinical Research Facility\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe participants home\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eOver the phone\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eVia an online video conferencing platform\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eInterview format\u003c/h2\u003e \u003cp\u003eInterviews will follow a semi-structured format to explore patients' perceptions, priorities, and experiences of living with and receiving treatment for aHSIL. This method involves open-ended questions to encourage a patient-led discussion, supplemented by prompts from a pre-prepared interview guide to ensure that key topics are addressed. The interview schedule may be modified iteratively using the experience yielded from successive patient interviews to ensure inclusion of items that have been raised by earlier participants are included in the interview schedule for subsequent discussions.\u003c/p\u003e \u003cp\u003eThe study can translate materials and conduct interviews in other languages using University of Manchester-approved translation services and interpreters from an approved NHS translator service. This allows inclusion of participants who do not speak or understand English.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eInterviews will be audio recorded, transcribed and interrogated for outcomes which may supplement the outcomes already gathered from the systematic review of the literature. Data will be analysed through thematic analysis[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] using NVivo 12 software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.qsrinternational.com/nvivo-qualitative-data-analysis-software/home\u003c/span\u003e\u003cspan address=\"https://www.qsrinternational.com/nvivo-qualitative-data-analysis-software/home\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, QSR International, Burlington, MA, USA). The data will be coded to produce a matrix of themes. Themes will be derived from issues raised by participants. From these themes, outcomes of key importance to patients with aHSIL will be developed. These outcomes will be combined with the results of the systematic review to create a \u0026lsquo;longlist\u0026rsquo; of potentially important outcomes.\u003c/p\u003e \u003cp\u003eA consultation exercise with the SSG will finalise the \u0026lsquo;longlist\u0026rsquo; for prioritisation in Stage 3, the Delphi survey. The consultation exercise will ensure clear and precise meanings are given to the outcomes identified and ensure there is no duplication of outcomes. Any outcomes deemed unrelated to treatment effect, such as adverse effects unrelated to treatment will be discussed with the SSG and dropped at this stage. Outcomes will be categorised into outcome domains, using COMET recommended taxonomy[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], so that similar or related outcomes are viewed together in the survey.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003ePhase two \u0026ndash; Determining the core outcomes\u003c/h2\u003e \u003cp\u003ePhase two comprises two further stages and uses consensus methods to determine the outcomes deemed most important for inclusion in the final COS. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarises the COrSIcA consensus process.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eStage 3. A Delphi survey \u0026ndash; Eliciting views about important outcomes\u003c/h2\u003e \u003cp\u003eA Delphi survey is an iterative process involving key stakeholders commonly used in COS development, to reach consensus on the most important outcomes for inclusion. The major advantage of the Delphi process is that it is anonymous and can be conducted remotely and online, thereby reaching an international audience and minimising the potential for bias toward more vocal participants or those whose views might be perceived as superior. Furthermore, it permits opportunity to suggest and include additional outcome items, and can be circulated to large numbers of potential participants.\u003c/p\u003e \u003cp\u003eThe aim of the Delphi process is to progress towards consensus for which outcomes from the longlist generated at the end of stage two should be included in the final COS. While there is no optimal methodological approach to conducting a Delphi survey, specific considerations for COrSIcA include:\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eParticipants will be recruited internationally from the three main stakeholder groups. All participants must be adults\u0026thinsp;\u0026gt;\u0026thinsp;18 years of age and able to complete a questionnaire in the English language.