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Clinical trial
Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal (PROTECTOR): protocol for a prospective non-randomised multi-center trial
  1. Faiza Gaba1,2,
  2. Sadiyah Robbani3,
  3. Naveena Singh4,
  4. W Glenn McCluggage5,
  5. Nafisa Wilkinson6,
  6. Raji Ganesan7,
  7. Gareth Bryson8,
  8. Gareth Rowlands9,
  9. Charlotte Tyson3,
  10. Rupali Arora6,
  11. Ertan Saridogan10,
  12. Helen Hanson11,
  13. Matthew Burnell12,
  14. Rosa Legood13,
  15. D Gareth Evans14,
  16. Usha Menon12 and
  17. Ranjit Manchanda1,2
  18. on behalf of the PROTECTOR team
    1. 1 Wolfson Institute of Preventive Medicine, Barts CRUK Cancer Centre, Queen Mary University of London, London, UK
    2. 2 Department of Gynaecological Oncology, St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK
    3. 3 Queen Mary University of London, London, UK
    4. 4 Barts Health NHS Trust, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    5. 5 Department of Pathology, Royal Belfast Hospital; United Kingdom, Belfast, UK
    6. 6 Department of Pathology, University College London Hospitals NHS Foundation Trust, London, UK
    7. 7 Birmingham Women’s Hospital NHS Foundation Trust, Birmingham, UK
    8. 8 NHS Greater Glasgow and Clyde, Glasgow, UK
    9. 9 Cardiff and Vale University Health Board, Cardiff, UK
    10. 10 Department of Gynaecology, University College London Hospitals NHS Foundation Trust, London, UK
    11. 11 St George’s University Hospitals NHS Foundation Trust, London, UK
    12. 12 University College London, London, UK
    13. 13 London School of Hygiene and Tropical Medicine, London, UK
    14. 14 The University of Manchester, Manchester, UK
    1. Correspondence to Dr Ranjit Manchanda, Wolfson Institute of Preventative Medicine, Barts CRUK Cancer Centre, Queen Mary University of London, London E1 4NS, UK; r.manchanda{at}qmul.ac.uk

    Abstract

    Background Risk-reducing salpingo-oophorectomy is the 'gold standard' for preventing tubo-ovarian cancer in women at increased risk. However, when performed in pre-menopausal women, it results in premature menopause and associated detrimental health consequences. This, together with acceptance of the central role of the fallopian tube in etiopathogenesis of high-grade serous carcinoma, by far the most common type of tubo-ovarian cancer, has led to risk-reducing early salpingectomy with delayed oophorectomy being proposed as a two-step surgical alternative for pre-menopausal women declining/delaying oophorectomy.

    Primary Objective To evaluate the impact on sexual function of risk-reducing early salpingectomy, within a two-step, risk-reducing, early salpingectomy with delayed oophorectomy tubo-ovarian cancer prevention strategy in pre-menopausal women at increased risk of tubo-ovarian cancer.

    Study Hypothesis Risk-reducing early salpingectomy is non-inferior for sexual and endocrine function compared with controls; risk-reducing early salpingectomy is superior for sexual/endocrine function, non-inferior for quality-of-life, and equivalent in satisfaction to the standard risk-reducing salpingo-oophorectomy.

    Trial Design Multi-center, observational cohort trial with three arms: risk-reducing early salpingectomy with delayed oophorectomy; risk-reducing salpingo-oophorectomy; controls (no surgery). Consenting individuals undergo an ultrasound, serum CA125, and follicle-stimulating hormone measurements and provide information on medical history, family history, quality-of-life, sexual function, cancer worry, psychological well-being, and satisfaction/regret. Follow-up by questionnaire takes place annually for 3 years. Women receiving risk-reducing early salpingectomy can undergo delayed oophorectomy at a later date of their choosing, or definitely by the menopause.

