Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal (PROTECTOR): protocol for a prospective non-randomised multi-center trial.

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 programme. Premenopausal 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 subtype of adnexal malignancy, from a precursor known as serous-tubal-intraepithelial-carcinoma has led to the attractive proposal of a two-step alternative tubo-ovarian-cancer surgical prevention strategy in premenopausal 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 menopause. Risk-reducing early-salpingectomy with delayed-oophorectomy has the advantage of providing some level of risk-reduction whilst conserving ovarian function and avoiding the negative health consequences of premature menopause. Lack of clarity on several key issues strengthens the case to offer 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-intraepithelial-carcinoma and the natural history, progression rates, outcomes and rate limiting step in development of tubo-ovarian-cancer associated with each type remains unknown. 7 In addition, there are a proportion of high-grade-serous-carcinoma with histologically normal tubes (even after complete examination using a sectioning-and-extensively-examining-the-fimbriated-end protocol) and serous-tubal-intraepithelial-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. There are concerns from clinicians regarding 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 to controls and 2) risk-reducing-early-salpingectomy is superior for sexual/endocrine function, noninferior in terms of quality-of-life, and equivalent in satisfaction compared to the standard risk-reducing-salpingo-oophorectomy.

Multi-centre, 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. Randomisation to a control-arm involving no surgery is unethical in high-risk women as is randomisation to a risk-reducing-early-salpingectomy-with-delayed-oophorectomy arm given the lack of clarity on tubo-ovarian-cancer risk reduction. Furthermore, randomisation is unacceptable to women and reported to be a barrier to participation in a similar clinical-trial amongst BRCA1/BRCA2 -carriers and gynaecological-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 in set up). The study is funded by Barts Charity and Rosetrees-Trust. Inclusion-criteria include premenopausal women ≥30years 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 ≥2 first–degree-relatives with tubo-ovarian-cancer or ≥3 relatives with tubo-ovarian-cancer (affected relatives must be on the same (maternal/paternal) side of the family)). Exclusion-criteria include, postmenopausal women (FSH >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 post cancer treatment, pregnancy, or those unable to provide informed consent. Recruitment is undertaken through cancer-genetics, high-risk familial cancer, gynaecological-oncology and general gynaecology outpatient clinics within NHS hospitals and primary-care. 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 premenopausal women at increased risk of tubo-ovarian-cancer. Secondary objectives are to evaluate 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 establish a national register to facilitate long-term follow-up of women undergoing risk-reducing-early-salpingectomy. The primary-endpoint is sexual function (measured by the Sexual-Activity-Questionnaire 10 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. Figure-1 summarises interventions and relevant time-points. A baseline hormonal profile (FSH) 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. Questionnaires used in the study have been derived from validated-questionnaires. Questionnaires include the Sexual-Activity-Questionnaire; Sexual-Quality-of-Life 3D questionnaire; endocrine-subscale of the Functional-Assessment of Cancer-Therapy-Endocrine-Symptom questionnaire; EQ5D-5L questionnaire; Hospital-Anxiety-&-Depression Scale; Impact-of-Events-Scale; Decision-Regret-Scale and 1-item from Madalinska 2005, (‘I am satisfied with the decision I have made’ on a 5-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 4-item four-point Likert-scale. 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 one-year post surgery (risk-reducing-early-salpingectomy and risk-reducing-salpingo-oophorectomy). 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 ( 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 counselling will be arranged if women are postmenopausal, and are not complaint with delayed-oophorectomy. Whilst 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 control arm women are using CHC (combined hormonal contraception) at age 50 years, they will be advised to stop the CHC, switch to non-hormonal contraception and have a repeat FSH in 3 months. 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 ( 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 gynaecological pathologists. Blocks from consenting participants are stored in a bio-resource facility for future translational work. Invasive disease is managed as per local clinical protocols. Participants will be referred to their regional cancer-centre gynaecological-oncology multidisciplinary-team for further investigations, staging and management. Table-1 summarises the management of serous-tubal-intraepithelial-carcinoma lesions. Investigation and treatment outcome data will be obtained by the co-ordinating centre from the treating clinician/regional cancer-centre. Participants are followed up actively at 1 month, 3 months (post-surgery in the surgical arms) and annually for three-years (all arms). Patients are followed up directly by the central coordinating centre trials unit as well as 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 as well as linkage via cancer registries, or databases such as Office-for-National-Statistics, Hospital-Episode-Statistics or NHS-Digital. Data-collection is standardised and is collected on electronic case-report-forms hosted on a customised study database via a web interface. Figure-1 summarises data-collection time-points. on electronic case-report-forms will be identified by a unique alphanumerical 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 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 to risk-reducing-salpingo-oophorectomy, to achieve a mean difference=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-randomised), 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 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. 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 (nonparametric) 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, subfertility, 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 0.5S.D worse than values from prior studies. 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 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-&-benefits and the analysis will be conducted using a healthcare perspective. A 3.5% discount rate will be applied to costs-&-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.

This trial protocol describes a prospective non-randomised multicentre 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 limit harmful consequences of premature menopause. Risk-reducing-early-salpingectomy also enables women who have completed childbearing but too young for oophorectomy by current clinical guidelines, the option of undergoing risk-reducing surgery. The trial will provide long-term outcome data to address 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 tubo-ovarian-cancer risk. The bio-resource generated will facilitate translational research and secondary-studies to provide further insights into disease biology. Currently, there are four other non-randomised trials 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 US (PSDO–Prophylactic-Salpingectomy with Delayed Oophorectomy; 14 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 three years after risk-reducing-early-salpingectomy. Delayed-oophorectomy is undertaken in premenopausal 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 40-50 years. While the TUBA and the PSDO trials only include 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 gold-standard for preventing tubo-ovarian-cancer in women at high-risk women. However, when performed in premenopausal women, it increases risk of coronary-heart-disease, osteoporosis, neurocognitive-decline, vasomotor-symptoms and sexual-dysfunction. Use of hormone-replacement-therapy until natural menopause mitigates risks and there is 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 of together with 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 address 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 to 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 in tubo-ovarian cancer risk) with risk-reducing-early-salpingectomy with delayed-oophorectomy and inform policy and management guidelines in the future.