\u003c/p\u003e \u003cp\u003eGiven anal HSIL\u0026rsquo;s association with HPV and \u0026lsquo;at-risk\u0026rsquo; populations crossing multiple medical disciplines, we will reach out to all clinical specialities likely to manage patients with aHSIL, including:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eColorectal surgeons\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eGynaecologists\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eClinical oncologists\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDermatologists\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eGastroenterologists\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eInfectious diseases / HIV physicians\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTransplant physicians\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eGeneral practitioners / Family physicians\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eNurse anoscopists\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSpecialist nurses\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eRecruitment and sampling\u003c/h2\u003e \u003cp\u003eAll UK centres managing aHSIL will be invited to become participant identification centres (PIC\u0026rsquo;s), targeting potential patient participants through their anal cancer MDTs and clinics. Centres unable to be PICs can advertise the study via posters for self-referral. International clinicians approached for the Delphi survey will also be encouraged to display the poster in relevant settings. As with the patient interviews, patient participants will also be recruited via links with patient groups and via snowball sampling.\u003c/p\u003e \u003cp\u003eFor clinicians, all UK anal cancer MDT members managing aHSIL and members of relevant international associations will be invited. Participants from the COrSIcA SSG and corresponding authors of recent phase 3 RCTs, non-randomised trials, and large observational studies on aHSIL will also be invited.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThere is no accepted or required \u0026lsquo;sample size\u0026rsquo; requirement for a Delphi survey[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The key consideration with sample size is that there is good representation from key stakeholder groups comprising experts (including those with lived experience) who have a deep understanding of the issues. We aim to recruit at least 100 participants, a realistic target based on the experience of successful COSs from allied disease group and/or similar methodological approach[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We will keep a record of the invitations made, the number of and source of all participants per stakeholder group. This will facilitate interpretation of the results of the Delphi. No new participants will be invited after the closure of Round 1.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eParticipant information\u003c/h2\u003e \u003cp\u003eParticipant information sheets will use terminology piloted within the PPIE group to ensure comprehensibility. Instructions for how to complete the questionnaire will be included at the start of each round.\u003c/p\u003e \u003cp\u003ePrior to commencing Round 1, patient participants will be asked to enter demographic information, and healthcare professionals/clinical trialists will be asked about their speciality and the volume of their aHSIL workload (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This will enable the exploration of the impact of language, cultural variation and clinical experience in relation to the Delphi survey responses.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInformation specific to each stakeholder group to be gathered:\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHealthcare professionals (including clinical trialists)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Age\u003c/p\u003e \u003cp\u003e\u0026bull; Sex and Gender\u003c/p\u003e \u003cp\u003e\u0026bull; Ethnicity\u003c/p\u003e \u003cp\u003e\u0026bull; Country\u003c/p\u003e \u003cp\u003e\u0026bull; Marital status\u003c/p\u003e \u003cp\u003e\u0026bull; Sexuality\u003c/p\u003e \u003cp\u003e\u0026bull; HIV status\u003c/p\u003e \u003cp\u003e\u0026bull; Other immunosuppression\u003c/p\u003e \u003cp\u003e\u0026bull; Any other HPV associate intraepithelial neoplasia / invasive carcinoma\u003c/p\u003e \u003cp\u003e\u0026bull; Details about aHSIL diagnosis and treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Speciality (coloproctology, infectious diseases, gynaecology, specialist nurse, etc).