    Major Inclusion/Exclusion Criteria Inclusion criteria: pre-menopausal; aged >30 years; at increased risk of tubo-ovarian cancer (mutation carriers or on the basis of a strong family history); completed their family (for surgical arms). Exclusion criteria: post-menopausal; previous bilateral salpingectomy or bilateral oophorectomy; pregnancy; previous tubal/ovarian/peritoneal malignancy; <12 months after cancer treatment; clinical suspicion of tubal/ovarian cancer at baseline.

    Primary Endpoint Sexual function measured by validated questionnaires.

    Sample Size 1000 (333 per arm).

    Estimated Dates for Completing Accrual and Presenting Results It is estimated recruitment will be completed by 2023 and results published by 2027.

    Trial Registration Number ISRCTN registry: 25 173 360 (https://doi.org/10.1186/ISRCTN25173360).

    • gynecologic surgical procedures
    • ovarian cancer
    • surgery

    https://doi.org/10.1136/ijgc-2020-001541

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      Introduction

      BRCA1/BRCA2 mutation carriers have a 17–44% lifetime risk of tubo-ovarian cancer and a 69–72% lifetime risk of breast cancer.1 Primary surgical prevention in the form of risk-reducing salpingo-oophorectomy is the most effective option and gold standard for tubo-ovarian cancer risk reduction, particularly given the absence of an effective national screening program. Pre-menopausal risk-reducing salpingo-oophorectomy leads to premature surgical menopause, which has detrimental long-term health sequelae (increased risk of coronary heart disease, osteoporosis, vasomotor symptoms, sexual dysfunction, neurocognitive decline), especially if individuals are unable to use hormone replacement therapy.2–5 Widespread acceptance of a central role for the fallopian tube as the site of origin of most high-grade serous carcinomas, by far the most common and aggressive sub-type of adnexal malignancy, from a precursor known as serous tubal intra-epithelial carcinoma, has led to the attractive proposal of a two-step alternative tubo-ovarian cancer surgical prevention strategy in pre-menopausal women who have completed their family but decline, or wish to delay, risk-reducing salpingo-oophorectomy. This involves risk-reducing early salpingectomy as the first step followed by delayed oophorectomy after the menopause. Risk-reducing early salpingectomy with delayed oophorectomy has the advantage of providing some level of risk reduction while conserving ovarian function and avoiding the negative health consequences of premature menopause. Lack of clarity on several key issues strengthens the case for offering risk-reducing early salpingectomy with delayed oophorectomy solely within a research setting. The precise estimate of tubo-ovarian cancer risk reduction and long-term health outcomes with risk-reducing early salpingectomy remain unclear. Salpingectomy will not prevent tubo-ovarian cancer arising outside the tube. Residual fimbrial tissue may remain on the ovarian surface after salpingectomy in 9.8% of cases,6 and could be a potential site for malignant transformation, which could also theoretically arise from tubal-type tissue within the ovarian stroma (endosalpingiosis/cortical inclusion cysts). The etiopathogenesis of tubo-ovarian cancer is complex and our current understanding incomplete. It has been suggested that there are different types of serous tubal intra-epithelial carcinoma and the natural history, progression rates, outcomes, and rate-limiting step in its development associated with each type remains unknown.7 In addition, a proportion of high-grade serous carcinoma have histologically normal tubes (even after complete examination using a sectioning and extensively examining the fimbriated end protocol) and serous tubal intra-epithelial carcinoma may not be the precursor of all high-grade serous carcinoma.8 The long-term impact of salpingectomy on sexual function, endocrine-function, and onset of menopause is unknown. Clinicians have concerns about attrition from delayed oophorectomy and a proportion of patients who do not undergo delayed oophorectomy may develop tubo-ovarian cancer. In addition, uncertainties remain around cost-effectiveness.