\u003c/p\u003e \u003cp\u003e\u0026bull; Treatments offered\u003c/p\u003e \u003cp\u003e\u0026bull; Duration of practice\u003c/p\u003e \u003cp\u003e\u0026bull; Country of practice\u003c/p\u003e \u003cp\u003e\u0026bull; Involvement with trials\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eNumber of Rounds\u003c/h2\u003e \u003cp\u003eDelphi surveys for the development of COSs typically contain two or three rounds[\u003cspan additionalcitationids=\"CR29 CR30 CR31\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], with three iterations sufficient to reach consensus in most cases[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. For practical purposes, COrSIcA will comprise a two-round Delphi, acknowledging that this approach may result in a higher number of outcomes for which consensus is not reached, thereby placing greater burden on the consensus meeting stage to attempt to reach consensus on these.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eStructure of the questionnaires and order of questionnaire items\u003c/h2\u003e \u003cp\u003eThe Delphi survey will be conducted online, but participants will also have the option to complete paper versions to accommodate those with limited internet access or skills. The questionnaire will be constructed and disseminated using Qualtrics survey software (Qualtrics, Provo, UT, USA. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.qualtrics.com\u003c/span\u003e\u003cspan address=\"https://www.qualtrics.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) approved by the University of Manchester. The electronic Delphi method has been validated as a reliable approach for achieving consensus on COS for various health conditions[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWithin the questionnaire, outcomes will be organised into domains, grouping similar or related outcomes for easier comparison. Each outcome will be described in plain language. The language used will be piloted with patients and HCPs before finalising the questionnaire. Involvement of the SSG and PPIE group will form a key element of this activity ensuring the questionnaire is accessible, comprehensible, and valid.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eAdditional open questions\u003c/h2\u003e \u003cp\u003eAt the end of Round 1 of the Delphi, participants will be asked to list any additional outcomes they feel have not been covered by the questionnaire. Any suggested outcomes deemed to represent a new outcome domain by the SSG (following discussion and a majority decision) will be included in Round 2 of the Delphi.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eScoring system\u003c/h2\u003e \u003cp\u003eParticipants will be asked to rate the importance of each outcome based a Likert scoring system as recommended by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working group for assessing the level of importance about research evidence[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Outcomes are graded in accordance to their level of importance on a 9-point scale. Scores of, 1 to 3 signify an outcome is of limited importance (\u0026lsquo;unimportant\u0026rsquo;), 4 to 6 \u0026lsquo;important but not critical\u0026rsquo;, and scores of 7 to 9 are considered \u0026lsquo;critically important\u0026rsquo; outcomes [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. An \u0026lsquo;unable to score\u0026rsquo; category will be included to allow for the fact that some stakeholder group members may not have the expertise to score certain outcomes.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eFeedback between rounds\u003c/h3\u003e\n\u003cp\u003eDescriptive statistics will be used and presented to participants to summarise the scores from each round. For each outcome, participants will see their individual score, the median score of each stakeholder group (HCPs and clinician trialists being combined at this stage into a single stakeholder group) and the overall median for all stakeholder groups combined. Histograms showing the number of people choosing a particular rating (1\u0026ndash;9) for each outcome will be presented, again broken down by stakeholder group.\u003c/p\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eRetaining or dropping items between rounds\u003c/h2\u003e \u003cp\u003eAll items in addition to new outcomes identified by participants in Round 1 will be carried forward for consideration in Round 2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eAttrition (between rounds) and attrition bias\u003c/h2\u003e \u003cp\u003eBased on previous studies of similar design [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] we anticipate attrition of up to 30% between rounds. In the study by Fish et al, attrition rates were found to be higher in those recruited through online routes than in those identified through in person approach[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. To minimise attrition, personalised reminder emails will be sent to participants (including updates on Delphi response rates).\u003c/p\u003e \u003cp\u003eIf a participant does not complete the second round of the Delphi survey, their scores from the previous round will be counted as valid and retained in the study. Similarly, if a participant fails to score a specific item during a survey round, the answers to other items will be held as valid and retained. The rate of missing responses will be reported with the results of the Delphi survey. The views of those who complete all rounds of the Delphi will be compared with those who drop out before completion to elicit any differences.\u003c/p\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003eMissing data\u003c/h2\u003e \u003cp\u003eWe do not anticipate any missing data from participants in the online Delphi, participants will be unable to submit their scores if there are any blanks. Any participants completing paper versions whom miss questions will be contacted and asked to rescore questions for which missing data exists. Should they be uncontactable only the data that is missing will be excluded from the analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003eConsensus definitions\u003c/h2\u003e \u003cp\u003eConsensus can be considered to have been reached if the majority of participants rank an outcome similarly. The thresholds defined below are based on the thresholds adopted in multiple previous similar studies[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. After the final round, for each stakeholder group, we will assign each outcome to one of three categories:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eConsensus in\u003c/b\u003e: 70% or more respondents within ALL stakeholder groups rate the outcome as critically important (7\u0026ndash;9) AND 15% or fewer rate the outcome as limited importance (1\u0026ndash;3).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eConsensus out\u003c/b\u003e: 50% or less of respondents within ALL stakeholder groups rate the outcome as of critical importance (7\u0026ndash;9) OR 50% or more rate the outcome as limited importance (1\u0026ndash;3).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eNo consensus\u003c/b\u003e: Neither of the above criteria are met.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eStage 4. A consensus meeting to approve the final COS.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe results of the Delphi process will be discussed at an online consensus meeting via Zoom involving an invited sample of Delphi participants from all stakeholder groups. This modality will allow for break out rooms should it become apparent that the views of individuals or particular stakeholder groups dominate. An independent facilitator will be used.\u003c/p\u003e \u003cp\u003eAll participants registering to complete the Delphi process will be offered participation in the consensus meeting. A sample of participants from each stakeholder group, who have indicated \u0026lsquo;yes\u0026rsquo; to this question and have completed all rounds of the Delphi, will be invited to attend the consensus meeting.\u003c/p\u003e \u003cp\u003eAt the meeting, it will be proposed that any outcome categorised as \u0026lsquo;consensus in\u0026rsquo; by all stakeholder groups be included in the final COS and any outcome categorised as \u0026lsquo;consensus out\u0026rsquo; across all stakeholder groups be excluded. Attendees will vote electronically (using Mentimeter (2024). \u003cem\u003eMentimeter\u003c/em\u003e (Version 3.4.1) [Software]. Retrieved from \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mentimeter.com\u003c/span\u003e\u003cspan address=\"https://www.mentimeter.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to accept this proposal or suggest outcomes from this group that warrant further discussion. All other outcomes, including those categorised as \u0026lsquo;consensus in\u0026rsquo; or \u0026lsquo;consensus out\u0026rsquo; by one or two stakeholder groups, and those categorised as \u0026lsquo;no-consensus\u0026rsquo; will then be discussed and further rounds of voting will be used to agree the final COS. If a final COS is not agreed at the end of the first consensus meeting, subsequent meetings will be considered.\u003c/p\u003e\u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eETHICS AND DISSEMINATION \u003c/p\u003e\n\u003cp\u003eThe study will be conducted in full conformance with all relevant legal requirements and the principles of the Declaration of Helsinki, Good Clinical Practice (GCP) and the UK Policy Framework for Health and Social Care Research 2017. \u003c/p\u003e\n\u003cp\u003eResearch ethics committee approval for the patient interviews was granted on 1st June 2023 by the Yorkshire \u0026amp; The Humber - South Yorkshire Research Ethics Committee, NHS/HRA REC reference 23/YH/0115 (IRAS ID 321687). \u003c/p\u003e\n\u003cp\u003eResearch ethics committee approval for the Delphi survey and Consensus meeting was granted on 16th July 2024 by the London - South East Research Ethics Committee, NHS/HRA REC reference 24/PR/0715 (IRAS ID 339389).