      We present the protocol for the ‘Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal’ (PROTECTOR) Trial, which evaluates risk-reducing early salpingectomy with delayed oophorectomy in UK women who are at increased risk of tubo-ovarian cancer. The full PROTECTOR protocol can be found at http://protector.org.uk/ (ISRCTN25173360). Our hypotheses are: (1) risk-reducing early salpingectomy is non-inferior for sexual and endocrine function compared with controls and (2) risk-reducing early salpingectomy is superior for sexual/endocrine function, non-inferior for quality-of-life, and equivalent in satisfaction compared with the standard risk-reducing salpingo-oophorectomy.

      Methods and Analysis

      Trial Design

      Multi-center, observational cohort trial with three arms: risk-reducing early salpingectomy with delayed oophorectomy; risk-reducing salpingo-oophorectomy; controls (no surgery). Eligible individuals self-select which of the three arms they wish to opt for. Randomization to a control arm involving no surgery is unethical in high-risk women as is randomization to a risk-reducing early salpingectomy with delayed oophorectomy arm given the lack of clarity on tubo-ovarian cancer risk reduction. Furthermore, randomization is unacceptable to women and reported to be a barrier to participation in a similar clinical trial among BRCA1/BRCA2 carriers and gynecological oncologists/geneticists.9

      A pragmatic way forward is a prospective observational cohort study based on a standardized nationally acceptable protocol, with a well-designed patient information sheet (highlighting advantages and limitations) and comprehensive evaluation of short- and long-term outcomes. This is a UK-wide study with 41 sites planned (30 currently active and 11 being set up).

      Participants

      Inclusion criteria include pre-menopausal women aged ≥30 years who have completed their family (surgical arms), and are at increased risk of tubo-ovarian cancer. Women may be at increased risk of tubo-ovarian cancer if they carry a pathogenic or likely pathogenic mutation in the BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 gene or based on a strong family history of tubo-ovarian cancer (BRCA-negative or BRCA-unknown with two or more first-degree relatives with tubo-ovarian cancer or three or more relatives with tubo-ovarian cancer (affected relatives must be on the same (maternal/paternal) side of the family)).

      Exclusion criteria include post-menopausal women (follicle-stimulating hormone >40), women who have undergone previous bilateral salpingectomy/bilateral oophorectomy, those with clinical suspicion of tubo-ovarian cancer at baseline, women with a history of tubo-ovarian/peritoneal malignancy, women <12 months after cancer treatment, pregnancy, or those unable to provide informed consent.

      Recruitment is undertaken through cancer genetics, high-risk familial cancer, gynecological oncology, and general gynecology outpatient clinics within NHS hospitals and primary care.

      Objectives

      The primary objective is to evaluate impact on sexual function of early salpingectomy within risk-reducing early salpingectomy with delayed oophorectomy, as a two-step tubo-ovarian cancer prevention strategy in pre-menopausal women at increased risk of tubo-ovarian cancer.

      Secondary objectives are to evaluate the impact of risk-reducing early salpingectomy with delayed oophorectomy on endocrine function; quality-of-life; health and well-being; psychological-health; satisfaction/regret; cancer-risk perception; incidence of tubal in situ and invasive tubo-ovarian cancer; surgical outcomes; to develop utility scores for early salpingectomy and determine cost-effectiveness; and to establish a national register to facilitate long-term follow-up of women undergoing risk-reducing early salpingectomy.

      Endpoints

      The primary endpoint is sexual function (measured by the Sexual Activity Questionnaire10 and Sexual Quality-of-Life 3D Questionnaire).11 Secondary endpoints include, but are not limited to, quality-of-life and psychological health, incidence of tubal in situ and invasive tubo-ovarian cancer, surgical morbidity, and cost-effectiveness.

      Interventions

      Figure 1 summarizes interventions and relevant time-points.