\u003c/p\u003e\n\u003cp\u003eCOrSIcA is registered with COMET and listed on the COMET searchable database of COS development projects. https://www.comet-initiative.org/Studies/Details/2511\u003c/p\u003e\n\u003cp\u003eThe final COS will be reported using Core Outcome Set-STAndards for Reporting: The COS-STAR Statement (COS-STAR) guidance[41] to ensure clarity for utilisation. It is anticipated that the COS will feed directly into future aHSIL trials in development from 2025. To facilitate adoption, the final COS will be available via the COMET database, submitted for publication in peer reviewed medical journals, presented at professional conferences and publicised through social media channels. Plain English summaries will be created for public contributors.\u003c/p\u003e\n\u003cp id=\"_Toc201528255\"\u003ePATIENT AND PUBLIC INVOLVEMENT\u003c/p\u003e\n\u003cp\u003ePatients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.\u003c/p\u003e\n\u003cp id=\"_Toc201528256\"\u003eDATA AVAILABILITY STATEMENT\u003c/p\u003e\n\u003cp\u003eData are available upon reasonable request. All data relevant to the study are included in the article.\u003c/p\u003e\n\u003cp id=\"_Toc201528257\"\u003eAUTHOR CONTRIBUTIONS\u003c/p\u003e\n\u003cp\u003eDAF planned and designed the study. RF, RM, EP, PM, PMH and AGR provided advice and guidance. DAF drafted the manuscript with all authors reviewing and subsequently approving the final draft.\u003c/p\u003e\n\u003cp id=\"_Toc201528258\"\u003eFUNDING STATEMENT\u003c/p\u003e\n\u003cp\u003eThis study forms part of a 3-year PhD project funded by the Department of General Surgery at Lancashire Teaching Hospitals NHS Foundation Trust (year 1), the NIHR Manchester Biomedical Research Centre (BRC) 2022 bid \u0026lsquo;North West\u0026rsquo; section (years 2 and 3), and the Rosemere Cancer Charity (years 2 and 3) (Registered Charity Number 1131583). Researcher salary and running expenses are covered by this funding.\u003c/p\u003e\n\u003cp id=\"_Toc201528259\"\u003eCOMPETING INTEREST STATEMENT\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCRUK. Anal cancer incidence statistics 2017-2019 [Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/anal-cancer/incidence.\u003c/li\u003e\n\u003cli\u003eNIH National Cancer Institute: Surveillance E, and End Results Program. Cancer Stat Facts: Anal Cancer 2021 [Available from: https://seer.cancer.gov/statfacts/html/anus.html.\u003c/li\u003e\n\u003cli\u003eSekhar H, Malcomson L, Kochhar R, et al. Temporal improvements in loco-regional failure and survival in patients with anal cancer treated with chemo-radiotherapy: treatment cohort study (1990-2014). Br J Cancer. 2020;122(6):749-58. 10.1038/s41416-019-0689-x\u003c/li\u003e\n\u003cli\u003eDarragh TM, Colgan TJ, Thomas Cox J, et al. The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Int J Gynecol Pathol. 2013;32(1):76-115. 10.1097/PGP.0b013e31826916c7\u003c/li\u003e\n\u003cli\u003eClifford GM, Georges D, Shiels MS, et al. A meta-analysis of anal cancer incidence by risk group: Toward a unified anal cancer risk scale. Int J Cancer. 2021;148(1):38-47. 10.1002/ijc.33185\u003c/li\u003e\n\u003cli\u003eDeshmukh AA, Damgacioglu H, Georges D, et al. Human Papillomavirus-Associated Anal Cancer Incidence and Burden Among US Men, According to Sexual Orientation, Human Immunodeficiency Virus Status, and Age. Clin Infect Dis. 2023;77(3):419-24. 10.1093/cid/ciad205\u003c/li\u003e\n\u003cli\u003ePalefsky JM, Lee JY, Jay N, et al. Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer. N Engl J Med. 2022;386(24):2273-82. 10.1056/NEJMoa2201048\u003c/li\u003e\n\u003cli\u003eStier EA, Clarke MA, Deshmukh AA, et al. International Anal Neoplasia Society\u0026apos;s consensus guidelines for anal cancer screening. Int J Cancer. 2024;154(10):1694-702. 10.1002/ijc.34850\u003c/li\u003e\n\u003cli\u003eBrogden DRL, Walsh U, Pellino G, et al. Evaluating the efficacy of treatment options for anal intraepithelial neoplasia: a systematic review. Int J Colorectal Dis. 2021;36(2):213-26. 10.1007/s00384-020-03740-6\u003c/li\u003e\n\u003cli\u003eWilliamson PR, Altman DG, Blazeby JM, et al. Developing core outcome sets for clinical trials: issues to consider. Trials. 2012;13:132. 10.1186/1745-6215-13-132\u003c/li\u003e\n\u003cli\u003eCOMET. Core Outcome Measures in Effectiveness Trials 2022 [Available from: https://www.comet-initiative.org.\u003c/li\u003e\n\u003cli\u003eWilliamson PR, Altman DG, Bagley H, et al. The COMET Handbook: version 1.0. Trials. 2017;18(Suppl 3):280. 10.1186/s13063-017-1978-4\u003c/li\u003e\n\u003cli\u003eFish R, Sanders C, Adams R, et al. A core outcome set for clinical trials of chemoradiotherapy interventions for anal cancer (CORMAC): a patient and health-care professional consensus. Lancet Gastroenterol Hepatol. 2018;3(12):865-73. 10.1016/S2468-1253(18)30264-4\u003c/li\u003e\n\u003cli\u003eSamuel R, Knight SR, Adams R, et al. International consensus to define outcomes for trials of chemoradiotherapy for anal cancer (CORMAC-2): defining the outcomes from the CORMAC core outcome set. eClinicalMedicine. 2024;78. 10.1016/j.eclinm.2024.102939\u003c/li\u003e\n\u003cli\u003eKirkham JJ, Davis K, Altman DG, et al. Core Outcome Set-STAndards for Development: The COS-STAD recommendations. PLoS Med. 2017;14(11):e1002447. 10.1371/journal.pmed.1002447\u003c/li\u003e\n\u003cli\u003eKirkham JJ, Gorst S, Altman DG, et al. Core Outcome Set-STAndardised Protocol Items: the COS-STAP Statement. Trials. 2019;20(1):116. 10.1186/s13063-019-3230-x\u003c/li\u003e\n\u003cli\u003eSaldanha IJ, Dodd S, Fish R, et al. Comparison of published core outcome sets with outcomes recommended in regulatory guidance from the US Food and Drug Administration and European Medicines Agency: cross sectional analysis. BMJ Med. 2022;1(1):e000233. 10.1136/bmjmed-2022-000233\u003c/li\u003e\n\u003cli\u003ePalinkas LA, Horwitz SM, Green CA, et al. Purposeful Sampling for Qualitative Data Collection and Analysis in Mixed Method Implementation Research. Adm Policy Ment Health. 2015;42(5):533-44. 10.1007/s10488-013-0528-y\u003c/li\u003e\n\u003cli\u003eLee RM. Doing research on sensitive topics. Thousand Oaks, CA, US: Sage Publications, Inc; 1993. 248- p.\u003c/li\u003e\n\u003cli\u003eAlkhaffaf B, Blazeby JM, Bruce IA, et al. Patient priorities in relation to surgery for gastric cancer: qualitative interviews with gastric cancer surgery patients to inform the development of a core outcome set. BMJ Open. 2020;10(2):e034782. 10.1136/bmjopen-2019-034782\u003c/li\u003e\n\u003cli\u003eSaunders B, Sim J, Kingstone T, et al. Saturation in qualitative research: exploring its conceptualization and operationalization. Qual Quant. 2018;52(4):1893-907. 10.1007/s11135-017-0574-8\u003c/li\u003e\n\u003cli\u003eFrancis JJ, Johnston M, Robertson C, et al. What is an adequate sample size? Operationalising data saturation for theory-based interview studies. Psychol Health. 2010;25(10):1229-45. 10.1080/08870440903194015\u003c/li\u003e\n\u003cli\u003eThomas DR. A General Inductive Approach for Analyzing Qualitative Evaluation Data. American Journal of Evaluation. 2006;27(2):237-46. 10.1177/1098214005283748\u003c/li\u003e\n\u003cli\u003eBraun V, Clarke V. Using thematic analysis in psychology. Qualitative Research in Psychology. 2006;3(2):77-101. 10.1191/1478088706qp063oa\u003c/li\u003e\n\u003cli\u003eDodd S, Clarke M, Becker L, et al. A taxonomy has been developed for outcomes in medical research to help improve knowledge discovery. J Clin Epidemiol. 2018;96:84-92. 10.1016/j.jclinepi.2017.12.020\u003c/li\u003e\n\u003cli\u003ePowell C. The Delphi technique: myths and realities. J Adv Nurs. 2003;41(4):376-82. 10.1046/j.1365-2648.2003.02537.x\u003c/li\u003e\n\u003cli\u003eAlkhaffaf B, Metryka A, Blazeby JM, et al. Core outcome set for surgical trials in gastric cancer (GASTROS study): international patient and healthcare professional consensus. Br J Surg. 2021. 10.1093/bjs/znab192\u003c/li\u003e\n\u003cli\u003eGorst SL, Gargon E, Clarke M, et al. Choosing Important Health Outcomes for Comparative Effectiveness Research: An Updated Review and User Survey. PLoS One. 2016;11(1):e0146444. 10.1371/journal.pone.0146444\u003c/li\u003e\n\u003cli\u003eGorst SL, Gargon E, Clarke M, et al. Choosing Important Health Outcomes for Comparative Effectiveness Research: An Updated Review and Identification of Gaps. PLoS One. 2016;11(12):e0168403. 10.1371/journal.pone.0168403\u003c/li\u003e\n\u003cli\u003eDavis K, Gorst SL, Harman N, et al. Choosing important health outcomes for comparative effectiveness research: An updated systematic review and involvement of low and middle income countries. PLoS One. 2018;13(2):e0190695. 10.1371/journal.pone.0190695\u003c/li\u003e\n\u003cli\u003eGargon E, Gorst SL, Harman NL, et al. Choosing important health outcomes for comparative effectiveness research: 4th annual update to a systematic review of core outcome sets for research. PLoS One. 2018;13(12):e0209869. 10.1371/journal.pone.0209869\u003c/li\u003e\n\u003cli\u003eGargon E, Gorst SL, Matvienko-Sikar K, et al. Choosing important health outcomes for comparative effectiveness research: 6th annual update to a systematic review of core outcome sets for research. PLoS One. 2021;16(1):e0244878. 10.1371/journal.pone.0244878\u003c/li\u003e\n\u003cli\u003eCuster RL, Scarcella JA, Stewart BR. The Modified Delphi Technique - A Rotational Modification. Journal of Career and Technical Education. 1999. 10.21061/jcte.v15i2.702\u003c/li\u003e\n\u003cli\u003eChevance A, Tran VT, Ravaud P. Controversy and Debate Series on Core Outcome Sets. Paper 1: Improving the generalizability and credibility of core outcome sets (COS) by a large and international participation of diverse stakeholders. J Clin Epidemiol. 