      Figure 1
      Figure 1

      PROTECTOR Trial flowchart. DO, delayed oophorectomy; ES, early salpingectomy; FU, follow-up; FSH, follicle-stimulating hormone; MDT, multidisciplinary team; PIS, participant information sheet; RRESDO, risk-reducing early salpingectomy and delayed oophorectomy; RRSO, risk-reducing salpingo-oophorectomy; USS, ultrasound scan.

      Baseline Screening Tests

      A baseline hormonal profile (follicle-stimulating hormone) is measured for all. Serum CA125 and ultrasound scans are done for risk-reducing salpingo-oophorectomy/risk-reducing early salpingectomy with delayed oophorectomy arms only.

      Interventional Questionnaires

      Questionnaires used in the study have been derived from validated questionnaires. Questionnaires include the Sexual Activity Questionnaire; Sexual Quality-of-Life 3D Questionnaire; endocrine sub-scale of the Functional Assessment of Cancer Therapy Endocrine Symptom Questionnaire; European Quality-of-life Scale Five Dimension Five Level (EQ5D-5L) Questionnaire; Hospital Anxiety and Depression Scale; Impact of Events Scale; Decision Regret-Scale; and one item from Madalinska 2005 (‘I am satisfied with the decision I have made’ on a five-point Likert Scale). Cancer risk perception is assessed with ‘Compared with other people of your age and sex, do you think your chances of getting cancer at some point in your life are much lower, lower, about the same, higher, much higher?’ An additional risk item used is ‘On a scale from 0 to 100, where 0=no chance at all and 100=absolutely certain, what do you think are the chances that you will get cancer sometime during your lifetime?’ Tubo-ovarian cancer worry is assessed by a four-item, four-point Likert Scale.

      Interviews

      A small number of women from each study arm are invited to one-to-one semi-structured in-depth interviews. Women who elect to have surgery will be followed up with another interview 1 year after surgery (risk-reducing early salpingectomy and risk-reducing salpingo-oophorectomy).

      Risk-Reducing Surgeries

      Volunteers opting for the risk-reducing salpingo-oophorectomy/risk-reducing early salpingectomy with delayed oophorectomy arms undergo bilateral salpingo-oophorectomy or early salpingectomy with delayed oophorectomy as per our surgical protocol (online supplementary 1). Timing of delayed oophorectomy in the risk-reducing early salpingectomy with delayed oophorectomy arm is non-prescriptive and dependent on the wishes of the individual. However, participants will be advised to undergo delayed oophorectomy once they become post-menopausal. Further counseling will be arranged if women are post-menopausal, and are not compliant with delayed oophorectomy. While minimal-access surgery is the preferred route, it is not mandatory and the choice of surgical route will be made by the treating clinician. Peritoneal washings are taken during all risk-reducing surgeries and sent for cytology. Participants who are in the control arm are also subsequently (in a few years’ time) free to switch to any one of the surgical intervention arms. If any women in the control arm are using combined hormonal contraception at age 50 years, they will be advised to stop the combined hormonal contraception, switch to non-hormonal contraception and have a repeat follicle-stimulating hormone measurement in 3 months.

      Supplemental material

      Pathological Examination and Central Pathology Review

      All ovaries and fallopian tubes are submitted in their entirety for histological examination and the tubes are processed using a sectioning and extensively examining the fimbriated end protocol (online supplementary 2). In addition to local histopathology reporting at recruitment sites, all tubal and ovarian histopathology slides and cytology slides from peritoneal washings are reviewed by an independent team of central specialist gynecological pathologists. Blocks from consenting participants are stored in a bio-resource facility for future translational work.

      Management of Abnormal Histopathology/Cytology Results

      Invasive disease is managed as per local clinical protocols. Participants will be referred to their regional cancer center gynecological oncology multidisciplinary team for further investigations, staging, and management. Table 1 summarizes the management of serous tubal intra-epithelial carcinoma lesions. Investigation and treatment outcome data will be obtained by the co-ordinating center from the treating clinician/regional cancer center.

      View this table:
      Table 1

      Management and follow-up of serous tubal intra-epithelial carcinoma (STIC) lesions (without invasion)

      Follow–up

      Participants are followed up actively at 1 month, 3 months (after surgery in the surgical arms) and annually for 3 years (all arms). Patients are followed up directly by the central coordinating center trials unit and the local clinical site. Follow-up compliance will be ensured by direct contact with the patient as well as good communication and liaison with the local site clinical team and the patient’s general practitioner. Long-term passive annual follow-up is planned through establishment of a national registry/database and linkage via cancer registries, or databases such as the Office for National Statistics, Hospital Episode Statistics or NHS Digital.

      Data Collection

      Data collection is standardized and is collected on electronic case report forms hosted on a customized study database via a web interface. Figure 1 summarizes data collection time points. Data on electronic case report forms will be identified by a unique alphanumeric volunteer reference number auto-generated by the database each time a new participant is enrolled into the trial. The database will enable participant flagging/tracking and electronic data upload/access.

      We aim to use the NHS number as the primary identifier when linking to national registries and to track individuals throughout the NHS.

      Sample Size

      Sample size is based on the primary outcome of sexual function, assessed by the Sexual Activity Questionnaire. Sample size is estimated for 90% power and with either alpha=0.05, two-sided (for superiority tests) or alpha=0.025, one-sided (for non-inferiority tests). For a non-inferiority margin (∆)=0.9 on the Sexual Activity Questionnaire pleasure scale, between risk-reducing early salpingectomy and controls, the sample size needed is 266/arm. For testing superiority of risk-reducing early salpingectomy compared with risk-reducing salpingo-oophorectomy, to achieve a mean difference of 1 on the Sexual Assessment Questionnaire pleasure scale (SD=3.2–3.5) the sample size needed is 237/arm.

      However, these calculations assume random allocation to the arms. Because participants self-select their arm (non-randomized), it will be necessary to adjust all tests for potential confounders that might relate to both arm and outcome. Assuming inclusion of confounders into a regression model reduces the partial r-squared brought about by the treatment arm by 20%, then the necessary sample size increase to maintain power is by 25%. For our primary-hypotheses, the largest sample size needed is therefore 266×1.25=333 per arm, resulting in an overall sample size of approximately 1000 patients allocated equally between each arm.

      Statistical Methods

      Baseline characteristics will be calculated using descriptive statistics. Appropriate statistical tests will be used for analyses. Chi-square tests will compare categorical variables, and t-test (parametric) and Mann-Whitney (non-parametric) tests will compare continuous outcome variables between groups. Random-effects models adjusted for covariates/confounders (including age, family history, pathogenic-variant type, parity, contraception, body mass index, sub-fertility, etc) will be used to compare outcomes between the different groups over time. Non-inferiority is established when the 97.5% CI does not cross the non-inferiority margin. A two-sided 95% CI will be used to test equivalency of satisfaction. The different non-inferiority/equivalency margins for various outcomes are based on clinically meaningful changes where available or set at no more than 0.5 SD worse than values from prior studies.

      Utility scores: index values from the Sexual Quality-of-Life-3D Questionnaire will be used to generate utility values for salpingectomy. Utility values generated will be used to calculate quality-adjusted life years, which will be used in an economic evaluation.

      Cost-effectiveness: a Markov-model will be developed for cost-effectiveness of risk-reducing early salpingectomy with delayed oophorectomy. A lifetime horizon will be used to capture all costs and benefits and the analysis will be conducted using a healthcare perspective. A 3.5% discount rate will be applied to costs and outcomes. Both deterministic and probabilistic sensitivity analyses will be performed. The incremental cost-effectiveness ratio will be calculated and compared with the National Institute for Health and Care Excellence cost-effectiveness willingness-to-pay threshold to determine cost-effectiveness of risk-reducing early salpingectomy with delayed oophorectomy.