2020;125:206-12.e1. 10.1016/j.jclinepi.2020.01.004\u003c/li\u003e\n\u003cli\u003eGRADE. GRADE Working Group [Available from: https://www.gradeworkinggroup.org/.\u003c/li\u003e\n\u003cli\u003eHarman NL, Bruce IA, Kirkham JJ, et al. The Importance of Integration of Stakeholder Views in Core Outcome Set Development: Otitis Media with Effusion in Children with Cleft Palate. PLoS One. 2015;10(6):e0129514. 10.1371/journal.pone.0129514\u003c/li\u003e\n\u003cli\u003eBennett WL, Robinson KA, Saldanha IJ, et al. High priority research needs for gestational diabetes mellitus. J Womens Health (Larchmt). 2012;21(9):925-32. 10.1089/jwh.2011.3270\u003c/li\u003e\n\u003cli\u003eSchmitt J, Langan S, Stamm T, et al. Core outcome domains for controlled trials and clinical recordkeeping in eczema: international multiperspective Delphi consensus process. J Invest Dermatol. 2011;131(3):623-30. 10.1038/jid.2010.303\u003c/li\u003e\n\u003cli\u003eMacLennan S, Williamson PR, Bekema H, et al. A core outcome set for localised prostate cancer effectiveness trials. BJU Int. 2017;120(5B):E64-E79. 10.1111/bju.13854\u003c/li\u003e\n\u003cli\u003eFish R, Blackwell S, Knight SR, et al. Defining standards and core outcomes for clinical trials in prehabilitation for colorectal surgery (DiSCO): modified Delphi methodology to achieve patient and healthcare professional consensus. Br J Surg. 2024;111(6). 10.1093/bjs/znae056\u003c/li\u003e\n\u003cli\u003eKirkham JJ, Gorst S, Altman DG, et al. Core Outcome Set-STAndards for Reporting: The COS-STAR Statement. PLoS Med. 2016;13(10):e1002148. 10.1371/journal.pmed.1002148\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Manchester","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Anal neoplasms, Outcome Studies, Outcome Measures","lastPublishedDoi":"10.21203/rs.3.rs-6949923/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6949923/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction\u003c/p\u003e\n\u003cp\u003eThere are multiple treatments for anal high-grade squamous intraepithelial lesion (aHSIL). The evidence for aHSIL treatments is scarce and of poor quality, such that the optimal approach cannot be defined. Existing trials in aHSIL have used different ways of measuring the effects of treatment. This makes comparing the results of trials very difficult. Trials are also likely to have been poor at reporting treatment effects important to patients. Treatment trials are needed to determine optimal approaches. Key to the quality of these trials is consistent and meaningful outcome measurement and reporting.\u003c/p\u003e\n\u003cp\u003eMethods and Analysis\u003c/p\u003e\n\u003cp\u003eThe Core Outcome measures in Squamous Intraepithelial precursor lesions of the Anus (COrSIcA) study aims to develop a core outcome set (COS) for use in future late-phase aHSIL treatment trials. This is a standardised set of outcomes deemed most important by key stakeholders, which should be measured and reported in all future treatment trials for the condition. Systematic review of current treatment studies, and interviews with patients who have lived experience of aHSIL, will determine a longlist of potentially important outcomes. Consensus methods (an international Delphi survey and consensus meeting), taking into account the views of key stakeholders (patients, healthcare professionals and clinician trialists) with experience of the condition, will determine which outcomes from the longlist are most important and subsequently be included in the COS.\u003c/p\u003e\n\u003cp\u003eEthics and Dissemination\u003c/p\u003e\n\u003cp\u003eUtilisation of the COS in future treatment trials will ensure outcomes reported are consistent and meaningful. NHS/HRA research ethics committee approval has been granted. The study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative and is listed in their database (Study ID 2511, https://www.comet-initiative.org/Studies/Details/2511).\u003c/p\u003e","manuscriptTitle":"The Core Outcome measures in Squamous Intraepithelial precursor lesions of the Anus (COrSIcA) study: A protocol for the development of a core outcome set for future anal high-grade squamous intraepithelial lesion (aHSIL) treatment trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-25 07:25:21","doi":"10.21203/rs.3.rs-6949923/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"31ace511-d11e-421d-92e9-25c1401f2033","owner":[],"postedDate":"June 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":50490640,"name":"Gastrointestinal Surgery"}],"tags":[],"updatedAt":"2025-06-25T07:25:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-25 07:25:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6949923","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6949923","identity":"rs-6949923","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}