      Discussion

      This trial protocol describes a prospective non-randomized multi-center UK cohort trial evaluating the impact of risk-reducing early salpingectomy with delayed oophorectomy in pre-menopausal women, at increased risk of tubo-ovarian cancer. PROTECTOR ensures that an early salpingectomy tubo-ovarian cancer prevention strategy can be offered to high-risk UK women who choose to decline/delay oophorectomy, within a safe clinical study setting, with strict protocols, proper consent, monitoring, and independent oversight. Risk-reducing early salpingectomy permits women to retain their natural hormones for longer and limits harmful consequences of premature menopause. Risk-reducing early salpingectomy also enables women who have completed childbearing, but who are too young for oophorectomy by current clinical guidelines, the option of undergoing risk-reducing surgery. The trial will provide long-term outcome data to examine knowledge gaps which currently exist, including impact of risk-reducing early salpingectomy on sexual/endocrine function, quality-of-life, psychosocial consequences, utility scores, and cost-effectiveness. Data will be collected on attrition from delayed oophorectomy and interval cancers. This study will generate new insights to inform provision of NHS care and tubo-ovarian cancer prevention guidelines in women at increased risk of tubo-ovarian cancer. The bio-resource generated will facilitate translational research and secondary studies to provide further insights into disease biology.

      Currently, four other non-randomized trials are investigating different aspects of risk-reducing early salpingectomy with delayed oophorectomy, being undertaken in France (Fimbriectomy Trial),12 the Netherlands (TUBA—TUbectomy with delayed oophorectomy to improve quality-of-life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers),13 and USA (PSDO–Prophylactic Salpingectomy with Delayed Oophorectomy14; WISP—Women Choosing Surgical Prevention Trial).15 The ongoing trials vary with respect to primary outcomes, design, and sample sizes. The Fimbriectomy trial is powered on tubo-ovarian/primary peritoneal cancer incidence, while the others are powered on menopause-related quality-of-life (TUBA), delayed oophorectomy uptake (PSDO), and sexual function (WISP). The Fimbriectomy trial does not involve delayed oophorectomy. delayed oophorectomy is undertaken in the TUBA trial at 40–45 years in BRCA1 and 45–50 years in BRCA2 carriers, and in the PSDO trial 3 years after risk-reducing early salpingectomy. Delayed oophorectomy is undertaken in pre-menopausal women well before onset of menopause in the TUBA and WISP studies. Similarly, in the WISP study, women are given the choice as to when to undergo delayed oophorectomy but are encouraged to have this done between ages 40 and 50. While the TUBA and the PSDO trials include only BRCA carriers, the Fimbriectomy trial also includes women ascertained using family history. The WISP trial in addition offers risk-reducing early salpingectomy with delayed oophorectomy to PALB2/BARD1/MSH2/MSH6/MLH1/PMS2/EPCAM mutation carriers. However, validated data linking BARD1/EPCAM/PMS2 mutations with increased tubo-ovarian cancer risk are currently lacking. In addition, mutations in the Lynch syndrome genes are not thought to be associated with an increased risk of high-grade serous carcinoma but with ovarian endometriosis-related neoplasms, such as endometrioid/clear-cell carcinoma, which typically present at earlier-stages with a better prognosis.

      In conclusion risk-reducing salpingo-oophorectomy remains the gold standard for preventing tubo-ovarian cancer in women at high-risk. However, when performed in pre-menopausal women, it increases the risk of coronary heart disease, osteoporosis, neurocognitive decline, vasomotor symptoms, and sexual dysfunction. Use of hormone replacement therapy until the natural menopause mitigates risks and there are data supporting safety of short-term hormone replacement therapy use in BRCA carriers without a personal history of breast cancer. Acceptance of the central role of the fallopian tube in tubo-ovarian cancer etiopathogenesis, together with the health consequences of premature menopause from early oophorectomy, has led to risk-reducing early salpingectomy with delayed oophorectomy being proposed as a two-step surgical alternative for pre-menopausal women who have completed childbearing but prefer to decline/delay oophorectomy. It is essential that this is robustly evaluated in clinical trials to deal with various knowledge-gaps and inform future practice. PROTECTOR, TUBA, and WISP are three trials offering risk-reducing early salpingectomy with delayed oophorectomy which are currently open for recruitment. These studies will generate important data and provide an evidence base to inform future international practice with respect to risk-reducing early salpingectomy with delayed oophorectomy in high-risk women. International collaboration is warranted to pool outcome data from these studies to better understand the benefits and safety profile (including reduction of tubo-ovarian cancer risk) with risk-reducing early salpingectomy with delayed oophorectomy and inform policy and management guidelines in the future.

      Acknowledgments

      We are grateful to the entire medical, nursing, and administrative staff who work on the PROTECTOR trial and to the independent members of the trial steering committee (chaired by Mr Tim Mould), data monitoring committee (chaired by Professor Richard Edmondson) and central pathology committee (chaired by Professor Naveena Singh). We acknowledge support provided by a number of charities and stakeholders including BRCA Umbrella (Caroline Presho), The Eve Appeal, Ovacome, Target Ovarian Cancer and Ovarian Cancer Action. We are grateful to the central trials coordinating team at the Centre for Experimental Cancer Medicine, QMUL including Charlotte Tyson and Kelly Mousa. We are grateful to the study sponsor, Queen Mary University of London. In addition, we are grateful to all our collaborators (supplementary material 3): Dr Munaza Ahmed (North East Thames Cancer Genetics Service, Great Ormond Street Hospital NHS Foundation Trust), Dr Aarti Sharma (Cardiff and Vale UHB), Dr Gautam Mehra (Guy’s and St Thomas’ NHS Foundation Trust), Dr Adam Rosenthal (University College London Hospitals NHS Foundation Trust), Dr Ian Harley (Belfast Health & Social Care Trust), Professor Emma Crosbie (Manchester University NHS Foundation Trust), Dr Michelle Mackintosh (Manchester University NHS Foundation Trust), Professor Sadaf Ghaem-Maghami (Imperial College Healthcare NHS Trust), Professor Omer Devaja (Maidstone and Tunbridge Wells NHS Trust), Professor Sudha Sundar (Sandwell and West Birmingham Hospitals NHS Trust), Dr Tim Duncan (Norfolk and Norwich University Hospitals NHS Foundation Trust), Dr Iain Cameron (Gateshead Health NHS Foundation Trust), Dr Claire Newton (University Hospitals Bristol NHS Foundation Trust), Dr Sonali Kaushik (Brighton and Sussex University Hospitals NHS Trust), Dr Angela Brady (London North West Healthcare NHS Trust), Dr Supratik Chattopadhyay (University Hospitals of Leicester NHS Trust), Dr Natalia Povolotskaya (Portsmouth Hospitals NHS Trust), Dr Rema Iyer (East Kent Hospitals University NHS Trust), Dr Lucy Side (University Hospital Southampton NHS Foundation Trust), Dr Katie Snape (St George's University Hospitals NHS Foundation Trust), Dr Anil Tailor (Royal Surrey County Hospital Foundation Trust), Dr Manon van Seters (Worcestershire Acute Hospital Trust), Dr Katherine Edey (Royal Devon & Exeter NHS Foundation Trust), Dr Sian Taylor (Liverpool Women's Hospital NHS Foundation Trust), Dr Suma Kodiathodi (North Tees and Hartlepool NHS Foundation Trust), Dr Partha Sengupta (County Durham and Darlington NHS Foundation Trust), Dr Scott Fegan (NHS Lothian), Dr Karin Williamson (Nottingham University Hospitals NHS Trust), Dr Mahalakshmi Gurumurthy (NHS Grampian), Dr Kalpana Ragupathy (NHS Tayside), Dr Andrew Phillips (University Hospitals of Derby and Burton NHS Foundation Trust), Dr Mark Willett (East Lancashire Hospitals NHS Trust), Dr Tony Chalhoub (The Newcastle upon Tyne Hospitals NHS Foundation Trust), Dr Sanjay Rao (South Tees Hospitals NHS Foundation Trust), Dr Nicholas Matthews (South Tyneside and Sunderland NHS Foundation Trust), Beena Abdul (Northampton General Hospitals NHS Trust), Ibraheem Hamoodi (Northumbria Healthcare NHS Foundation Trust), Claire Park (Royal United Hospitals Bath NHS Foundation Trust), Jane Borley (Royal Cornwall Hospitals NHS Trust), Thumuluru Kavitha Madhuri (Royal Surrey County Hospital Foundation Trust), Richard Hutson (Leeds Teaching Hospitals NHS Trust), Kerryn Lutchman-Singh (Swansea Bay University Health Board), Richard Peevor (Betsi Cadwaladr University Health Board).

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      Supplementary materials

      • Supplementary Data

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      • Supplementary Data

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Footnotes

      • Twitter @ProfManchanda

      • Correction notice Since the Online First publication of this article, the authors have noticed that Emma Crosbie and Thumuluru Kavitha Madhuri were omitted from the list of PROTECTOR team members in the Collaborators section. These names have now been added.

      • Collaborators PROTECTOR team: Katie Snape, Sadaf Ghaem-Maghami, Gautam Mehra, Angela Brady, Adam Rosenthal, Michelle MacKintosh, Emma Crosbie, Ian Harley, Sudha Sundar, Claire Newton, Omer Devaja, Tim Duncan, Supratik Chattopadhyay, Natalia Povolotskaya, Rema Iyer, Lucy Side, Anil Tailor, Manon van Seters, Suma Kodiathodi, Partha Sengupta, Iain Cameron, Sonali Kaushik, Karin Williamson, Katherine Edey, Sian Taylor, Andrew Phillips, Mark Willett, Tony Chalhoub, Sanjay Rao, Nicholas Matthews, Aarti Sharma, Scott Fegan, Mahalakshmi Gurumurthy, Kalpana Ragupathy, Beena Abdul, Ibraheem Hamoodi, Claire Park, Jane Borley, Thumuluru Kavitha Madhuri, Richard Hutson, Kerryn Lutchman-Singh, Richard Peevor.

      • Contributors Trial conception and design: RM. Protocol development: RM, UM, DGE, NS, FG, MB, RL, WGM, RG, NW, GB, GR. Pathology committee: NS, WGM, NW, RG, GB, GR, RA, RM, FG. Trial management: RM, FG, SR, CT, NS, UM, DGE, ES, HH. Preparation of tables and figures: FG, RM. Initial draft of manuscript: FG, RM. Statistical aspects: MB, RM, RL. Manuscript writing and approval: all authors.

      • Funding This trial is funded by Barts and The London Charity and Roseetrees Trust.

      • Competing interests RM declares research funding from Barts and The London Charity and Roseetrees Trust for the PROTECTOR Study and is chief investigator. RM declares research funding from The Eve Appeal and Cancer Research UK outside this work, as well as an honorarium for grant review from Israel National Institute for Health Policy Research and from MSD and Astrazneca for advisory board meetings. RM is supported by an NHS Innovation Accelerator (NIA) Fellowship for population testing. UM has a financial interest in Abcodia, Ltd, a company formed to develop academic and commercial development of biomarkers for screening and risk prediction. The authors declare no conflict of interest. GE is supported through the NIHR Manchester Biomedical Research Centre (IS-BRC1215-20007).

      • Patient consent for publication Not required.

      • Provenance and peer review Commissioned; internally peer reviewed.

      • Data availability statement All relevant data are included in the article or uploaded as supplementary information. A copy of the protocol can be requested from the corresponding author or the study team.